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Biomedical subjects

R Dixon

Publications and source records attributed to R Dixon.

At least 37 records · Page 2Linked to original sources
PubMed2000

Signal transduction to the Azotobacter vinelandii NIFL-NIFA regulatory system is influenced directly by interaction with 2-oxoglutarate and the PII regulatory protein.

PII-like signal transduction proteins, which respond to the nitrogen status via covalent modification and signal the carbon status through the binding of 2-oxoglutarate, have been implicated in the regulation of nitrogen fixation in several diazotrophs. The NIFL-NIFA two-component regulatory system, which integrates metabolic signals to fine-tune regulation of nitrogenase synthesis in Azotobacter vinelandii, is a potential target for PII-mediated signal transduction. Here we demonstrate that the inhibitory activity of the A.vinelandii NIFL protein is stimulated by interaction with the non-uridylylated form of PII-like regulatory proteins. We also observe that the NIFL-NIFA system is directly responsive to 2-oxoglutarate. We propose that the PII protein signals the nitrogen status by interaction with the NIFL-NIFA system under conditions of nitrogen excess, and that the inhibitory activity of NIFL is relieved by elevated levels of 2-oxoglutarate when PII is uridylylated under conditions of nitrogen limitation. Our observations suggest a model for signal transduction to the NIFL-NIFA system in response to carbon and nitrogen status which is clearly distinct from that suggested from studies on other diazotrophs.

Adenine Nucleotides↗
PubMed2000

Responses of cloned rainbow trout Oncorhynchus mykiss to an attenuated strain of infectious hematopoietic necrosis virus.

The objective of this work was to examine the response of homozygous clones of rainbow trout to vaccination by an attenuated strain (Nan Scott Lake; NSL) of infectious hematopoietic necrosis virus (IHNV). Adult rainbow trout of the Hot Creek Strain (YY males maintained in a recirculating system at 12 degrees C) were injected 3 times with 10(5) to 10(7) plaque forming units (pfu) of NSL. Intraperitoneal injections were given at Day 0 and at 2 and 4 mo post-infection. All fish were nonlethally bled at monthly intervals for 18 mo. Serum from each fish was analyzed by the complement-dependent neutralization assay and by western blot against purified NSL virus. The highest virus neutralization titers were detected 4 mo after the first injection, and peaked at 1280. When sera were analyzed by western blot, the predominating responses of the serum from immunized fish on the reduced western blot were against M1, a matrix protein of the virus and to a 90 kDa stress protein. The 90 kDa protein was identified by a monoclonal antibody as a stress protein derived from the CHSE-214 cells in which the purified IHN virus was grown and which associates with the virus during purification.

Animals↗
PubMed2000

Exclusion limits on the WIMP-nucleon cross section from the cryogenic dark matter search.

The Cryogenic Dark Matter Search (CDMS) employs Ge and Si detectors to search for weakly interacting massive particles (WIMPs) via their elastic-scattering interactions with nuclei while discriminating against interactions of background particles. CDMS data, accounting for the neutron background, give limits on the spin-independent WIMP-nucleon elastic-scattering cross section that exclude unexplored parameter space above 10 GeV/c2 WIMP mass and, at >75% C.L., the entire 3sigma allowed region for the WIMP signal reported by the DAMA experiment.

Journal Article↗
PubMed2000

Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance.

OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

The neurotoxicity of the venom phospholipases A(2), notexin and taipoxin.

The presynaptically active, toxic phospholipases known as notexin and taipoxin are principal components of the venom of the Australian tiger snake and the Australian taipan respectively. The inoculation of the toxins into one hind limb of rats caused, within 1 h, the depletion of transmitter from the motor nerve terminals of the soleus muscle. This was followed by the degeneration of the motor nerve terminals and of the axonal cytoskeleton. By 24 h 70% of muscle fibers were completely denervated. Regeneration and functional reinnervation were almost fully restored by 5 days, but collateral innervation was common in the regenerated muscles, and this abnormality persisted for at least 9 months. The data provide an explanation for both the severity of neuromuscular paralysis that can accompany envenoming bites by tiger snakes and taipans and the difficulty experienced by physicians in managing the envenomed subjects.

Acetylcholinesterase↗
PubMed2000

Cultural identity and psychological adjustment of adolescent Chinese immigrants in New Zealand.

Based on an integration of acculturation and developmental models, this study examined the relationship between psychological adjustment and cultural identity determined by the relative strength of identification with own ethnic group, and the mainstream society. Over 400 immigrant Chinese students completed questionnaires and 24 participated in interviews. Results indicated that adolescents who were integrated had higher self-esteem than their peers who were separated or marginalized p<0.001). This finding is consistent with research on ethnic minority adolescents in other countries, and suggests that integration has important implications on the psychological well-being of these adolescent immigrants.

Acculturation↗
PubMed2000

Albumin stimulates p44/p42 extracellular-signal-regulated mitogen-activated protein kinase in opossum kidney proximal tubular cells.

The presence of protein in the urine of patients with renal disease is an adverse prognostic feature. It has therefore been suggested that proteinuria per se may be responsible for the development of renal tubulo-interstitial scarring and fibrosis, and disturbances in tubular cell growth and proliferation. We have used the opossum kidney proximal tubular cell line to investigate the effects of albumin on cell growth. The effect of albumin on cell proliferation was investigated by cell counting and measurement of [(3)H]thymidine incorporation. We studied the effect of recombinant human albumin on the activity of p44/p42 extracellular-signal-regulated mitogen-activated protein kinase (MAP kinase ) using an in vitro kinase assay, and immunoblotting with antibodies against active extracellular-signal-regulated kinase (ERK). The effects of the ERK inhibitor PD98059 were also examined. Recombinant human albumin was found to stimulate proliferation of opossum kidney cells in a dose-dependent manner, with maximal stimulation at a concentration of 1 mg/ml. In addition, recombinant human albumin activated ERK in a time-dependent (maximal after 5 min) and dose-dependent (maximal at 1 mg/ml) fashion. These effects on cell proliferation and ERK activity were inhibited by PD98059, and were not reproduced by ovalbumin or mannitol. The data therefore indicate that albumin is able to stimulate growth and proliferation of proximal tubular cells that is dependent on the ERK family of MAP kinases. The potential importance of this pathway in the development of renal disease is discussed.

Animals↗
PubMed2000

Is there a learning curve in diagnosing urolithiasis with noncontrast helical computed tomography?

OBJECTIVE: To report one department's experience with helical computed tomographic (HCT) evaluation of patients with suspected renal colic to diagnose ureteral calculi; to determine whether there is a learning curve in performing HCT in this context; and to determine whether HCT for the evaluation of renal colic exposes patients to more radiation than the standard intravenous pyelography (IVP) combined with nephrotomography. METHODS: All patients presenting to the emergency department with flank or abdominal pain were evaluated with nonreformatted noncontrast HCT. To determine changes in diagnostic accuracy, patients were divided into 2 groups: those evaluated between September 1996 and January 1997 (group 1, 67 patients), and those seen from February to June 1997 (group 2, 53 patients). A radiation exposure study was performed using phantoms, and radiation exposure for HCT, IVP and nephrotomography was measured. RESULTS: Review of HCT scans to diagnose ureteral calculi had a sensitivity of 91.7%, specificity of 82.6%, and accuracy of 87.2% in group 1, and a sensitivity of 95.5%, specificity of 86.7%, and accuracy of 91.9% in group 2. Patients undergoing IVP with nephrotomography were exposed to an effective dose equivalent of 343 mrem (dSv) (for men) and 664 mrem (for women). The effective dose equivalent for an HCT scan was 180 mrem. CONCLUSION: HCT offers excellent, rapid diagnostic accuracy without the need for intravenous contrast medium and with a lower radiation exposure level than IVP in evaluating patients with acute flank pain. There is a small but real learning curve in evaluating patients with acute flank pain with HCT.

Adolescent↗
PubMed1999

The upstream region of the nodD3 gene of Sinorhizobium meliloti carries enhancer sequences for the transcriptional activator NtrC.

In Sinorhizobium meliloti the expression of the nodulation genes nodABC is regulated in response to the level of fixed nitrogen (ammonia). Previous results suggested that the response to the nitrogen status is mediated by the two-component NtrB/NtrC system which controls transcription of the nodD3 gene, encoding a positive regulatory protein for the activation of nodABC transcription. Here we confirm by DNase I footprinting and gel shift assays that NtrC, when phosphorylated by NtrB, is able to interact with the enhancer sequences present upstream of nodD3. A model is proposed whereby NtrC functions to control the transcription from the two promoters in the upstream region of nodD3 in response to nitrogen status.

Bacterial Proteins↗
PubMed1999

Comparison of the kinetics of the specific cellular immune response to duck hepatitis B virus in infected and immune ducks.

The kinetics of the cell mediated immune response by ducks acutely and chronically infected with, or immune to infection by duck hepatitis B virus (DHBV) was determined. This was measured by an antigen specific blastogenesis assay to duck hepatitis B surface antigen (DHBsAg) and duck hepatitis B core antigen (DHBcAg) using peripheral blood mononuclear cells (PBMC). The three outcomes of acute infection by DHBV were either clearance from both serum and liver, clearance from serum but not liver, or the development of persistent viraemia. Acutely infected ducks that failed to clear the infection also failed to develop a significant cellular immune response to both antigens. Ducks with chronic infection acquired as neonates or as the result of the failure to clear acute infection had an increasing cellular immune response over time. Two groups of immune ducks were examined. These were either ducks that had become immune following infection or that had been vaccinated. Both groups of ducks demonstrated significant cellular responses following challenge with DHBV irrespective of the level of their responses before challenge. However, there was a reduction in the response of their PBMC over a 4-week-period postchallenge. The range of cellular immune responses to DHBV antigens observed in this study has a number of counterparts in hepatitis B infection of humans. Coupled with the defined clinical outcomes that can be established in the duck/DHBV model, further study of the cellular immune response to DHBV is warranted.

Animals↗
PubMed1999

Ranking ligand binding affinities with avidin: a molecular dynamics-based interaction energy study.

The binding of 14 biotin analogues to avidin is examined to evaluate the viability of calculating binding free energy based on molecular dynamics (MD) trajectories. Two approaches were investigated in this work. The first one uses the linear interaction energy approximation, while the other approach utilizes the interaction free energy. The results obtained from these two methods were found to correlate well with the experimental binding free energy data for 10 out of 14 ligands. For the other four ligands, both methods overestimate their binding strength by more than 7 kcal/mol. Free energy calculations using the thermodynamic integration method are employed to understand this overestimation. The effect of protein flexibility on binding free energy calculation and the effect of charged or neutral ligands on the calculated results are discussed. MD simulations are shown to be able to provide insight into the interactions occurring in the active site and the origins of variations in binding free energy.

Avidin↗
PubMed1999

Effects of zolmitriptan (Zomig) on central serotonergic neurotransmission as assessed by active oddball auditory event-related potentials in volunteers without migraine.

In this randomized, double-blind, three-period crossover trial, 24 healthy volunteers without migraine received zolmitriptan 5 mg, dexfenfluramine 15 mg or placebo orally. At 2, 6, and 24 h postdose, auditory stimuli of 1000 Hz (nontarget tone) and 2000 Hz (target tone) were randomly and binaurally presented in an active oddball paradigm (4:1 ratio). Cortical auditory evoked responses were recorded for 500 msec poststimulus. Plasma concentrations of zolmitriptan and a 17-lead quantitative EEG were assessed at the same timepoints. Relative to placebo, zolmitriptan reduced the maximum absolute amplitude, amplitude difference (from nontarget tone noise) and area under the curve of the cortical auditory target tone event-related potential (P300 ERP). The most dramatic effect of zolmitriptan was to diminish the point estimate of noise during the 200-400 msec poststimulus epoch. The effect of zolmitriptan appeared concentration dependent. The latency of the P300 ERP was unaffected by zolmitriptan and there was no clinically significant effect on the EEG. Modification by zolmitriptan of the cortical electrical activity evoked by auditory stimuli confirms a central action of this drug in humans, which appears to affect cortical information processing without global alteration of the quantitative EEG.

Acoustic Stimulation↗
PubMed1999

A comparison of the pharmacokinetics and tolerability of the novel antimigraine compound zolmitriptan in adolescents and adults.

This open-label, parallel-group study assessed pharmacokinetics and tolerability of zolmitriptan, a 5-HT1B/1D agonist for the acute treatment of migraine, and its active metabolite, 183C91, in adolescents compared with adults. Twenty-one healthy adolescent and 18 healthy adult volunteers (with and without history of migraine) received a single 5-mg dose of zolmitriptan. Mean ages were 14.5 years (range 12-17) for adolescents (13 girls, 8 boys) and 39.1 years (range 18-65) for adults (12 women, 6 men). The area under the curve (AUC) and highest observed plasma concentration (Cmax) of zolmitriptan were similar in both age groups; the half-life was 3.01 hours in adolescents versus 3.75 hours in adults. The AUC and Cmax of 183C91, however, were 36% and 39% higher in adolescents, respectively; the half-life was similar in both age groups. Adverse events were similar in both groups in terms of nature, intensity, and frequency. Exposure to zolmitriptan was not significantly different in adolescents compared with adults, but a shorter half-life in adolescents suggests faster elimination in this age group. Exposure to 183C91 was higher in adolescents, suggesting that formation of the metabolite is at least one of the elimination routes of zolmitriptan that occurs at a faster rate in adolescents.

Adolescent↗
PubMed1999

Progress of quality-associated costing: extension to platelet transfusion practice and the manufacturing scope for plasma proteins.

Realistic estimates about the potential misallocation of health service resources, in relation to the cost-beneficial use of blood products, is enabled by tracing manufacturing costs, through product specification elements to corresponding post-transfusion outcomes. This quality-associated costing (QAC) philosophy is completed in this article by understanding the issues that surround the manufacture of platelets, and by its comparison with the generally used but arbitrary methods for blood product costing. Without QAC, cost-beneficial platelet therapy will not be realized, due to an estimated Western underfunding of approximately one quarter of a billion pounds per annum by arbitrary methods. A reciprocal consequence of such platelet QAC is a significant reduction in the currently perceived cost of source plasma. Western estimates, based upon this, demonstrate that the not-for-profit fractionation of source plasma into purified proteins is probably underfunded by approximately one fifth of a billion pounds per annum through the use of arbitrary costing methods.

Blood Banks↗
PubMed1999

Isolation and properties of the complex between the enhancer binding protein NIFA and the sensor NIFL.

In Azotobacter vinelandii, activation of nif gene expression by the transcriptional regulatory enhancer binding protein NIFA is controlled by the sensor protein NIFL in response to changes in levels of oxygen and fixed nitrogen in vivo. NIFL is a novel redox-sensing flavoprotein which is also responsive to adenosine nucleotides in vitro. Inhibition of NIFA activity by NIFL requires stoichiometric amounts of the two proteins, implying that the mechanism of inhibition is by direct protein-protein interaction rather than by catalytic modification of the NIFA protein. The formation of the inhibitory complex between NIFL and NIFA may be regulated by the intracellular ATP/ADP ratio. We show that adenosine nucleotides promote complex formation between purified NIFA and NIFL in vitro, allowing isolation of the NIFL-NIFA complex. The complex can also be isolated from cell extracts containing coexpressed NIFL and NIFA in the presence of MgADP. Removal of the nucleotide causes dissociation of the complex. Experiments with truncated proteins demonstrate that the amino-terminal domain of NIFA and the C-terminal region of NIFL potentiate the ADP-dependent stimulation of NIFL-NIFA complex formation.

Adenosine Diphosphate↗
PubMed1999

Activation of mitogenic pathways by albumin in kidney proximal tubule epithelial cells: implications for the pathophysiology of proteinuric states.

Albumin is filtered into the proximal tubule in large quantities in nephrotic states. It has been proposed that this protein may have a toxic effect on tubular epithelial cells and may be responsible for the initiation of interstitial inflammation and scarring. The mitogenic effect of recombinant human albumin in wild-type opossum kidney cells and in similar cells transfected with a dominant negative p85 subunit (deltap85) of phopshatidylinositide 3-kinase (PI 3-kinase) has been studied. This study demonstrates that recombinant human albumin stimulates proliferation of opossum kidney cells in culture. This effect is mediated via PI 3-kinase, and is inhibited by wortmannin and deltap85 expression. Albumin stimulates PI 3-kinase activity in opossum kidney cells as determined by three different experimental procedures. Recombinant albumin also stimulates pp70(s6) kinase activity in a kinase cascade downstream of PI 3-kinase. Activity of pp70(s6) kinase is essential for albumin-induced proliferation of opossum kidney cells. It is proposed that this mitogenic pathway may have a critical role in proximal tubular homeostasis and pathophysiology of proteinuric states.

Albumins↗
PubMed1999

Cellular immune response of ducks to duck hepatitis B virus infection.

Duck hepatitis B virus (DHBV) has been a useful model for hepadnavirus infection. There have been few studies on immunity to DHBV and none describing the cell-mediated immune response by acute and chronically infected ducks. A duck hepatitis B antigen-specific blastogenesis assay was used to measure DHBV antigen-specific responses of duck peripheral blood (PBMC) and splenic mononuclear cells (SMCs) from uninfected control ducks, ducks acutely or chronically infected with DHBV, and ducks immune to DHBV. A comparison of the group mean responses by PBMC to DHBV surface antigen (DHBsAg) found that the immune group was significantly different to the other three groups (controls or unexposed, P < 0.0001; acutely infected, P< 0.01; chronically infected, P < 0.01). The responses to DHBsAg by PBMC of the acute group (P< 0.01) were significantly different also to that of the unexposed group. For DHBV core antigen (DHBcAg), significant differences in the responses were found between immune ducks and unexposed (P < 0.0005) and acutely infected (P < 0.05) groups. The SMC showed a significant difference between unexposed ducks and immune ducks (P< 0.05) in the group mean responses to DHBsAg. The responses to DHBcAg were significantly different between the immune group and the acute (P < 0.01) and unexposed (P < 0.01) groups. The group mean of unexposed ducks was also significantly different to that of acutely infected ducks (P < 0.01). This study indicates that the cellular immune response in immune animals differs from acutely and chronically infected ducks. Further studies of these differences may provide some explanations for the differing outcomes of DHBV infection.

Acute Disease↗