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Biomedical subjects

J Chapman

Publications and source records attributed to J Chapman.

At least 109 records · Page 6Linked to original sources

High b-value q-space analyzed diffusion-weighted MRI: application to multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sensory functions, and permanent disability. High b-value diffusion-weighted MR images (b of up to 14000 s/mm(2)) were acquired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexponential, were analyzed using the q-space approach that emphasizes the diffusion characteristics of the slow-diffusing component. From this analysis, displacement and probability maps were constructed. The computed q-space analyzed MR images that were compared with conventional T(1), T(2) (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this q-space analyzed MR maps, provided a pronounced differentiation between normal tissue and tissues classified as MS plaques by the FLAIR images. More importantly, a pronounced differentiation was also observed between tissues classified by the FLAIR MR images as normal-appearing white matter (NAWM) in the MS brains, which are known to be abnormal, and the respective control tissues. The potential diagnostic capacity of high b-value diffusion q-space analyzed MR images is discussed, and experimental data that explains the consequences of using the q-space approach once the short pulse gradient approximation is violated are presented.

Animals↗

Design, synthesis and pharmacological characterization of new highly selective CRF(2) antagonists: development of 123I-K31440 as a potential SPECT ligand.

Novel analogs of antisauvagine-30 (aSvg-30), a specific antagonist for corticotropin-releasing factor (CRF) receptor, type 2 (CRF(2)), have been synthesized and characterized in vitro and in vivo. The N-terminal amino acid D-phenylalanine in aSvg-30 was replaced by a D-tyrosine residue for specific radioactive labeling with 123I. Additionally, Met(17) of aSvg-30 was substituted by norleucine and the N-terminus of the peptide was acetylated to increase in vivo metabolic stability. The aSvg-30 analogs were tested for their ability to displace [125I-Tyr(0)]Svg in binding experiments and to inhibit Svg-stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF(1) (hCRF(1)), hCRF(2alpha) and hCRF(2beta) receptor. Ac-[D-Tyr(11), His(12), Nle(17)Svg(11-40), named K31440, showed high specific binding to hCRF(2alpha) (K(i) = 1.48 +/- 0.34 nM) and hCRF(2beta) (K(i) = 2.05 +/- 0.61 nM) but not the hCRF(1) receptor (K(i) = 288 +/- 13 nM) and decreased Svg-stimulated cAMP activity in hCRF(2)-expressing cells in a similar fashion as aSvg-30. In biodistribution studies specific uptake of 123I-K31440 was detected after 1 h in small intestine of BALB/c nude mice. These data demonstrate that 123I-K31440 may serve as a useful tool to detect native CRF(2) receptors and elucidate their role in gastrointestinal disorders and diseases such as irritable bowel syndrome or cancer.

Amino Acid Sequence↗

Broad-spectrum virus reduction in red cell concentrates using INACTINE PEN110 chemistry.

BACKGROUND AND OBJECTIVES: The risk of transmission of blood-borne pathogens by transfusion is a persistent problem in medicine. To address this safety issue, INACTINE PEN110 chemistry is being utilized to develop a process for preparing pathogen-reduced red blood cell concentrates (RBCC). The purpose of this study was to characterize the virucidal effectiveness of the INACTINE PEN110 chemistry in full units of RBCC by using a panel of viruses with diverse properties in composition, size and shape. MATERIALS AND METHODS: The panel included four enveloped (bovine viral diarrhoea virus, pseudorabies virus, vesicular stomatitis Indiana virus and sindbis virus), six non-enveloped (porcine parvovirus, human adenovirus 2, reovirus 3, vesicular exanthema of swine virus, bluetongue virus, and foot and mouth disease virus) and cell-associated (human immunodeficiency) viruses. All viruses were individually spiked into CPD/AS-1, CP2D/AS-3 and CPD/AS-5 RBCC units and treated with 0.1% PEN110 (vol/vol) at 22 +/- 2 degrees C for up to 22 +/- 2 h. The PEN110 treatment reaction was stopped by chemical quenching, and residual virus was assayed. The cytotoxicity effect of PEN110-treated RBCC on indicator cells and the potential interference with the ability of the virus to infect indicator cells was determined and taken into consideration for calculating the virus-reduction factors, to avoid underestimation or overestimation of the virus reduction. RESULTS: The kinetics of inactivation for viruses spiked into CPD/AS-1, CP2D/AS-3 and CPD/AS-5 RBCC were equivalent. All viruses analysed in this study were reduced to the limit of detection of the assay. The reduction factors for the virus panel ranged from 4.2 to 7.5 log10/ml. CONCLUSIONS: The results from the study demonstrate for the first time that a pathogen-reduction technology for RBCC can achieve a broad-spectrum virucidal effect against both enveloped and non-enveloped viruses. The broad spectrum of virucidal activity of INACTINE PEN110, and equivalent kinetics of virus inactivation in RBCC prepared using different commercially available RBC storage solutions, demonstrate the robustness of this pathogen-reduction process.

Animals↗

Behavioral and cognitive deficits occur only after prolonged exposure of mice to antiphospholipid antibodies.

The antiphospholipid (Hughes) syndrome (APS) includes systemic and central nervous system (CNS) pathology associated with antibodies to a complex of phospholipids and beta2-glycoprotein I (beta2-GPI). Beta2-GPI immunized mice develop systemic manifestations of APS and we presently examined CNS manifestations in this APS model. Female BALB/c mice were immunized once with beta2-GPI in complete Freund's adjuvant (CFA) or with CFA alone (controls). A staircase test and a T-maze alternation test were performed to test behavior and cognition in independent groups of mice 6, 12 and 18 weeks following the immunization. The APS mice developed elevated levels of antibodies against negatively charged phospholipids and beta2-GPI. Neurological impairment was detected only 18 weeks after the induction of the APS and consisted of both cognitive (53 +/- 4 vs 71 +/- 3% correct choices in the T-maze alternation for APS vs control mice, P < 0.001) and behavioral changes (higher number of rears (18 +/- 2 vs 11 +/- 1, P < 0.006) and higher number of stairs climbed (12 +/- 2 vs 7 +/- 1, P < 0.02). This is the first report of cognitive deficits in this APS model and demonstrates the time course for the development of previously described behavioral changes. The mechanism involved in these CNS manifestations remains to be elucidated.

Animals↗

Search for gluinos and squarks using like-sign dileptons in pp macro collisions at square root of s = 1.8 TeV.

We present results of the first search for like-sign dilepton ( e(+/-)e(+/-), e(+/-)mu(+/-), mu(+/-)mu(+/-)) events associated with multijets and large missing energy using 106 pb(-1) of data in pp macro collisions at square root of s = 1.8 TeV collected during 1992-1995 by the CDF experiment. Finding no events that pass our selection, we examine pair production of gluinos (tilde g) and squarks (tilde q) in a constrained framework of the minimal supersymmetric standard model. At tan beta = 2 and mu = -800 GeV/c(2), we set 95% confidence level limits of M(tilde g)>221 GeV/c(2) for M(tilde g) approximately M(tilde q), and M(tilde q)>168 GeV/c(2) for M(tilde q)>>M(tilde g), both with small variation as a function of mu.

Journal Article↗

Observation of diffractive J/psi production at the Fermilab Tevatron.

We report the first observation of diffractive J/psi(--> mu+mu-) production in pp collisions at root square[s] = 1.8 TeV. Diffractive events are identified by their rapidity gap signature. In a sample of events with two muons of transverse momentum p(mu)T>2 GeV/c within the pseudorapidity region /eta/ < 1.0, the ratio of diffractive to total J/psi production rates is found to be R(J/psi) = [1.45 +/- 0.25]%. The ratio R(J/psi)(x) is presented as a function of x-Bjorken. By combining it with our previously measured corresponding ratio R(jj)(x) for diffractive dijet production, we extract a value of 0.59 +/- 0.15 for the gluon fraction of the diffractive structure function of the proton.

Journal Article↗

Charged-particle multiplicity pp collisions at square root of (s) = 1.8 TeV.

We report on a measurement of the mean charged-particle multiplicity of jets in dijet events with dijet masses in the range 80-630 GeV/c(2), produced at the Tevatron in pp collisions with square root (s) = 1.8 TeV and recorded by the Collider Detector at Fermilab. The data are fit to perturbative-QCD calculations carried out in the framework of the modified leading log approximation and the hypothesis of local parton-hadron duality. The fit yields values for two parameters in that framework: the ratio of parton multiplicities in gluon and quark jets, r identical withN(g-jet)(partons)/N(q-jet)(partons) = 1.7+/-0.3, and the ratio of the number of charged hadrons to the number of partons in a jet, K(charged)(LPHD) identical with N(charged)(hadrons)/N(partons) = 0.57+/-0.11.

Journal Article↗

Search for quark-lepton compositeness and a heavy W' Boson using the enu channel in p p macro collisions at square root of [s] = 1.8 TeV.

We present searches for quark-lepton compositeness and a heavy W' boson at high electron-neutrino transverse mass. We use approximately 110 pb(-1) of data collected in p p macro collisions at square root of [s] = 1.8 TeV by the CDF Collaboration during 1992-1995. The data are consistent with standard model expectations. Limits are set on the quark-lepton compositeness scale Lambda, the ratio of partial cross sections sigma(W'-->enu)/sigma(W-->enu), and the mass of a W' boson with standard model couplings. We exclude Lambda<2.81 TeV and a W' boson with mass below 754 GeV/c(2) at the 95% confidence level. Combining with our previously published limit obtained using the muon channel, we exclude a W' boson with mass below 786 GeV/c(2) at the 95% confidence level.

Journal Article↗

The Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid, suppresses experimental allergic encephalomyelitis.

AIM: To evaluate the effects of the synthetic Ras-pathway inhibitor, S-trans-trans-farnesylthiosalicylic acid (FTS) on acute and chronic experimental autoimmune encephalomyelitis (EAE and CR-EAE). BACKGROUND: Treatment of EAE and MS is based on immunosuppression aiming at downregulation of the proliferating myelin-reactive lymphocytes. One of the pathways of lymphocyte activation involves the GTP-binding protein Ras. FTS destabilizes the attachment of Ras to the cell membrane, resulting in an inhibition of the Ras-mediated signal transduction pathways. MATERIALS AND METHODS: EAE was induced in SJL/J mice by immunization with spinal cord homogenate (MSCH) in adjuvant and two i.v. boosts of pertussis antigen and CR-EAE with passive transfer of proteolipid protein (PLP)-activated lymphocytes. Animals were treated daily starting either from the day of EAE-induction (or cell transfer) or at a later stage, with i.p. injections of FTS (5 mg/kg/day). The clinical severity of the disease was evaluated daily and scored using a 0-6 scale. RESULTS: In six separate experiments, 27 of the 38 (71.7%) vehicle-treated animals developed clinical signs of EAE compared to 17/38 (44.7%) of the FTS-treated mice (p=0.02, t-test). The maximal average score in the control group was 2.94+/-2.2, whereas in the FTS group it was significantly lower (1.63+/-2.2, p=0.01). Mortality was 26.3% and 10.5% in the two groups, respectively (p=0.03). When treatment was initiated at a later stage, just before the onset of the clinical signs, the protective effect was even more pronounced. A significant suppression of clinical signs was also observed in the CR-EAE model (p=0.02). Lymphocyte proliferation assays demonstrated a more than twofold decrease in the reactivity to myelin antigens (MBP and PLP) and downregulation of the activated lymphocytes (expressing the CD62L, and IA-k-MHC Class I markers and the Vb17 T-cell receptor) in the FTS-treated group; in vitro FTS suppressed the Ras activity of lymphocytes and inhibited the proliferative ability of the lymphocytes in a dose-dependent manner. CONCLUSIONS: FTS suppresses EAE by downregulation of myelin-reactive activated T-lymphocytes. Since FTS did not induce generalized immunosuppressive effects, it may offer significant advantages over the broad immunosuppressive modalities and may be a candidate treatment for autoimmune diseases, such as MS.

Animals↗

The effects of APOE genotype on age at onset and progression of neurodegenerative diseases.

APOE genotype influences the age at onset of some neurodegenerative diseases such as AD and the rate of progression in others such as MS. The authors hypothesize that APOE genotype ubiquitously determines the efficacy of neuronal maintenance and repair in these diseases and that the seemingly divergent clinical effects are due to the stage of disease at which the diagnosis is made. Early diagnosis facilitates the measurement of effects on disease progression rate, whereas late diagnosis results in a marked effect of APOE genotype on disease onset.

Age of Onset↗

Should we give detailed advice and information booklets to patients with back pain? A randomized controlled factorial trial of a self-management booklet and doctor advice to take exercise for back pain.

STUDY DESIGN: Randomized controlled factorial trial. OBJECTIVE: To assess the effectiveness of a booklet and of physician advice to take regular exercise. SUMMARY OF BACKGROUND DATA: Educational booklets are one of the simplest interventions for back pain but have not been shown to alter pain and function. Although there is evidence that advice to mobilize is effective, doctors have also been advised to encourage regular exercise-but there is no evidence that such advice alone improves outcomes. METHOD: Eight doctors from six practices randomized 311 patients with a new episode of back pain using sealed numbered opaque envelopes to receive a detailed self-management booklet, advice to take regular exercise, both, or neither. All groups were advised to mobilize and to use simple analgesia. Patients were telephoned during the first week after entry into the study, and after 3 weeks to assess a validated numerical pain/function score (0 = no pain normal activities to 100 = extreme pain no normal activities). Patients also returned a postal questionnaire in the first week with the Aberdeen pain and function scale, a knowledge score, and a reliable satisfaction scale (mean score of 4 items: 0 = not satisfied to 100 = extremely satisfied). RESULTS: Pain/function scores were obtained in 239 (77%) patients. There were interactions between exercise and booklet groups for both pain/function scores and the Aberdeen scale, which are unlikely to have been chance findings (P = 0.009 and P = 0.012, respectively). In comparison with the control group, there were reductions in the pain/function score in the first week with a booklet (-8.7, 95% CI -17.4 to -0.03) or advice to exercise (-7.9; -16.7 to 0.8) but much less effect with both together (-0.08, -9.0 to 8.9). Similarly, the Aberdeen scale was lower in the booklet group (-3.8, -7.7 to 0.07) and in the exercise advice group (-5.3; -9.3 to -1.38) but much less with both combined (-1.9, -5.8 to 2.1). There was no significant difference between groups in pain/function scores by week 3, when 58% reported being back to normal. Satisfaction was increased in booklet (7.9, 1.3 to 14.4) and exercise groups (7.4, 0.8 to 13.9)), and a booklet also increased knowledge (Kruskal-Wallis chi2 27.2, P = 0.001). CONCLUSION: Doctors can increase satisfaction and moderately improve functional outcomes in the period immediately after the consultation when back pain is worst, by using very simple interventions: either by endorsing a self-management booklet or by giving advice to take exercise. Previous studies suggest that simple advice and the same written information provide reinforcement. This study supports evidence that it may not be helpful to provide a detailed information booklet and advice together, where the amounts or formats of information differ.

Activities of Daily Living↗

Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis.

APOE epsilon4 allele is associated with poorer outcome in degenerative neurological diseases. Its role in amyotrophic lateral sclerosis (ALS) is still unclear. The aim of the present study was to further analyze the association of APOE epsilon4 allele with progression and survival of ALS. One hundred consecutive ALS patients (53 males) and 133 controls were genotyped for the APOE epsilon4 allele. The association of this allele with survival to death or tracheostomy was analyzed by Kaplan-Meier survival analysis. The frequency of the APOE epsilon4 allele in ALS patients was slightly higher (15.1%) than in the control group (10.9%). Patients with or without an APOE epsilon4 allele had a similar age of onset and frequency of bulbar onset. There was a significant shortening of the 50% probability of survival (by 32 months) in patients carrying the APOE epsilon4 allele (p=0.03). In conclusion, carrying an APOE epsilon4 allele is a poor prognostic factor in ALS. This is compatible with a role of apolipoprotein on neuronal survival and repair.

Adult↗

Double diffraction dissociation at the Fermilab Tevatron collider.

We present results from a measurement of double diffraction dissociation in pp collisions at the Fermilab Tevatron collider. The production cross section for events with a central pseudorapidity gap of width Deltaeta(0)>3 (overlapping eta = 0) is found to be 4.43+/-0.02(stat)+/-1.18(syst) mb [ 3.42+/-0.01(stat)+/-1.09(syst) mb] at square root of (s) = 1800[630] GeV. Our results are compared with previous measurements and with predictions based on Regge theory and factorization.

Journal Article↗

Measurement of d sigma/dM and forward-backward charge asymmetry for high-mass Drell-Yan e(+)e(-) pairs from pp macro collisions at square root of s = 1.8 TeV.

We report on a measurement of the mass dependence of the forward-backward charge asymmetry, A(FB), and production cross section d sigma/dM for e(+)e(-) pairs with mass M(ee)>40 GeV/c(2). The data sample consists of 108 pb(-1) of pp macro collisions at square root of s = 1.8 TeV taken by the Collider Detector at Fermilab during 1992-1995. The measured asymmetry and d sigma/dM are compared with the predictions of the standard model and a model with an extra Z' gauge boson.

Journal Article↗

Measurement of the top quark p(T) distribution.

We have measured the p(T) distribution of top quarks that are pair produced in pp collisions at sqrt[s] = 1.8 TeV using a sample of tt decays in which we observe a single high- p(T) charged lepton, a neutrino, and four or more jets. We use a likelihood technique that corrects for the experimental bias introduced due to event reconstruction and detector resolution effects. The observed distribution is consistent with the standard model prediction. We use these data to place limits on the production of high- p(T) top quarks suggested in some models of anomalous top quark pair production.

Journal Article↗

Quantitative measurements of mouse brain thrombin-like and thrombin inhibition activities.

Thrombin-like enzymatic activity was measured in mouse brain homogenates and slices by cleavage of a peptide substrate, N-p-Tosyl-Gly-Pro-Arg-7-amido-4-methylcoumarin. The activity was localized mainly to white matter. However, it was not affected by specific thrombin inhibitors, and was found to represent the sum of at least two enzyme activities, a prolyl endopeptidase and an aminopeptidase. By specifically inhibiting this endogenous activity in combination with exogenously added thrombin, mouse brain tissue was shown to express a capacity of thrombin inhibitory activity equivalent to 0.2 mU thrombin/mg brain tissue. The present study offers a simple and reliable method for measuring total thrombin inhibitory activity in brain.

Aminopeptidases↗

Rat glutathione S-transferase M4-4: an isoenzyme with unique structural features including a redox-reactive cysteine-115 residue that forms mixed disulphides with glutathione.

Although the existence of the rat glutathione S-transferase (GST) M4 (rGSTM4) gene has been known for some time, the corresponding protein has not as yet been purified from tissue. A recombinant rGSTM4-4 was thus expressed in Escherichia coli from a chemically synthesized rGSTM4 gene. The catalytic efficiency (k(cat)/K(m)) of rGSTM4-4 for the 1-chloro-2,4-dinitrobenzene (CDNB) conjugation reaction was 50-180-fold less than that of the well-characterized homologous rGSTM1-1, and the pH optimum for the same reaction was 8.5 for rGSTM4-4 as opposed to 6.5 for rGSTM1-1. Molecular-modelling studies predict that key substitutions in the helix alpha4 region of rGSTM4-4 account for this pK(a) difference. A notable structural feature of rGSTM4-4 is the Cys-115 residue in place of the Tyr-115 of other Mu-class GSTs. The thiol group of Cys-115 is redox-reactive and readily forms a mixed disulphide even with GSH; the S-glutathiolated form of the enzyme is catalytically active. A mutated rGSTM4-4 (C115Y) had 6-10-fold greater catalytic efficiency than the wild-type rGSTM4-4. Trp-45, a conserved residue among Mu-class GSTs, is essential in rGSTM4-4 for both enzyme activity and binding to glutathione affinity matrices. Antibodies directed against either the unique C-terminal undecapeptide or tridecapeptide of rGSTM4 reacted with rat and mouse liver GSTs to reveal an orthologous mouse GSTM4-4 present at low basal levels but which is inducible in mouse liver. This subclass of rodent Mu GSTs with redox-active Cys-115 residues could have specialized physiological functions in response to oxidative stress.

Amino Acid Sequence↗

Search for neutral supersymmetric Higgs bosons in pp collisions at sqrt[s] = 1.8TeV.

We present the results of a search for neutral Higgs bosons produced in association with b quarks in pp-->bb(phi)-->bbb final states with 91+/-7 pb(-1) of pp collisions at sqrt[s] = 1.8 TeV recorded by the Collider Detector at Fermilab. We find no evidence of such a signal and the data are interpreted in the context of the neutral Higgs sector of the minimal supersymmetric extension of the standard model. With basic parameter choices for the supersymmetric scale and the stop-quark mixing, we derive 95% C.L. lower mass limits for neutral Higgs bosons for tan(beta) values in excess of 35.

Journal Article↗