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1.  Familial Glucocorticoid Resistance Caused by a Novel Frameshift Glucocorticoid Receptor Mutation 
Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia.
The aim was to determine the cause of apparent glucocorticoid resistance in a young woman.
Patients and Methods
We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess.
The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (Δ612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR.
Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.
PMCID: PMC4110505  PMID: 20861124
2.  Thiazolidinediones are Partial Agonists for the Glucocorticoid Receptor 
Endocrinology  2008;150(1):75-86.
Although thiazolidinediones were designed as specific PPARγ-ligands there is evidence for some off-target effects mediated by a non-PPARγ mechanism. Previously we have shown that Rosiglitazone has anti-inflammatory actions not explicable by activation of PPARγ, but possibly by the glucocorticoid receptor (GR).
Rosiglitazone induces nuclear translocation both of GR-GFP, and endogenous GR in HeLa and U20S cells but with slower kinetics than Dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding specific effect.
Rosiglitazone drives luciferase expression from a simple GRE containing reporter gene in a GR-dependent manner (EC50 4μM), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits Dexamethasone driven reporter gene activity (IC50 2.9μM) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPARγ-null cells suggesting both GR-dependence and PPARγ-independence.
Rosiglitazone also activates a GAL4-GR chimera, driving a UAS promoter, demonstrating DNA template sequence independence, and furthermore enhanced SRC1-GR interaction, measured by a mammalian two-hybrid assay.
Both Ciglitazone and Pioglitazone, structurally related to Rosiglitazone, show similar effects on the GR.
The antiproliferative effect of Rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of Rosiglitazone action.
Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the anti-diabetic actions of Rosiglitazone.
PMCID: PMC4110506  PMID: 18801908
Rosiglitazone; Glucocorticoids; Glucocorticoid Receptor; PPARγ; Diabetes
4.  Identifying the seasonal origins of human campylobacteriosis 
Epidemiology and infection  2012;141(6):1267-1275.
Human campylobacteriosis exhibits a distinctive seasonality in temperate regions. This paper aims to identify the origins of this seasonality. Clinical isolates [typed by multi-locus sequence typing (MLST)] and epidemiological data were collected from Scotland. Young rural children were found to have an increased burden of disease in the late spring due to strains of non-chicken origin (e.g. ruminant and wild bird strains from environmental sources). In contrast the adult population had an extended summer peak associated with chicken strains. Travel abroad and UK mainland travel were associated with up to 17% and 18% of cases, respectively. International strains were associated with chicken, had a higher diversity than indigenous strains and a different spectrum of MLST types representative of these countries. Integrating empirical epidemiology and molecular subtyping can successfully elucidate the seasonal components of human campylobacteriosis. The findings will enable public health officials to focus strategies to reduce the disease burden.
PMCID: PMC4003528  PMID: 22989449
Bacterial typing; Campylobacter; foodborne zoonoses; modelling; molecular epidemiology
5.  Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients 
American journal of surgery  2012;204(1):37-43.
Vitamin D deficiency is the most common nutritional deficiency in the United States. It is seldom measured or recognized, and rarely is treated, particularly in critically ill patients. The purpose of this study was to investigate the prevalence and impact of vitamin D deficiency in surgical intensive care unit patients. We hypothesized that severe vitamin D deficiency increases the length of stay, mortality rate, and cost in critically ill patients admitted to surgical intensive care units.
We performed a prospective observational study of vitamin D status on 258 consecutive patients admitted to the Surgical Intensive Care Unit at Grady Memorial Hospital between August 2009 and January 2010. Vitamin D levels (25 [OH]2 vitamin-D3) were measured by high-pressure liquid chromatography and tandem mass spectrometry. Vitamin D deficiency was defined as follows: severe deficiency was categorized as less than 13 ng/mL; moderate deficiency was categorized as 14 to 26 ng/mL; mild deficiency was categorized as 27 to 39 ng/mL; and normal levels were categorized as greater than 40 ng/mL.
Of the 258 patients evaluated, 70.2% (181) were men, and 29.8% (77) were women; 57.6% (148) were African American and 32.4% (109) were Caucasian. A total of 138 (53.5%) patients had severe vitamin D deficiency, 96 (37.2%) had moderate deficiency, 18 (7.0%) had mild deficiency, and 3 (1.2%) of the patients had normal vitamin D levels. The mean length of stay in the Surgical Intensive Care Unit for the severe vitamin D–deficient group was 13.33 ± 19.5 days versus 7.29 ± 15.3 days and 5.17 ± 6.5 days for the moderate and mild vitamin D-deficient groups, respectively, which was clinically significant (P = .002). The mean treatment cost during the patient stay in the surgical intensive care unit was $51,413.33 ± $75,123.00 for the severe vitamin D–deficient group, $28,123.65 ± $59,752.00 for the moderate group, and $20,414.11 ± $25,714.30 for the mild vitamin D–deficient group, which also was clinically significant (P = .027). More importantly, the mortality rate for the severe vitamin D–deficient group was 17 (12.3%) versus 11 (11.5%) in the moderate group (P = .125). Because no deaths occurred in the mildly or normal vitamin D–deficient groups, we compared the mortality rate between severe/moderate and mild/normal vitamin D groups (P = .047).
In univariate analysis, severe and moderate vitamin D deficiency was related inversely to the length of stay in the surgical intensive care unit (r = .194; P = .001), related inversely to surgical intensive care unit treatment cost (r = .194; P = .001) and mortality (r = .125; P = .023), compared with the mild vitamin D–deficient group, after adjusting for age, sex, race, and comorbidities (myocardial infarctions, acute renal failure, and pneumonia); the length of stay, surgical intensive care unit cost, and mortality remained significantly associated with vitamin D deficiency.
PMCID: PMC3992708  PMID: 22325335
Vitamin D; Deficiency; Surgical intensive care unit; Severe
6.  Reproductive Counseling by Clinic Healthcare Workers in Durban, South Africa: Perspectives from HIV-Infected Men and Women Reporting Serodiscordant Partners 
Background. Understanding HIV-infected patient experiences and perceptions of reproductive counseling in the health care context is critical to inform design of effective pharmaco-behavioral interventions that minimize periconception HIV risk and support HIV-affected couples to realize their fertility goals. Methods. We conducted semistructured, in-depth interviews with 30 HIV-infected women (with pregnancy in prior year) and 20 HIV-infected men, all reporting serodiscordant partners and accessing care in Durban, South Africa. We investigated patient-reported experiences with safer conception counseling from health care workers (HCWs). Interview transcripts were reviewed and coded using content analysis for conceptual categories and emergent themes. Results. The study findings indicate that HIV-infected patients recognize HCWs as a resource for periconception-related information and are receptive to speaking to a HCW prior to becoming pregnant, but seldom seek or receive conception advice in the clinic setting. HIV nondisclosure and unplanned pregnancy are important intervening factors. When advice is shared, patients reported receiving a range of information. Male participants showed particular interest in accessing safer conception information. Conclusions. HIV-infected men and women with serodiscordant partners are receptive to the idea of safer conception counseling. HCWs need to be supported to routinely initiate accurate safer conception counseling with HIV-infected patients of reproductive age.
PMCID: PMC3426202  PMID: 22927713
7.  Healthcare Outcome Disparities in Trauma Care 
PMCID: PMC3415824  PMID: 22900117
8.  From phenotype to genotype: a Bayesian solution 
The study of biological systems commonly depends on inferring the state of a ‘hidden’ variable, such as an underlying genotype, from that of an ‘observed’ variable, such as an expressed phenotype. However, this cannot be achieved using traditional quantitative methods when more than one genetic mechanism exists for a single observable phenotype. Using a novel latent class Bayesian model, it is possible to infer the prevalence of different genetic elements in a population given a sample of phenotypes. As an exemplar, data comprising phenotypic resistance to six antimicrobials obtained from passive surveillance of Salmonella Typhimurium DT104 are analysed to infer the prevalence of individual resistance genes, as well as the prevalence of a genomic island known as SGI1 and its variants. Three competing models are fitted to the data and distinguished between using posterior predictive p-values to assess their ability to predict the observed number of unique phenotypes. The results suggest that several SGI1 variants circulate in a few fixed forms through the population from which our data were derived. The methods presented could be applied to other types of phenotypic data, and represent a useful and generic mechanism of inferring the genetic population structure of organisms.
PMCID: PMC3061133  PMID: 20980306
phenotype to genotype; Bayesian; mixture model; latent class model; antimicrobial resistance; posterior predictive p-value
9.  Associations between the Presence of Virulence Determinants and the Epidemiology and Ecology of Zoonotic Escherichia coli▿  
Applied and Environmental Microbiology  2010;76(24):8110-8116.
The severity of human infection with pathogenic Escherichia coli depends on two major virulence determinants (eae and stx) that, respectively, produce intimin and Shiga toxin. In cattle, both may enhance colonization, but whether this increases fitness by enhancing cattle-to-cattle transmission in the field is unknown. In E. coli O157, the almost uniform presence of the virulence determinants in cattle isolates prevents comparative analysis. The availability to this study of extensive non-O157 E. coli data, with much greater diversity in carriage of virulence determinants, provides the opportunity to gain insight into their potential impact on transmission. Dynamic models were used to simulate expected prevalence distributions for serogroups O26 and O103. Transmission parameters were estimated by fitting model outputs to prevalence data from Scottish cattle using a Bayesian Markov chain Monte Carlo (MCMC) approach. Despite similar prevalence distributions for O26 and O103, their transmission dynamics were distinct. Serogroup O26 strains appear well adapted to the cattle host. The dynamics are characterized by a basic reproduction ratio (R0) of >1 (allowing sustained cattle-to-cattle transmission), a relatively low transmission rate from environmental reservoirs, and substantial association with eae on transmission. The presence of stx2 was associated with reduced transmission. In contrast, serogroup O103 appears better adapted to the noncattle environment, characterized by an R0 value of <1 for plausible test sensitivities, a significantly higher transmission rate from noncattle sources than serogroup O26, and an absence of fitness benefits associated with the carriage of eae. Thus, the association of eae with enhanced transmission depends on the E. coli serogroup. Our results suggest that the capacity of E. coli strains to derive fitness benefits from virulence determinants influences the prevalence in the cattle population and the ecology and epidemiology of the host organism.
PMCID: PMC3008222  PMID: 20952647
10.  The stress of starvation: glucocorticoid restraint of beta cell development 
Diabetologia  2010;54(2):223-226.
Developmental insults during gestation, such as under-nutrition, are known to restrict the number of beta cells that form in the fetal pancreas and are maintained in adulthood, leading to increased risk of type 2 diabetes. There are now substantial data indicating that glucocorticoids mediate this effect of under-nutrition on beta cell mass and that even at physiological levels they restrain fetal beta cell development in utero. There are emerging clues that this occurs downstream of endocrine commitment by neurogenin 3 but prior to terminal beta cell differentiation. Deciphering the precise mechanism will be important as it might unveil new pathways by which to manipulate beta cell mass that could be exploited as novel therapies for patients with diabetes.
PMCID: PMC3017310  PMID: 21072627
Beta cell; Corticosterone; Cortisol; Development; Glucocorticoid; Glucocorticoid receptor; Human; Insulin; Mouse; Neurogenin 3; Pancreas; Under-nutrition
11.  Interferon-inducible factor 16 is a novel modulator of glucocorticoid action 
The FASEB Journal  2010;24(6):1700-1713.
Previously, we used cDNA expression profiling to identify genes associated with glucocorticoid (Gc) sensitivity. We now identify which of these directly influence Gc action. Interferon-inducible protein 16 (IFI16), bone morphogenetic protein receptor type II (BMPRII), and regulator of G-protein signaling 14 (RGS14) increased Gc transactivation, whereas sialyltransferase 4B (SIAT4B) had a negative effect. Amyloid β (A4) precursor-protein binding, family B, member 1 (APBB1/Fe65) and neural cell expressed developmentally down-regulated 9 (NEDD9) were without effect. Only IFI16 potentiated Gc repression of NF-κB. In addition, IFI16 affected basal expression, and Gc induction of endogenous target genes. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand-dependent repression of GR expression, or the ligand-dependent induction of GR phosphorylation on Ser-211 or Ser-203. Coimmunoprecipitation revealed an interaction, suggesting that IFI16 modulation of GR function is mediated by protein crosstalk. Transfection analysis with GR mutants showed that the ligand-binding domain of GR binds IFI16 and is the target domain for IFI16 regulation. Analysis of human lung sections identified colocalization of GR and IFI16, suggesting a physiologically relevant interaction. We demonstrate that IFI16 is a novel modulator of GR function and show the importance of analyzing variation in Gc sensitivity in humans, using appropriate technology, to drive discovery.—Berry, A., Matthews, L. Jangani, M., Plumb, J., Farrow, S., Buchan, N., Wilson, P. A., Singh, D., Ray, D., W., Donn, R. P. Interferon-inducible factor 16 is a novel modulator of glucocorticoid action.
PMCID: PMC3000051  PMID: 20086048
IFI16; steroid sensitivity; nuclear receptor; inflammation
12.  DNA sequence and analysis of human chromosome 9 
Humphray, S. J. | Oliver, K. | Hunt, A. R. | Plumb, R. W. | Loveland, J. E. | Howe, K. L. | Andrews, T. D. | Searle, S. | Hunt, S. E. | Scott, C. E. | Jones, M. C. | Ainscough, R. | Almeida, J. P. | Ambrose, K. D. | Ashwell, R. I. S. | Babbage, A. K. | Babbage, S. | Bagguley, C. L. | Bailey, J. | Banerjee, R. | Barker, D. J. | Barlow, K. F. | Bates, K. | Beasley, H. | Beasley, O. | Bird, C. P. | Bray-Allen, S. | Brown, A. J. | Brown, J. Y. | Burford, D. | Burrill, W. | Burton, J. | Carder, C. | Carter, N. P. | Chapman, J. C. | Chen, Y. | Clarke, G. | Clark, S. Y. | Clee, C. M. | Clegg, S. | Collier, R. E. | Corby, N. | Crosier, M. | Cummings, A. T. | Davies, J. | Dhami, P. | Dunn, M. | Dutta, I. | Dyer, L. W. | Earthrowl, M. E. | Faulkner, L. | Fleming, C. J. | Frankish, A. | Frankland, J. A. | French, L. | Fricker, D. G. | Garner, P. | Garnett, J. | Ghori, J. | Gilbert, J. G. R. | Glison, C. | Grafham, D. V. | Gribble, S. | Griffiths, C. | Griffiths-Jones, S. | Grocock, R. | Guy, J. | Hall, R. E. | Hammond, S. | Harley, J. L. | Harrison, E. S. I. | Hart, E. A. | Heath, P. D. | Henderson, C. D. | Hopkins, B. L. | Howard, P. J. | Howden, P. J. | Huckle, E. | Johnson, C. | Johnson, D. | Joy, A. A. | Kay, M. | Keenan, S. | Kershaw, J. K. | Kimberley, A. M. | King, A. | Knights, A. | Laird, G. K. | Langford, C. | Lawlor, S. | Leongamornlert, D. A. | Leversha, M. | Lloyd, C. | Lloyd, D. M. | Lovell, J. | Martin, S. | Mashreghi-Mohammadi, M. | Matthews, L. | McLaren, S. | McLay, K. E. | McMurray, A. | Milne, S. | Nickerson, T. | Nisbett, J. | Nordsiek, G. | Pearce, A. V. | Peck, A. I. | Porter, K. M. | Pandian, R. | Pelan, S. | Phillimore, B. | Povey, S. | Ramsey, Y. | Rand, V. | Scharfe, M. | Sehra, H. K. | Shownkeen, R. | Sims, S. K. | Skuce, C. D. | Smith, M. | Steward, C. A. | Swarbreck, D. | Sycamore, N. | Tester, J. | Thorpe, A. | Tracey, A. | Tromans, A. | Thomas, D. W. | Wall, M. | Wallis, J. M. | West, A. P. | Whitehead, S. L. | Willey, D. L. | Williams, S. A. | Wilming, L. | Wray, P. W. | Young, L. | Ashurst, J. L. | Coulson, A. | Blöcker, H. | Durbin, R. | Sulston, J. E. | Hubbard, T. | Jackson, M. J. | Bentley, D. R. | Beck, S. | Rogers, J. | Dunham, I.
Nature  2004;429(6990):369-374.
Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.
PMCID: PMC2734081  PMID: 15164053
13.  The DNA sequence and analysis of human chromosome 13 
Dunham, A. | Matthews, L. H. | Burton, J. | Ashurst, J. L. | Howe, K. L. | Ashcroft, K. J. | Beare, D. M. | Burford, D. C. | Hunt, S. E. | Griffiths-Jones, S. | Jones, M. C. | Keenan, S. J. | Oliver, K. | Scott, C. E. | Ainscough, R. | Almeida, J. P. | Ambrose, K. D. | Andrews, D. T. | Ashwell, R. I. S. | Babbage, A. K. | Bagguley, C. L. | Bailey, J. | Bannerjee, R. | Barlow, K. F. | Bates, K. | Beasley, H. | Bird, C. P. | Bray-Allen, S. | Brown, A. J. | Brown, J. Y. | Burrill, W. | Carder, C. | Carter, N. P. | Chapman, J. C. | Clamp, M. E. | Clark, S. Y. | Clarke, G. | Clee, C. M. | Clegg, S. C. M. | Cobley, V. | Collins, J. E. | Corby, N. | Coville, G. J. | Deloukas, P. | Dhami, P. | Dunham, I. | Dunn, M. | Earthrowl, M. E. | Ellington, A. G. | Faulkner, L. | Frankish, A. G. | Frankland, J. | French, L. | Garner, P. | Garnett, J. | Gilbert, J. G. R. | Gilson, C. J. | Ghori, J. | Grafham, D. V. | Gribble, S. M. | Griffiths, C. | Hall, R. E. | Hammond, S. | Harley, J. L. | Hart, E. A. | Heath, P. D. | Howden, P. J. | Huckle, E. J. | Hunt, P. J. | Hunt, A. R. | Johnson, C. | Johnson, D. | Kay, M. | Kimberley, A. M. | King, A. | Laird, G. K. | Langford, C. J. | Lawlor, S. | Leongamornlert, D. A. | Lloyd, D. M. | Lloyd, C. | Loveland, J. E. | Lovell, J. | Martin, S. | Mashreghi-Mohammadi, M. | McLaren, S. J. | McMurray, A. | Milne, S. | Moore, M. J. F. | Nickerson, T. | Palmer, S. A. | Pearce, A. V. | Peck, A. I. | Pelan, S. | Phillimore, B. | Porter, K. M. | Rice, C. M. | Searle, S. | Sehra, H. K. | Shownkeen, R. | Skuce, C. D. | Smith, M. | Steward, C. A. | Sycamore, N. | Tester, J. | Thomas, D. W. | Tracey, A. | Tromans, A. | Tubby, B. | Wall, M. | Wallis, J. M. | West, A. P. | Whitehead, S. L. | Willey, D. L. | Wilming, L. | Wray, P. W. | Wright, M. W. | Young, L. | Coulson, A. | Durbin, R. | Hubbard, T. | Sulston, J. E. | Beck, S. | Bentley, D. R. | Rogers, J. | Ross, M. T.
Nature  2004;428(6982):522-528.
Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.
PMCID: PMC2665288  PMID: 15057823
15.  Epidemiological implications of the contact network structure for cattle farms and the 20–80 rule 
Biology Letters  2005;1(3):350-352.
The network of movements of cattle between farm holdings is an important determinant of the potential rates and patterns of spread of infectious diseases. Because cattle movements are uni-directional, the network is unusual in that the risks of acquiring infection (by importing cattle) and of passing infection on (by exporting cattle) can be clearly distinguished, and there turns out to be no statistically significant correlation between the two. This means that the high observed degree of heterogeneity in numbers of contacts does not result in an increase in the basic reproduction number, R0, in contrast to findings from studies of other contact networks. Despite this, it is still the case that just 20% of holdings contribute at least 80% of the value of R0.
PMCID: PMC1617140  PMID: 17148204
basic reproduction number; heterogeneity; infectious diseases; livestock; movements
16.  Neighbourhood control policies and the spread of infectious diseases. 
We present a model of a control programme for a disease outbreak in a population of livestock holdings. Control is achieved by culling infectious holdings when they are discovered and by the pre-emptive culling of livestock on holdings deemed to be at enhanced risk of infection. Because the pre-emptive control programme cannot directly identify exposed holdings, its implementation will result in the removal of both infected and uninfected holdings. This leads to a fundamental trade-off: increased levels of control produce a greater reduction in transmission by removing more exposed holdings, but increase the number of uninfected holdings culled. We derive an expression for the total number of holdings culled during the course of an outbreak and demonstrate that there is an optimal control policy, which minimizes this loss. Using a metapopulation model to incorporate local clustering of infection, we examine a neighbourhood control programme in a locally spreading outbreak. We find that there is an optimal level of control, which increases with increasing basic reproduction ratio, R(0); moreover, implementation of control may be optimal even when R(0) < 1. The total loss to the population is relatively insensitive to the level of control as it increases beyond the optimal level, suggesting that over-control is a safer policy than under-control.
PMCID: PMC1691422  PMID: 12964992
17.  The construction and analysis of epidemic trees with reference to the 2001 UK foot-and-mouth outbreak. 
The case-reproduction ratio for the spread of an infectious disease is a critically important concept for understanding dynamics of epidemics and for evaluating impact of control measures on spread of infection. Reliable estimation of this ratio is a problem central to epidemiology and is most often accomplished by fitting dynamic models to data and estimating combinations of parameters that equate to the case-reproduction ratio. Here, we develop a novel parameter-free method that permits direct estimation of the history of transmission events recoverable from detailed observation of a particular epidemic. From these reconstructed 'epidemic trees', case-reproduction ratios can be estimated directly. We develop a bootstrap algorithm that generates percentile intervals for these estimates that shows the procedure to be both precise and robust to possible uncertainties in the historical reconstruction. Identifying and 'pruning' branches from these trees whose occurrence might have been prevented by implementation of more stringent control measures permits estimation of the possible efficacy of these alternative measures. Examination of the cladistic structure of these trees as a function of the distance of each case from its infection source reveals useful insights about the relationship between long-distance transmission events and epidemic size. We demonstrate the utility of these methods by applying them to data from the 2001 foot-and-mouth disease outbreak in the UK.
PMCID: PMC1691228  PMID: 12590749
18.  The basic reproduction number for scrapie. 
The basic reproduction number R0 provides a quantitative assessment of the ability of an infectious agent to invade a susceptible host population. A mathematical expression for R0 is derived based on a recently developed model for the spread of scrapie through a flock of sheep. The model incorporates sheep demography, a long and variable incubation period, genetic variation in susceptibility to scrapie, and horizontal and vertical routes of transmission. The sensitivity of R0 to a range of epidemiologically important parameters is assessed and the effects of genetic variation in susceptibility are examined. A reduction in the frequency of the susceptibility allele reduces R0 most effectively when the allele is recessive, whereas inbreeding may increase R0 when the allele is recessive, increasing the chance of an outbreak. Using this formulation, R0 is calculated for an outbreak of scrapie in a flock of Cheviot sheep.
PMCID: PMC1689932  PMID: 10380685
19.  Population dynamics of scrapie in a sheep flock. 
A detailed analysis of an outbreak of natural scrapie in a flock of Cheviot sheep is described. A total of 137 cases was reported over 13 years among 1307 sheep born into the flock. The epidemiology of scrapie can only be understood with reference to sheep demography, the population genetics of susceptibility to scrapie, pathogenesis during a long incubation period, and the rate of transmission (by both vertical and horizontal routes), all of which interact in complex ways. A mathematical model incorporating these features is described, parameter values and model inputs are derived from available information from the flock and from independent sources, and model outputs are compared with the field data. The model is able to reproduce key features of the outbreak, including its long duration and the ages of cases. The analysis supports earlier work suggesting that many infected sheep do not survive to show clinical signs, that most cases arise through horizontal transmission, and that there is strong selection against susceptible genotypes. However, important aspects of scrapie epidemiology remain poorly understood, including the possible role of carrier genotypes and of an environmental reservoir of infectivity, and the mechanisms maintaining alleles giving susceptibility to scrapie in the sheep population.
PMCID: PMC1692552  PMID: 10365400
20.  Epidemiology and control of scrapie within a sheep flock. 
Mathematical models of the transmission dynamics of scrapie are used to explore the expected course of an outbreak in a sheep flock, and the potential impacts of different control measures. All models incorporate sheep demography, a long and variable scrapie incubation period, horizontal and vertical routes of transmission and genetic variation in susceptibility. Outputs are compared for models which do and do not incorporate an environmental reservoir of infectivity, and which do and do not incorporate carrier genotypes. Numerical analyses using parameter values consistent with available data indicate that, in a closed flock, scrapie outbreaks may have a duration of several decades, reduce the frequency of susceptible genotypes, and may become endemic if carrier genotypes are present. In an open flock, endemic scrapie is possible even in the absence of carriers. Control measures currently or likely to become available may reduce the incidence of cases but may be fully effective only over a period of several years.
PMCID: PMC1689197  PMID: 9699313
21.  Concurrent schedule assessment of food preference in cows 
Six dairy cows (Bos taurus) were trained on several pairs of concurrent variable-interval schedules with different types of food available on each alternative. The required response was a plate press made by the animal's muzzle. Performance generally replicated that found with other species. The generalized matching law accounted for the preference data, showing that food preference could be quantitatively analyzed as a special case of response bias. The preference functions showed that the response- and time-allocation ratios were not as extreme as obtained reinforcement rate ratios (undermatching).
PMCID: PMC1332899  PMID: 16812149
different reinforcers; concurrent schedules; matching law; nose-plate press; cows
23.  London's immigrant apothecaries, 1600-1800. 
Medical History  1974;18(3):262-274.
PMCID: PMC1081579  PMID: 4618302
25.  An unrecorded William Allen caricature? 
Medical History  1971;15(3):305-306.
PMCID: PMC1034179  PMID: 4934512

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