Biomedical subjects

E A Thompson

Publications and source records attributed to E A Thompson.

At least 19 recordsLinked to original sources

PubMed2006

Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT.

In hematopoietic cells the transforming potential of the ecotropic viral integration site 1 (Evi1) oncogene is thought to be dependent upon the ability to inhibit TGFbeta signaling. Although Evi1 has recently been implicated in certain epithelial cancers, the effects of Evi1 on transformation and TGFbeta signaling in epithelial cells are not completely understood. Herein, we have determined the effects of Evi1 on TGFbeta signaling in intestinal epithelial cells. Stable expression of Evi1 in non-transformed intestinal epithelial cells inhibited induction of some Smad3-dependent TGFbeta target genes, such as PAI1. However, TGFbeta-mediated induction of cellular adhesion signaling components such as integrin1 and paxillin was not inhibited by Evi1; nor did Evi1 inhibit TGFbeta-mediated epithelial to mesenchymal transition. Likewise, Evi1 did not inhibit TGFbeta-mediated downregulation of cyclin D1 or block TGFbeta-mediated growth inhibition. However, Evi1 did inhibit TGFbeta-mediated apoptosis by a process that involves phosphoinositide-3-kinase (PI3K) and its downstream effector AKT. The ability of Evi1 to suppress apoptosis is not restricted to TGFbeta-mediated cell death, since Evi1 also protects intestinal epithelial cells from taxol-mediated apoptosis. Evi1 is overexpressed in some human colon cancer cell lines, and overexpression is associated with amplification of the Evi1 gene. Knockdown of Evi1 by siRNA inhibited AKT phosphorylation in HT-29 human colon cancer cells and increased their sensitivity to taxol-mediated apoptosis. These data indicate that Evi1 functions as a survival gene in intestinal epithelial cells and colon cancer cells, activating PI3K/AKT and conveying resistance to both physiological and therapeutic apoptotic stimuli.

Animals↗

PubMed2004

The placebo-controlled trial as a test of complementary and alternative medicine: observations from research experience of individualised homeopathic treatment.

The authors' experience of conducting clinical trials in homeopathy and analysing data from these has drawn attention to a fundamental problem with the interpretation of results from placebo controlled trials in homeopathy: It is not reasonable to assume that the specific effects of homeopathic medicine and the non-specific effects of consultations are independent of each other-specific effects of the medicine (as manifested by patients' reactions) may influence the nature of subsequent consultations and the non-specific effects of the consultation may enhance or diminish the effects of the medicine. For clinical trials of homeopathy to be accurate representations of practice, we need modified designs that take into account the complexity of the homeopathic intervention. Only with such trials will the results be generalisable to homeopathic practice in the real world. The authors propose that comparative trials are a meaningful way of evaluating the effectiveness of homeopathic treatment.

Adult↗

PubMed2003

A model for the length of tracts of identity by descent in finite random mating populations.

Linkage disequilibrium (LD) reflects coinheritance of an ancestral segment by chromosomes in a population. To begin to understand the effects of population history on the extent of LD, we model the length of a tract of identity-by-descent (IBD) between two chromosomes in a finite, random mating population. The variance of an IBD tract is large: a model described by (Genet. Res. Cambridge 35 (1980) 131) underestimates this variance. Using Fisher's concept of junctions, we predict the mean length of an IBD tract, given the age of the population and the population sizes over time. We derive results also for subdivided populations, given times of subdivision events and sizes of the resulting subpopulations. The model demonstrates that population growth and subdivision strongly affect the expected length of an IBD tract in small populations. These effects are less dramatic in large populations.

Chromosomes↗

PubMed2003

The homeopathic approach to the treatment of symptoms of oestrogen withdrawal in breast cancer patients. A prospective observational study.

This paper reports on an investigation of the homeopathic approach to the management of symptoms of oestrogen withdrawal in women with breast cancer. Forty-five patients entered the study. The most common presenting symptoms were hot flushes (HF) (n=38), mood disturbance (n=23), joint pain (n=12), and fatigue (n=16). Other symptoms included sleeplessness, reduced libido, weight gain, cystitis, vaginal dryness and skin eruptions. The active intervention was an individualised homeopathic medicine. Forty women (89%) completed the study. Significant improvements in mean symptom scores were seen over the study period and for the primary end-point 'the effect on daily living' scores. Symptoms other than HF such as fatigue and mood disturbance appear to be helped. Significant improvements in anxiety, depression and quality of life were demonstrated over the study period. The homeopathic approach appears to be clinically useful in the management of oestrogen withdrawal symptoms in women with breast cancer whether on or off Tamoxifen and improves mood disturbance. A placebo-controlled trial would be the next stage in this line of inquiry.

Adult↗

PubMed2003

Over-expression of cyclin D1 regulates Cdk4 protein synthesis.

Increased Cdk4 expression occurs coincident with over-expression of cyclin D1 in many human tumours and tumourigenic mouse models. Here, we investigate both in vivo and in vitro the mechanism by which Cdk4 expression is regulated in the context of cyclin D1 over-expression. Cdk4 mRNA levels in cyclin D1-over-expressing tissue and cultured cells were unchanged compared with controls. In contrast, Cdk4 protein levels were increased in cyclin D1-over-expressing tissue and cells versus their respective controls. This increase was not due to altered protein stability, but appeared to be due to an increase in Cdk4 protein synthesis. We also performed immunoprecipitation and in vitro kinase assays to demonstrate an increase in cyclin D1-Cdk4 complex formation and associated kinase activity. Blocking cyclin D1 expression resulted in diminished Cdk4 protein but not mRNA levels. These findings suggest a mechanism by which Cdk4 expression is increased in the context of cyclin D1 over-expression during tumourigenesis.

Animals↗

PubMed2002

A model-based method for identifying species hybrids using multilocus genetic data.

We present a statistical method for identifying species hybrids using data on multiple, unlinked markers. The method does not require that allele frequencies be known in the parental species nor that separate, pure samples of the parental species be available. The method is suitable for both markers with fixed allelic differences between the species and markers without fixed differences. The probability model used is one in which parentals and various classes of hybrids (F(1)'s, F(2)'s, and various backcrosses) form a mixture from which the sample is drawn. Using the framework of Bayesian model-based clustering allows us to compute, by Markov chain Monte Carlo, the posterior probability that each individual belongs to each of the distinct hybrid classes. We demonstrate the method on allozyme data from two species of hybridizing trout, as well as on two simulated data sets.

Animals↗

PubMed2002

The homeopathic approach to symptom control in the cancer patient: a prospective observational study.

The aims of this study were to describe a population of patients with cancer referred for complementary therapies to an NHS homeopathic hospital, and to explore the homeopathic approach to symptom control and its impact on mood disturbance and quality of life. One hundred consecutive patients attending a designated research cancer clinic were seen for a consultation, lasting up to 60 min, and prescription of a homeopathic remedy. A maximum of three symptoms were identified and rated by the patient as a problem, using a numerical self-rating scale. The effect these symptoms have on daily life and overall sense of well being were recorded using similar scales. Patients completed the Hospital Anxiety and Depression Scale (HADS) and the European Organization for Research and Treatment in Cancer--Quality of Life Questionnaire--Core 30 (EORTC QLQ-30) at the initial consultation and at four to six consultations later. After this time, the patients completed a final assessment questionnaire asking about satisfaction with the homeopathic approach, how helpful they had found the approach for the targeted symptoms and what factors they felt may have contributed to the changes perceived. One hundred patients were entered into the study. Thirty-nine patients had metastatic disease. Nine patients were refusing conventional cancer treatments. The most common symptoms were pain, fatigue and hot flushes. Symptom scores for fatigue and hot flushes improved significantly over the study period but not for pain scores. Side effects included a transient worsening of symptoms in a few cases, which settled on stopping the remedy. Fifty-two patients completed the study, and in those patients satisfaction was high, and 75% (n=38) rated the approach as helpful or very helpful for their symptoms. Results suggest that further research is warranted to explore the management of hot flushes in women with breast cancer and fatigue in the cancer diagnosis.

Adult↗

PubMed2001

Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein.

We have cloned and characterized a new member of the phosphatidylinositol kinase (PIK)-related kinase family. This gene, which we term human SMG-1 (hSMG-1), is orthologous to Caenorhabditis elegans SMG-1, a protein that functions in nonsense-mediated mRNA decay (NMD). cDNA sequencing revealed that hSMG-1 encodes a protein of 3031 amino acids containing a conserved kinase domain, a C-terminal domain unique to the PIK-related kinases and an FKBP12-rapamycin binding-like domain similar to that found in the PIK-related kinase mTOR. Immunopurified FLAG-tagged hSMG-1 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK-related kinase substrate PHAS-1. hSMG-1 kinase activity is inhibited by high nanomolar concentrations of wortmannin (IC(50) = 105 nm) but is not inhibited by a FKBP12-rapamycin complex. Mutation of conserved residues within the kinase domain of hSMG-1 abolishes both autophosphorylation and substrate phosphorylation, demonstrating that hSMG-1 exhibits intrinsic protein kinase activity. hSMG-1 phosphorylates purified hUpf1 protein, a phosphoprotein that plays a critical role in NMD, at sites that are also phosphorylated in whole cells. Based on these data, we conclude that hSMG-1 is the human orthologue to C. elegans SMG-1. Our data indicate that hSMG-1 may function in NMD by directly phosphorylating hUpf1 protein at physiologically relevant sites.

Amino Acid Sequence↗

PubMed2001

The importance of connections: joining components of the Hutterite pedigree.

We analyzed a quantitative trait (serum IgE levels), and a binary trait (asthma), in four Hutterite sub-pedigrees. A genome screen for asthma was performed using GENEHUNTER, and interesting regions were followed up using extended pedigrees and the FASTLINK package. Markov chain Monte Carlo (MCMC) methods were used to assess haplotype sharing among affected individuals (MORGAN/AUTOZYG), and to perform a combined oligogenic segregation and linkage analysis (LOKI) for log10(IgE). We found evidence for at least two susceptibility loci for asthma on chromosome 5, and a QTL for log10(IgE) on chromosome 1. Our analyses demonstrate that using the most complete pedigree structure possible is advisable, with attention to the possibility of heterogeneity among subunits of a very large pedigree.

Adult↗

PubMed2001

Linkage disequilibrium mapping: the role of population history, size, and structure.

Linkage disequilibrium mapping attempts to infer the location of a disease gene from observed associations between marker alleles and disease phenotype. This approach can be quite powerful when disease chromosomes are descended from a single founder mutation and the markers considered are tightly linked to the disease locus. The success of linkage disequilibrium map ping in fine-scale localization has led to the suggestion that genome-wide association testing might be useful in the detection of susceptibility genes for complex traits. Such studies would likely be performed in small, relatively isolated founder populations, where heterogeneity of the disease is less likely. To interpret the patterns of association observed in such populations, we need to understand the effect of population size, history, and structure on linkage disequilibrium. In this chapter, we first review measures of allelic association at a single locus. Measures of association between two loci are described, and some theoretical results are reviewed. We then consider some methods for inferring linkage between a marker and a rare disease, focusing on those that model the ancestry of the disease chromosomes. Next we discuss factors whose effect on disequilibrium are understood, and finally we describe the characteristics of some human populations that may be useful for disequilibrium mapping of complex traits.

Analysis of Variance↗

PubMed2001

Theoretical development of nursing interventions for sudden cardiac arrest survivors using social cognitive theory.

This article discusses the theoretical development of a nursing intervention program to enhance recovery over the first year following sudden cardiac arrest. Concepts from social cognitive theory and domains of concern following sudden cardiac arrest underpin a tailored and standardized nursing intervention. The nursing intervention program is designed for delivery by means of telephone and through the mail. Testing of the nursing intervention program is underway using a clinical trial design.

Defibrillators, Implantable↗

PubMed2001

Evaluation of indicated suicide risk prevention approaches for potential high school dropouts.

OBJECTIVES: This study evaluated the efficacy of 2 indicated preventive interventions, postintervention and at 9-month follow-up. METHODS: Drawn from a pool of potential high school dropouts, 460 youths were identified as being at risk for suicide and participated in 1 of 3 conditions randomly assigned by school: (1) Counselors CARE (C-CARE) (n = 150), a brief one-to-one assessment and crisis intervention; (2) Coping and Support Training (CAST) (n = 155), a small-group skills-building and social support intervention delivered with C-CARE; and (3) usual-care control (n = 155). Survey instruments were administered pre-intervention, following C-CARE (4 weeks), following CAST (10 weeks), and at a 9-month follow-up. RESULTS: Growth curve analyses showed significant rates of decline in attitude toward suicide and suicidal ideation associated with the experimental interventions. C-CARE and CAST, compared with usual care, also were effective in reducing depression and hopelessness. Among females, reductions in anxiety and anger were greater in response to the experimental programs. CAST was most effective in enhancing and sustaining personal control and problem-solving coping for males and females. CONCLUSIONS: School-based, indicated prevention approaches are feasible and effective for reducing suicidal behaviors and related emotional distress and for enhancing protective factors.

Adaptation, Psychological↗

PubMed2000

Glucocorticoid-mediated destabilization of cyclin D3 mRNA involves RNA-protein interactions in the 3'-untranslated region of the mRNA.

Glucocorticoids regulate the expression of the G(1) progression factor, cyclin D3. Cyclin D3 messenger RNA (CcnD3 mRNA) stability decreases rapidly when murine T lymphoma cells are treated with the synthetic glucocorticoid dexamethasone. Basal stability of CcnD3 mRNA is regulated by sequences within the 3'-untranslated region (3'-UTR). RNA-protein interactions occurring within the CcnD3 3'-UTR have been analyzed by RNA electrophoretic mobility shift assay. Three sites of RNA-protein interaction have been mapped using this approach. These elements include three pyrimidine-rich domains of 25, 26, and 37 nucleotides. When the cyclin D3 3'-UTR was stably overexpressed, the endogenous CcnD3 mRNA was no longer regulated by dexamethasone. Likewise, overexpression of a 215-nucleotide transgene that contains the 26- and 37-nucleotide elements blocks glucocorticoid inhibition of CcnD3 mRNA expression. These observations suggest that the 215-nucleotide 3'-UTR element may act as a molecular decoy, competing for proteins that bind to the endogenous transcript and thereby attenuating glucocorticoid responsiveness. UV-cross-linking experiments showed that two proteins of approximate molecular weight 37,000 and 52,000 bind to this 3'-UTR element.

3' Untranslated Regions↗

PubMed2000

Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan-Meier survival analysis.

OBJECTIVE: To determine seizure outcome and its predictors in patients with medically refractory temporal lobe epilepsy (TLE) after temporal lobectomy (TL). BACKGROUND: TL is the most common surgical procedure performed in adolescents and adults for the treatment of medically refractory TLE. Seizure outcome has been reported extensively during the first few postoperative years, but little is known beyond that time. METHODS: The authors analyzed seizure outcome in 79 patients who underwent TL for epilepsy at the Duke University Medical Center from 1962 through 1984. Patients with less than 2 years of follow-up and degenerative disorders were excluded. Predictors of seizure outcome were analyzed using Kaplan-Meier survival analyses. RESULTS: The mean follow-up was 14 years (range, 2.1 to 33.6 years). Using Engel's classification, 65% of patients were class I, 15% were class II, 11% were class III, and 9% were class IV. At least one postoperative seizure occurred in 55% of subjects. The majority of recurrences (86%) took place within 2 years of surgery. Later recurrences tended not to lead to medical intractability. Higher monthly preoperative seizure frequency was associated with poor seizure outcome. A seizure-free state at 2 years was found to be a better predictor of long-term outcome than the 6-, 12-, and 18-month landmarks. CONCLUSIONS: TL provides sustained, long-term benefit in patients with medically refractory TLE. Seizure-free status at 2 years from the time of surgery is predictive of long-term remission.

Adult↗

PubMed2000

Bias in multipoint linkage analysis arising from map misspecification.

Multipoint linkage analysis methods are often used in human genetic studies. Although multipoint methods increase power for a linkage analysis and will become essential if use of diallelic markers becomes widespread, the methods in use assume an accurate meiotic marker map. Unfortunately, uncertainties in estimates of between-marker meiotic distances are large. Also, sex-averaged maps are generally used, but recombination rates differ in males and females. Both these types of map misspecification can lead to lod score bias, but such bias has not previously been systematically quantified. We examine multipoint lod score bias arising from these map misspecifications, in both the presence and absence of actual linkage. We define bias as the expected difference between the lod score computed under the misspecified map and that computed under the true map. With actual linkage, any map misspecification causes negative bias in lod scores, resulting in loss of power to detect linkage. In most cases, bias is modest, only reaching clearly detectable levels when both types of misspecification are substantial. In the absence of linkage, map misspecification can cause positive or negative bias: falsely assuming a 1:1 female:male ratio always causes positive bias; using too large a distance gives a positive bias; using too small a distance gives a negative bias. This bias can inflate the false-positive rate, especially when the sample size is modest. We conclude that although current sex-averaged maps are suitable for a first-pass multipoint screen, the potential for bias from map misspecification should be evaluated in following up results from such an analysis.

Bias↗

PubMed2000

Comparison of GLUT1, GLUT3, and GLUT4 mRNA and the subcellular distribution of their proteins in normal human muscle.

Basal, "insulin-independent" glucose uptake into skeletal muscle is provided by glucose transporters positioned at the plasma membrane. The relative amount of the three glucose transporters expressed in muscle has not been previously quantified. Using a combination of qualitative and quantitative ribonuclease protection assay (RPA) methods, we found in normal human muscle that GLUT1, GLUT3, and GLUT4 mRNA were expressed at 90 +/- 10, 46 +/- 4, and 156 +/- 12 copies/ng RNA, respectively. Muscle was fractionated by DNase digestion and differential sedimentation into membrane fractions enriched in plasma membranes (PM) or low-density microsomes (LDM). GLUT1 and GLUT4 proteins were distributed 57% to 67% in LDM, whereas GLUT3 protein was at least 88% in the PM-enriched fractions. These data suggest that basal glucose uptake into resting human muscle could be provided in part by each of these three isoforms.

Adult↗

PubMed2000

A coalescent model of ancestry for a rare allele.

In disequilibrium mapping from data on a rare allele, interest may focus on the ancestry of a random sample of current descendants of a mutation. The mutation is assumed to have been introduced into the population as a single copy a known time ago and to have reached a given copy number within the population. Theory has been developed to describe the ancestral distribution under arbitrary patterns of population expansion. Further results permit convenient realization of the ancestry for a random sample of copies of a rare allele within populations of constant size or within populations growing or shrinking at constant exponential rate. In this article, we present an efficient approximate method for realizing coalescence times under more general patterns of population growth. We also apply diagnostics, checking the age of the mutation. In the course of the derivation, some additional insight is gained into the dynamics of the descendants of the mutation.

Alleles↗

PubMed2000

Monte Carlo evaluation of the likelihood for N(e) from temporally spaced samples.

A population's effective size is an important quantity for conservation and management. The effective size may be estimated from the change of allele frequencies observed in temporally spaced genetic samples taken from the population. Though moment-based estimators exist, recently Williamson and Slatkin demonstrated the advantages of a maximum-likelihood approach that they applied to data on diallelic genetic markers. Their computational methods, however, do not extend to data on multiallelic markers, because in such cases exact evaluation of the likelihood is impossible, requiring an intractable sum over latent variables. We present a Monte Carlo approach to compute the likelihood with data on multiallelic markers. So as to be computationally efficient, our approach relies on an importance-sampling distribution constructed by a forward-backward method. We describe the Monte Carlo formulation and the importance-sampling function and then demonstrate their use on both simulated and real datasets.

Algorithms↗