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Biomedical subjects

G Miller

Publications and source records attributed to G Miller.

At least 37 records · Page 2Linked to original sources
PubMed2002

Interaction between smoking and the stromelysin-1 (MMP3) gene 5A/6A promoter polymorphism and risk of coronary heart disease in healthy men.

Smoking is a major risk factor for coronary heart disease (CHD), but this risk may be modified by an individual's genotype. A common functional 5A/6A polymorphism in the promoter of the stromelysin-1 (matrix metalloproteinase 3, MMP3) gene has been identified. The 6A allele has been consistently associated with faster progression of angiographically determined CHD, while the 5A allele has recently been associated with risk of acute myocardial infarction (MI) in patients with unstable angina. To date there has been no prospective study of the relationship of this genotype to CHD risk in smokers and non-smokers. DNA was available from 2,743 middle-aged men, free of CHD at baseline, recruited through nine general practices in the UK for prospective surveillance. To date there have been almost 24,000 person-years of follow-up with 125 CHD events (fatal and non-fatal MI, sudden coronary death, need for coronary artery surgery or new major ECG Q-wave abnormality). Men with events were each matched for age, practice and cholesterol level with three healthy men. Smoking habit was determined by questionnaire. 5A/6A genotype was determined using a heteroduplex generator method. Associations between genotype and disease outcome, according to smoking status, were assessed using conditional logistic regression. Overall, current smoking was associated with a relative risk (RR) of 1.99 (95% CI 1.30-3.06) as compared with never-smokers and ex-smokers combined (p&0.002). In non-smoking men, and after adjustment for conventional risk factors, compared with the 5A5A group, the RR was 1.37 (0.64-2.94) in those with the genotype 5A6A and 3.02 (1.38-6.61) in those with the genotype 6A6A. Smoking increased risk 1.4 fold in the 5A6A group to 1.91 (1.84-4.36), by 1.3 fold in the 6A6A group to 4.01 (1.57-10.24), but by 3.81 fold (1.54-9.40) in the 5A5A group (smoking-genotype interaction p = 0.01). The data indicate a key role for stromelysin in the atherosclerotic process. Men with the stromelysin genotype 5A5A represent 29% of the general population, and their high risk, if smokers, provides a further strong argument for smoking avoidance.

Alleles↗
PubMed2002

Bayesian internal dosimetry calculations using Markov Chain Monte Carlo.

A new numerical method for solving the inverse problem of internal dosimetry is described. The new method uses Markov Chain Monte Carlo and the Metropolis algorithm. Multiple intake amounts, biokinetic types, and times of intake are determined from bioassay data by integrating over the Bayesian posterior distribution. The method appears definitive, but its application requires a large amount of computing time.

Algorithms↗
PubMed2001

Prevalence of antibodies to human herpesvirus 8 (HHV-8) in Saudi Arabian patients with and without renal failure.

BACKGROUND: Kaposi's sarcoma (KS) is the most common cancer occurring in renal transplant recipients in Saudi Arabia, where the reported incidence of posttransplantation KS is 10 times higher than the incidence in the United States and Western Europe. The reason for the particularly high incidence of posttransplantation KS in this geographic area is unknown. METHODS: To explore the possibility that the high incidence of posttransplantation KS might be the result of widespread infection with human herpesvirus 8 (HHV-8), we determined the prevalence of antibodies to HHV-8 in 201 patients with end-stage renal disease (ESRD) and a comparison group of 358 individuals without renal disease who were similar in age, sex, and area of residence. Antibodies to lytic cycle antigens of HHV-8 were determined by indirect immunofluorescence and confirmed by immunoblots using tetradecanoyl phorbol ester acetate-induced BC-3 cell extracts and recombinant small viral capsid antigen (ORF65). RESULTS: Antibodies to HHV-8 were detected in serum samples from 14 (6.97%) of 201 ESRD patients and from 10 (3.88%) of 258 in the comparison group (P=0.14). HHV-8 seropositive individuals were on average 10 years older than seronegative subjects (55.3 years vs. 46.9 years). Among HHV-8 seropositive subjects, 71% were male and 29% were female. CONCLUSIONS: Serologic evidence of HHV-8 infection was numerically more common in men and in patients with ESRD. However, among patients with and without ESRD, the strongest association was with increasing age.

Antibodies, Viral↗
PubMed2001

Impact of different variables on the outcome of patients with clinically confined prostate carcinoma: prediction of pathologic stage and biochemical failure using an artificial neural network.

BACKGROUND: The advent of advanced computing techniques has provided the opportunity to analyze clinical data using artificial intelligence techniques. This study was designed to determine whether a neural network could be developed using preoperative prognostic indicators to predict the pathologic stage and time of biochemical failure for patients who undergo radical prostatectomy. METHODS: The preoperative information included TNM stage, prostate size, prostate specific antigen (PSA) level, biopsy results (Gleason score and percentage of positive biopsy), as well as patient age. All 309 patients underwent radical prostatectomy at the University of Colorado Health Sciences Center. The data from all patients were used to train a multilayer perceptron artificial neural network. The failure rate was defined as a rise in the PSA level > 0.2 ng/mL. The biochemical failure rate in the data base used was 14.2%. Univariate and multivariate analyses were performed to validate the results. RESULTS: The neural network statistics for the validation set showed a sensitivity and specificity of 79% and 81%, respectively, for the prediction of pathologic stage with an overall accuracy of 80% compared with an overall accuracy of 67% using the multivariate regression analysis. The sensitivity and specificity for the prediction of failure were 67% and 85%, respectively, demonstrating a high confidence in predicting failure. The overall accuracy rates for the artificial neural network and the multivariate analysis were similar. CONCLUSIONS: Neural networks can offer a convenient vehicle for clinicians to assess the preoperative risk of disease progression for patients who are about to undergo radical prostatectomy. Continued investigation of this approach with larger data sets seems warranted.

Adult↗
PubMed2001

hRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters.

A crucial step in transcription is the recruitment of RNA polymerase to promoters. In the transcription of human rRNA genes by RNA Polymerase I (Pol I), transcription factor SL1 has a role as the essential core promoter binding factor. Little is known about the mechanism by which Pol I is recruited. We provide evidence for an essential role for hRRN3, the human homologue of a yeast Pol I transcription factor, in this process. We find that whereas the bulk of human Pol I complexes (I alpha) are transcriptionally inactive, hRRN3 defines a distinct subpopulation of Pol I complexes (I beta) that supports specific initiation of transcription. Human RRN3 interacts directly with TAF(I)110 and TAF(I)63 of promoter-selectivity factor SL1. Blocking this connection prevents recruitment of Pol I beta to the rDNA promoter. Furthermore, hRRN3 can be found in transcriptionally autonomous Pol I holoenzyme complexes. We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription.

Binding Sites↗
PubMed2001

The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

Administration, Oral↗
PubMed2001

Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice.

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.

Animals↗
PubMed2001

Treatment of steroid-resistant acute graft-versus-host disease with anti-thymocyte globulin.

Acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation. Although initial treatment with corticosteroids is effective in the majority of patients, 30--60% develop steroid resistance. Anti-thymocyte globulin (ATG) is commonly used as first-line therapy for steroid resistant (SR) aGVHD. However, data on its efficacy are limited. At two institutions we reviewed the results of treatment with ATG of 58 patients with SR aGVHD. Initial manifestations of aGVHD were treated with 2 mg/kg/day of methylprednisolone (MP). Equine ATG was administered as first-line therapy for SR aGVHD, a median of 9 days (range, 3 to 39) after initiation of MP. At the time of initiation of ATG, IBMTR severity indices B, C and D were observed in 6%, 40% and 54% of patients, respectively. Improvement was observed in 30% of patients treated with ATG. Skin disease was more likely to improve with ATG (79%), while progression of gut and liver aGVHD was observed in 40% and 66% of patients, respectively. Despite initial improvement, 52 patients (90%) died a median of 40 days after ATG therapy from progressive aGVHD and/or infection (74%), ARDS (15%), or relapse (11%). Only six patients (10%), three of whom had aGVHD limited to the skin at the time ATG was administered, are long-term survivors. We conclude that initial improvement of SR aGVHD occurs with ATG in a minority of patients, and very few patients become long-term survivors. Furthermore, this treatment is associated with a high rate of major complications.

Actuarial Analysis↗
PubMed2001

Internal dosimetry for inhalation of hafnium tritide aerosols.

Metal tritides with low dissolution rates may have residence times in the lungs which are considerably longer than the biological half-time normally associated with tritium in body water, resulting in long-term irradiation of the lungs by low energy beta particles and bremsstrahlung X rays. Samples of hafnium tritide were placed in a lung simulant fluid to determine approximate lung dissolution rates. Hafnium hydride samples were analysed for particle size distribution with a scanning electron microscope. Lung simulant data indicated a biological dissolution half-time for hafnium tritide on the order of 10(5) d. Hafnium hydride particle sizes ranged between 2 and 10 microns, corresponding to activity median aerodynamic diameters of 5 to 25 microns. Review of in vitro dissolution data, development of a biokinetic model, and determination of secondary limits for 1 micron AMAD particles are presented and discussed.

Aerosols↗
PubMed2001

Bayesian prior probability distributions for internal dosimetry.

The problem of choosing a prior distribution for the Bayesian interpretation of measurements (specifically internal dosimetry measurements) is considered using a theoretical analysis and by examining historical tritium and plutonium urine bioassay data from Los Alamos. Two models for the prior probability distribution are proposed: (1) the log-normal distribution, when there is some additional information to determine the scale of the true result, and (2) the 'alpha' distribution (a simplified variant of the gamma distribution) when there is not. These models have been incorporated into version 3 of the Bayesian internal dosimetry code in use at Los Alamos (downloadable from our web site). Plutonium internal dosimetry at Los Alamos is now being done using prior probability distribution parameters determined self-consistently from population averages of Los Alamos data.

Bayes Theorem↗
PubMed2001

Autostimulation of the Epstein-Barr virus BRLF1 promoter is mediated through consensus Sp1 and Sp3 binding sites.

As an essential step in the lytic cascade, the Rta homologues of gammaherpesviruses all activate their own expression. Consistent with this biologic function, the Epstein-Barr virus (EBV) Rta protein powerfully stimulates the promoter of its own gene, Rp, in EBV-positive B cells in transient-transfection reporter-based assays. We analyzed the activity of RpCAT in response to Rta by deletional and site-directed mutagenesis. Two cognate Sp1 binding sites located at -279 and -45 relative to the transcriptional start site proved crucial for Rta-mediated activation. Previously described binding sites for the cellular transcription factor Zif268 and the viral transactivator ZEBRA were found to be dispensable for activation of RpCAT by Rta. Gel shift analysis, using extracts of B cells in latency or induced into the lytic cycle, identified Sp1 and Sp3 as the predominant cellular proteins bound to Rp near -45. During the lytic cycle, ZEBRA bound Rp near the Sp1/Sp3 site. The binding of Sp1 and Sp3 to Rp correlated with the reporter activities in the mutagenesis study, establishing a direct link between transcriptional activation of Rp by Rta and DNA binding by Sp1 and/or Sp3. The relative abundance or functional state of the cellular Sp1 and Sp3 transcription factors may be altered in response to stimuli that induce the BRLF1 promoter and thereby contribute to the activation of the viral lytic cycle.

B-Lymphocytes↗
PubMed2001

CD4+ T-cell effectors inhibit Epstein-Barr virus-induced B-cell proliferation.

In immunodeficient hosts, Epstein-Barr virus (EBV) often induces extensive B-cell lymphoproliferative disease and lymphoma. Without effective in vitro immune surveillance, B cells infected by the virus readily form immortalized cell lines. In the regression assay, memory T cells inhibit the formation of foci of EBV-transformed B cells that follows recent in vitro infection by EBV. No one has yet addressed which T cell regulates the early proliferative phase of B cells newly infected by EBV. Using new quantitative methods, we analyzed T-cell surveillance of EBV-mediated B-cell proliferation. We found that CD4+ T cells play a significant role in limiting proliferation of newly infected, activated CD23+ B cells. In the absence of T cells, EBV-infected CD23+ B cells divided rapidly during the first 3 weeks after infection. Removal of CD4+ but not CD8+ T cells also abrogated immune control. Purified CD4+ T cells eliminated outgrowth when added to EBV-infected B cells. Thus, unlike the killing of EBV-infected lymphoblastoid cell lines, in which CD8+ cytolytic T cells play an essential role, prevention of early-phase EBV-induced B-cell proliferation requires CD4+ effector T cells.

Adult↗
PubMed2001

ANX7 as a bio-marker in prostate and breast cancer progression.

The ANX7 gene codes for a Ca2+-activated GTPase, which has been implicated in both exocytotic secretion in cells and control of growth. In this review, we summarize information regarding increased tumor frequency in the Anx7 knockout mice, ANX7 growth suppression of human cancer cell lines, and ANX7 expression in human tumor tissue micro-arrays. The loss of ANX7 is significant in metastatic and hormone refractory prostate cancer compared to benign prostatic hyperplasia. In addition, ANX7 expression has prognostic value for predicting survival of breast cancer patients.

Animals↗
PubMed2001

Specific changes to the mechanism of cell locomotion induced by overexpression of beta-actin.

Overexpression of beta-actin is known to alter cell morphology, though its effect on cell motility has not been documented previously. Here we show that overexpressing beta-actin in myoblasts has striking effects on motility, increasing cell speed to almost double that of control cells. This occurs by increasing the areas of protrusion and retraction and is accompanied by raised levels of beta-actin in the newly protruded regions. These regions of the cell margin, however, show decreased levels of polymerised actin, indicating that protrusion can outpace the rate of actin polymerisation in these cells. Moreover, the expression of beta*-actin (a G244D mutant, which shows defective polymerisation in vitro) is equally effective at increasing speed and protrusion. Concomitant changes in actin binding proteins show no evidence of a consistent mechanism for increasing the rate of actin polymerisation in these actin overexpressing cells. The increase in motility is confined to poorly spread cells in both cases and the excess motility can be abolished by blocking myosin function with butanedione monoxime (BDM). Our observations on normal myoblasts are consistent with the view that they protrude by the assembly and cross linking of actin filaments. In contrast, the additional motility shown by cells overexpressing beta-actin appears not to result from an increase in the rate of actin polymerisation but to depend on myosin function. This suggests that the additional protrusion arises from a different mechanism. We discuss the possibility that it is related to retraction-induced protrusion in fibroblasts. In this phenomenon, a wave of increased protrusion follows a sudden collapse in cell spreading. This view could explain why it is only the additional motility that depends on spreading, and has implications for understanding the differences in locomotion that distinguish tissue cells from highly invasive cell types such as leucocytes and malignant cells.

Actin Depolymerizing Factors↗