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Biomedical subjects

J D Bradley

Publications and source records attributed to J D Bradley.

At least 19 recordsLinked to original sources
PubMed2006

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose-volume outcome relationships.

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

Computer Simulation↗
PubMed2002

The use of a genetically engineered herpes simplex virus (R7020) with ionizing radiation for experimental hepatoma.

The herpes simplex virus (HSV) recombinant virus R7020 is an attenuated virus designed as a candidate for immunization against both HSV-1 and HSV-2 infections. It was extensively tested in an experimental animal system and in a healthy human adult population without significant untoward effects. We report on the use of R7020 with ionizing radiation as an oncolytic agent for hepatomas. Two hepatoma cell lines were studied, Hep3B and Huh7. R7020 replicated to higher titers in Hep3B cells than in Huh7 cells. Tissue culture studies correlated with hepatoma xenograft responses to R7020. R7020 was more effective in mediating Hep3B tumor xenograft regression compared with Huh7. Ionizing radiation combined with R7020 also showed differential results in antitumor efficacy between the two cell lines in tumor xenografts. Ionizing radiation enhanced the replication of R7020 in Hep3B xenografts. Moreover, the combination of ionizing radiation and virus caused a greater regression of xenograft volume than either R7020 or radiation alone. Ionizing radiation had no effect on the replication of R7020 virus in Huh7 xenografts. These results indicate that a regimen involving infection with an appropriate herpesvirus such as R7020 in combination with ionizing radiation can be highly effective in eradicating certain tumor xenografts.

Animals↗
PubMed2001

Biological contributions to the presentation and understanding of attention-deficit/hyperactivity disorder: a review.

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed disorder in children today with estimated prevalence rates falling between 3 and 5% of children (American Psychiatric Association, 1994). From inception, research has focused on studying varying facets of this disorder with initial efforts primarily focusing on treatment outcome. However, prominent efforts have been made in recent research efforts to shed light on the etiology of this disorder. Such research has discovered the contribution of genetic inheritance, as well as environmental factors that lead to the development of this disorder. Furthermore, studies using neurological and neuropsychological assessment measures have implicated the involvement of various Parts of the brain. This article critically reviews this body of research in light of its impact on the current specific neuropsychologically based etiological theories, as well as the most beneficial directions for future research.

Adolescent↗
PubMed2001

Regulation of both gene expression and protein stability provides genetically assisted target evaluation (GATE) for microbial target validation.

The attempt to develop novel antibiotics, active against organisms resistant to current therapies, has led researchers to seek and explore new drug targets. The rapid sequencing and analysis of entire microbial genomes has identified large numbers of genes that may be sufficiently different from their human counterparts to be exploited as targets for antimicrobial treatment. As a first step, the importance of the various putative targets for microbial growth and survival must be assessed. Emerging validation technologies are becoming increasingly sophisticated and, in certain cases, allow prioritisation of the best targets. In this paper, genetically assisted target evaluation (GATE) is introduced as a versatile target validation technology. GATE concomitantly manipulates both synthesis and stability of the targeted protein using copper ions as an effector. This technology allows rapid quantitation of the lethal consequences of inactivation of targeted gene products in Saccharomyces cerevisiae. Additional tools can then be applied to extend these results into pathogenic organisms, such as Candida albicans.

Animals↗
PubMed2001

Severity of knee pain does not predict a better response to an antiinflammatory dose of ibuprofen than to analgesic therapy in patients with osteoarthritis.

OBJECTIVE: To determine whether greater pain intensity at initiation of treatment predicted better response to ibuprofen than to acetaminophen in subjects with knee osteoarthritis (OA). METHODS: Data from 182 patients with knee OA who had taken part in a 4 week randomized, double blind, parallel comparison of 4,000 mg/day acetaminophen vs either 1,200 or 2,400 mg/day ibuprofen were reanalyzed using Pearson correlation coefficients for baseline pain severity, treatment assignment, and treatment response. Pain measures were visual analog scales for overall pain, resting pain, and walking pain. Baseline pain severity was divided into low, medium, and high tertiles, and treatment related differences in pain response were sought with pairwise t tests. Two-factor analysis of variance (ANOVA) models were used to seek interactions between baseline pain severity and treatment group, which would indicate differential drug treatment responsiveness. RESULTS: Greater baseline pain predicted greater pain relief with all 3 treatments. Patients with a high level of baseline rest pain appeared to respond better to ibuprofen 2,400 mg/day than to the other treatments, but this difference was not evident after correction for multiple statistical tests. ANOVA did not reveal significant differences in response to the 3 treatments or a significant interaction. CONCLUSION: Our data suggest that acetaminophen and ibuprofen are comparably effective in treating knee OA pain, even when the pain is severe.

Acetaminophen↗
PubMed2000

Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors.

Presenilins are integral membrane protein involved in the production of amyloid beta-protein. Mutations of the presenilin-1 and -2 gene are associated with familial Alzheimer's disease and are thought to alter gamma-secretase cleavage of the beta-amyloid precursor protein, leading to increased production of longer and more amyloidogenic forms of A beta, the 4-kDa beta-peptide. Here, we show that radiolabeled gamma-secretase inhibitors bind to mammalian cell membranes, and a benzophenone analog specifically photocross-links three major membrane polypeptides. A positive correlation is observed among these compounds for inhibition of cellular A beta formation, inhibition of membrane binding and cross-linking. Immunological techniques establish N- and C-terminal fragments of presenilin-1 as specifically cross-linked polypeptides. Furthermore, binding of gamma-secretase inhibitors to embryonic membranes derived from presenilin-1 knockout embryos is reduced in a gene dose-dependent manner. In addition, C-terminal fragments of presenilin-2 are specifically cross-linked. Taken together, these results indicate that potent and selective gamma-secretase inhibitors block A beta formation by binding to presenilin-1 and -2.

Amyloid Precursor Protein Secretases↗
PubMed2000

Prediction of WAIS-R indices based on performance on the Luria Nebraska Neuropsychological Battery-III.

The purpose of this research was to examine the clinical utility of the Luria-Nebraska Neuropsychological Battery-Third Edition (LNNB-III) in estimating intellectual functioning as measured by the WAIS-R. Ninety-one subjects were administered the WAIS-R and the LNNB-III. Multiple regression were calculated to examine the ability of the LNNB-III clinical scales to predict FSIQ, VIQ, and PIQ indices. The LNNB-III General Intelligence Scale (GI) predicted FSIQ within 10 points 79% of the time, and within 15 points 97% of the time. Similarly, GI predicted VIQ and PIQ indices with 67% accuracy within 10 points and with 91% and 87% accuracy, respectively, within 15 points. A combination of LNNB clinical scales fared no better than GI alone when predicting the FSIQ index. However, a combination of LNNB-III scales predicted VIQ with 80% accuracy within 10 points and with 94% accuracy within 15 points. In contrast, a combination of LNNB-III clinical scales predicted the PIQ index 76% of the time within 10 points and 90% of the time within 15 points. GI appears to be a good alternative when an estimate of intellectual functioning is desired given its less than 10 minute administration time. When greater specificity regarding VIQ and PIQ estimates are desired, a combination of specific LNNB-III scales appear preferable.

Adult↗
PubMed1999

Clinical assessment and significance of inflammation in knee osteoarthritis.

The recognition of the role of cytokines in osteoarthritis (OA) has suggested new approaches for therapy of the disease, and also increases the importance of clinical assessment of inflammation. Accurate identification of the presence and degree of inflammation might allow the clinician to predict which individuals would respond to therapy with anti-inflammatory drugs. Several laboratory and clinical markers have been evaluated which may also serve as predictors and indicators of response to therapy and overall outcome.

Aged↗
PubMed1999

Internal consistency and discriminant validity of the Luria Nebraska Neuropsychological Battery-III.

This research presents data pertaining to the development of the recently revised Luria Nebraska Neuropsychological Battery-III. The final version of this test battery consists of 31 clinical scales yielding 35 scores. The battery was given to 109 non brain-injured controls and 119 brain-injured subjects. High internal consistency was demonstrated for each clinical scale. Results further indicated that the test battery was very effective at discriminating between normal and brain-injured subjects, as significant between-group differences on 33 of 35 scores were observed. Significant between-group differences were also observed on 25 of the 35 scores when age and education were covaried out of the analyses; those scales not displaying significant between-group differences generally measured very basic over-learned skills.

Adolescent↗
PubMed1999

Ionizing radiation improves survival in mice bearing intracranial high-grade gliomas injected with genetically modified herpes simplex virus.

Malignant gliomas remain incurable with current interventions. Encouraging investigational approaches include the use of genetically modified herpes simplex-1 (HSV-1) viruses as direct cytotoxic agents. Combining attenuated HSV-1 with standard therapy, human U-87 malignant glioma xenografts grown in the hind limb or intracranially in athymic nude mice were exposed to ionizing radiation, inoculated with genetically modified HSV R3616, or received both virus and radiation. The combination of virus with fractionated ionizing radiation suggests a synergistic action and results in reduced tumor volumes and longer survivals when compared with treatment with either modality alone.

Animals↗
PubMed1994

Multivalent ligand-receptor binding interactions in the fibroblast growth factor system produce a cooperative growth factor and heparin mechanism for receptor dimerization.

The binding interactions for the three primary reactants of the fibroblast growth factor (FGF) system, basic FGF (bFGF), an FGF receptor, FGFR1, and the cofactor heparin/heparan sulfate (HS), were explored by isothermal titrating calorimetry, ultracentrifugation, and molecular modeling. The binding reactions were first dissected into three binary reactions: (1) FGFR1 + bFGF<==>FGFR1/bFGF, K1 = 41 (+/- 12) nM; (2) FGFR1 + HS<==>FGFR1/HS, K2 = 104 (+/- 17) microM; and (3) bFGF + HS<==>bFGF/HS, K3 = 470 (+/- 20) nM, where HS = low MW heparin, approximately 3 kDa. The first, binding of bFGF to FGFR1 in the absence of HS, was found to be a simple binary binding reaction that is enthalpy dominated and characterized by a single equilibrium constant, K1. The conditional reactions of bFGF and FGFR1 in the presence of heparin were then examined under conditions that saturate only the bFGF heparin site (1.5 equiv of HS/bFGF) or saturate the HS binding sites of both bFGF and FGFR1 (1.0 mM HS). Both 3-and 5-kDa low MW heparins increased the affinity for FGFR1 binding to bFGF by approximately 10-fold (Kd = 4.9 +/- 2.0 nM), relative to the reaction with no HS. In addition, HS, at a minimum of 1.5 equiv/bFGF, induced a second FGFR1 molecule to bind to another lower affinity secondary site on bFGF (K4 = 1.9 +/- 0.7 microM) in an entropy-dominated reaction to yield a quaternary complex containing two FGFR1, one bFGF, and at least one HS. Molecular weight estimates by analytical ultracentrifugation of such fully bound complexes were consistent with this proposed composition. To understand these binding reactions in terms of structural components of FGFR1, a three-dimensional model of FGFR1 was constructed using segment match modeling. Electrostatic potential calculations confirmed that an elongated cluster, approximately 15 x 35 A, of nine cationic residues focused positive potential (+2kBT) to the solvent-exposed beta-sheet A, B, E, C' surface of the D(II) domain model, strongly implicating this locus as the HS binding region of FGFR1. Structural models for HS binding to FGFR1, and HS binding to bFGF, were built individually and then assembled to juxtapose adjacent binding sites for receptor and HS on bFGF, against matching proposed growth factor and HS binding sites on FGFR1. The calorimetric binding results and the molecular modeling exercises suggest that bFGF and HS participate in a concerted bridge mechanism for the dimerization of FGFR1 in vitro and presumably for mitogenic signal transduction in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

Deduction of pulmonary microvascular hematocrit from indicator dilution curves.

We have developed a new model describing the relationship between plasma and red cell tracers flowing through the lung. The model is the result of an analysis of the transport of radiolabeled plasma albumin between two flowing phases and shows that differences between red cell and plasma tracer curves are related to microvascular hematocrit. The model was tested in an isolated, blood-perfused dog lung preparation in which we injected 51Cr-labeled red cells and 125I-labeled plasma albumin into the pulmonary artery. From the tracer concentration-time curves at the venous outflow, we calculated hr, the ratio of microvascular hematocrit to large-vessel hematocrit. In 18 baseline experiments, hr = 0.92 +/- 0.01 (mn +/- sem) at a blood flow rate of 10.7 +/- 0.3 ml s-1. We determined the effects of (a) glass bead embolization, (b) alloxan, and (c) lobe ligation on hr. Embolization attenuated the separation between plasma and red cells (increased hr), probably as a consequence of passive vasodilation. Alloxan enhanced separation of plasma and red cells (decreased hr), possibly as a result of arteriolar vasoconstriction. Ligation of a fraction of the perfused tissue at constant flow did not cause significant change in hr in the remaining perfused tissue. The model assumes that large-vessel transit times are uniform and that all dispersion occurs in the microvasculature. A theoretical analysis apportioning dispersion between large and small vessels disclosed that the error associated with these assumptions is likely to be less than 15% of the measured hr. We conclude from this study that the microvascular hematocrit model describes experimental plasma and red cell curves. The results imply that hr can be readily deduced from tagged red cells and plasma and can be accounted for in calculating permeability-surface area in diffusing tracer experiments.

Animals↗