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Biomedical subjects

A R Bell

Publications and source records attributed to A R Bell.

16 recordsLinked to original sources
PubMed2006

Effect of target composition on proton energy spectra in ultraintense laser-solid interactions.

We study how the proton density in a target irradiated by an ultraintense laser affects the proton spectrum, with analytical models and Vlasov simulations. A low relative proton density gives rise to peaks in the energy spectrum. Furthermore, a target with the protons confined to a thin, low density layer produces a quasimonoenergetic spectrum. This is a simple technique for producing proton beams with a narrow energy spread for proton radiography of laser-plasma interactions.

Journal Article↗
PubMed2003

Resistive collimation of electron beams in laser-produced plasmas.

Intense relativistic electron beams, produced by high-intensity short-pulse laser irradiation of a solid target, have many potential applications including fusion by fast ignition. Using a unique Fokker-Planck code, supported by analytic calculations, we show that fast electrons can be collimated into a beam even when the fast electron source is not strongly anisotropic, and we derive a condition for collimation to occur.

Journal Article↗
PubMed2003

mRNA and protein expression of dog liver cytochromes P450 in relation to the metabolism of human CYP2C substrates.

1. Interpretation of novel drug exposure and toxicology data from the dog is tempered by our limited molecular and functional knowledge of dog cytochromes P450 (CYPs). The aim was to study the mRNA and protein expression of hepatic dog CYPs in relation to the metabolism of substrates of human CYP, particularly those of the CYP2C subfamily. 2. The rate of 7-hydroxylation of S-warfarin (CYP2C9 in humans) by dog liver microsomes (mean +/- SD from 12 (six male and six female) dogs = 10.8 +/- 1.9 fmol mg(-1) protein min(-1)) was 1.5-2 orders of magnitude lower than that in humans. 3. The rate of 4'-hydroxylation of S-mephenytoin, catalysed in humans by CYP2C19, was also low in dog liver (4.6 +/-1.5 pmol mg(-1) protein min(-1)) compared with human liver. In contrast, the rate of 4'-hydroxylation of the R-enantiomer of mephenytoin by dog liver was much higher. The kinetics of this reaction (range of K(m) or K(0.5) 15-22 micro M, V(max) 35-59 pmol mg(-1) protein min(-1), n = 4 livers) were consistent with the involvement of a single enzyme. 4. In contrast to our findings for S-mephenytoin, dog liver microsomes 5'-hydroxylated omeprazole (also catalysed by CYP2C19 in humans) at considerably higher rates (range of K(m) 42-64 micro M, V(max) 22-46 pmol mg(-1) protein min(-1), n = 4 livers). 5. For all the substrates except omeprazole, a sex difference in their metabolism was observed in the dog (dextromethorphan N-demethylation: female range = 0.7-0.9, male = 0.4-0.8 nmol mg(-1) protein min(-1) (p < 0.02); S-warfarin 7-hydroxylation: female = 9-15.5, male = 8-12 fmol mg(-1) protein min(-1) (p < 0.02); R-mephenytoin 4'-hydroxylation: female = 16-35, male = 11.5-19 pmol mg(-1) protein min(-1) (p < 0.01); omeprazole 5'-hydroxylation: female = 15-20, male 13-22 pmol mg(-1) protein min(-1) (p < 0.2)). 6. All dog livers expressed mRNA and CYP3A12, CYP2B11, CYP2C21 proteins, with no sex differences being found. Expression of CYP2C41 mRNA was undetectable in the livers of six of 11 dogs. 7. Correlation analysis suggested that CYP2B11 catalyses the N-demethylation of dextromethorphan (mediated in humans by CYP3A) and the 4'-hydroxylation of mephenytoin (mediated in humans by CYP2C19) in the dog, and that this enzyme and CYP3A12 contribute to S-warfarin 7-hydroxylation (mediated in humans by CYP2C9). 8. In conclusion, we have identified a distinct pattern of hepatic expression of the CYP2C41 gene in the Alderley Park beagle dog. Furthermore, marked differences in the metabolism of human CYP2C substrates were observed in this dog strain compared with humans with respect to rate of reaction, stereoselectivity and CYP enzyme selectivity.

Algorithms↗
PubMed2002

Nonlocal magnetic-field generation in plasmas without density gradients.

Conventional theories of magnetic-field generation by laser pulses in collisional plasmas require the presence of density gradients or anisotropic pressure. Using the first two-dimensional Fokker-Planck code to self-consistently include magnetic fields, we find that magnetic fields can be spontaneously generated when a collisional plasma is nonuniformly heated even though inverted delta n = 0 and the pressure is purely isotropic. These magnetic fields, which can become strong enough to significantly affect transport, are attributed to nonlocal effects that are missing in the standard, local theories.

Journal Article↗
PubMed2000

Species differences in peroxisome proliferation; mechanisms and relevance.

Peroxisome proliferators are a class of structurally diverse chemicals, which induce liver carcinogenesis in rodents through interaction and activation of the Peroxisome Proliferator-Activated Receptor alpha (PPARalpha). PPARalpha agonists elicit a powerful pleiotropic response, which include hypolipidaemia. We have examined the response of species that are classically unresponsive to peroxisome proliferators. Whereas hamster responds to PPARalpha agonists by hepatomegaly and induction of marker genes, the guinea pig does not undergo hepatomegaly or induction of marker genes, such as CYP4A13. Both the hamster and the guinea pig have PPARalpha, and the guinea pig receptor has been characterised to be fully functional, as demonstrated in reporter gene expression assays. However, the guinea pig PPARalpha is expressed at low levels in liver, and the currently favoured hypothesis to explain species differences in hepatic peroxisome proliferation invokes the low level of PPARalpha as the principal determinant of species responsiveness. However, the demonstration that guinea pigs and humans undergo hypolipidaemia induced by PPARalpha-agonists calls into question the mode of action of PPARalpha agonists in "non-responsive" species.

Animals↗
PubMed1999

Magnetic focusing and trapping of high-intensity laser-generated fast electrons at the rear of solid targets.

The transport of fast electrons generated by a 1 ps, 20 J, 10(19) W cm(-2), 1 microm wavelength laser pulse through 70-250 microm thick deuterated polyethylene (CD2) targets is modeled with a Fokker-Planck hybrid code in r-z geometry. Initially, electric field generation inhibits propagation, which then proceeds by the formation of a low resistivity channel due to Ohmic heating. The magnetic field generated at the edge of the channel leads to strong collimation. This is observed for a wide range of parameters. Reflection of electrons at the rear surface forms a magnetic field which focuses the incident electrons on to the rear surface and forces the reflected electrons outwards. This would lead to the formation of a small diameter plasma on the rear surface, as observed in experiments. The reflected electrons are confined to a cone by a self-generated magnetic field, enhancing energy deposition at the rear of the target.

Journal Article↗
PubMed1998

Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARalpha is functional and mediates peroxisome proliferator-induced hypolipidaemia.

The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor alpha (PPARalpha) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARalpha. The guinea-pig PPARalpha showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P approximately 0.06). The guinea-pig PPARalpha cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARalpha RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARalpha mediated any physiological effects, guinea pigs were exposed to two selective PPARalpha agonists, Wy-14, 643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators.

Amino Acid Sequence↗
PubMed1997

Long-term survival in allogeneic bone marrow transplant recipients following acyclovir prophylaxis for CMV infection. The European Acyclovir for CMV Prophylaxis Study Group.

Recipients of HLA-matched, related or unrelated allogeneic BMT who were CMV seropositive or those receiving unmanipulated marrow from a seropositive donor were randomised to receive one of three treatment regimens, i.v. acyclovir 500 mg/m2 three times a day from 5 days before transplant to 30 days after transplant followed by oral acyclovir 800 mg four times a day for a further 6 months, i.v. acyclovir followed by placebo, or 400 mg oral acyclovir four times a day followed by placebo (control). This paper reports the 1 year data on the same cohort of patients which was previously reported. Intravenous acyclovir (i.v./PCB) significantly reduced the risk of CMV infection when compared to the control group. The frequency of adverse events reported was comparable among the three groups. The mortality rate was significantly reduced by the sequential use of i.v. acyclovir followed by oral acyclovir, resulting in a 19% survival advantage at 1 year from transplant.

Acyclovir↗
PubMed1995

Chromosomal localisation, inducibility, tissue-specific expression and strain differences in three murine peroxisome-proliferator-activated-receptor genes.

Three murine peroxisome-proliferator-activated-receptor (PPAR) genes were localised to chromosome 15 (PPAR alpha), chromosome 17 (PPAR beta) and chromosome 6 (PPAR gamma). The expression of the three PPAR RNAs was determined using a specific RNase protection assay. In liver RNA, PPAR alpha was expressed at the highest level, with 20-fold lower levels of PPAR beta, and very low levels of PPAR gamma. The three PPAR RNAs showed no sex-specific differences in expression, and the levels of these transcripts were unaffected by treatment of mice with testosterone or the potent peroxisome proliferator, methylclofenapate. In agreement with this data, the level of PPAR alpha protein in liver was unchanged after treatment of mice with methylclofenapate. Investigation of the tissue-specific distribution revealed that the PPAR alpha RNA was expressed at highest levels in liver, to moderate levels in kidney and brown adipose tissue, and at low levels elsewhere. PPAR beta was expressed at moderate levels in liver, and lower levels in other tissues, including brown adipose tissue. In contrast, PPAR gamma RNA was expressed at low levels in liver or epididymal white adipose tissue and at very low levels elsewhere, but was expressed at high levels in brown adipose tissue. The tissue distribution of these receptors suggests an important role in lipid metabolism and toxicity for individual members of the PPAR family. The expression of PPAR alpha and PPAR beta RNAs was examined in 13 strains of mice, and the levels of expression varied within a fourfold range. Polymorphism in the size of PPAR alpha RNA from Swiss-Webster mice was detected, and shown to be due to a 2-bp mutation in the 3' non-coding region of PPAR alpha in Swiss Webster mice.

Adipose Tissue, Brown↗
PubMed1994

Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Our aim was to study the prophylactic effect of high-dose intravenous acyclovir given around the time of BMT followed by oral acyclovir on CMV infection and survival. 310 BMT recipients at risk of developing CMV infection were randomised to one of three regimens in a double-blind and double-dummy design: intravenous acylclovir (500 mg/m2, three times a day) for 1 month followed by oral acyclovir (800 mg four times a day for a further 6 months) (intravenous/oral group); intravenous acyclovir followed by oral placebo (intermediate group); or low-dose oral acyclovir (200 or 400 mg, four times a day) followed by placebo ("controls"). Analysis was by intention-to-treat. Intravenous acyclovir significantly reduced the probability of and delayed the onset of CMV infection. There was no further reduction in infection risk with the addition of long-term oral acyclovir. Time to CMV viraemia was delayed in the intravenous/oral acyclovir group compared with controls. Extending the prophylaxis with oral acyclovir significantly improved survival: 79 of 105 recipients were still alive at 7 months compared with 60 of 102 controls (p = 0.012). Although the intravenous/oral acyclovir group did significantly better than controls in terms of survival, the difference between the intravenous/oral acyclovir group and the intermediate group was of borderline statistical significance (p = 0.054). Adverse events that were possibly treatment related were similar in all three groups. The most commonly reported events were nausea, vomiting, elevated creatinine, and renal failure. High-dose intravenous followed by oral acyclovir improved survival and was of benefit in prophylaxis against the effects of CMV after BMT. Interpretation of CMV infection was made difficult because an intermediate treatment (intravenous acyclovir followed by oral placebo) was as effective as high-dose intravenous/oral acyclovir.

Acyclovir↗
PubMed1993

Oral acyclovir to prevent dissemination of varicella in immunocompromised children.

Twenty-five immunocompromised children with varicella were treated with oral acyclovir 800 mg, five times daily for 7 days. Two patients were transferred from the oral to the intravenous route: one had signs of varicella pneumonitis on routine X-ray, the other had continuing new lesion formation on day 4 of oral treatment. The disease healed in all patients, with no other evidence of dissemination. In an historical placebo treated group, 12 of 25 patients were transferred to intravenous acyclovir. The reduction to two of 25 is statistically significant (P < 0.01). The mean peak plasma acyclovir concentration in these patients was 6.56 mumol/l. Mild, self-limiting diarrhoea in nine patients was the only adverse event considered to be related to acyclovir. It is concluded that immunocompromised children with varicella can be treated safely and effectively with oral acyclovir. All patients should be observed closely by a physician.

Acyclovir↗
PubMed1983

Quantitative structure-activity relationships for 2-[(phenylmethyl)sulfonyl]pyridine 1-oxide herbicides.

Phenyl-substituted analogues of 2-[(phenylmethyl)sulfonyl]pyridine 1-oxide preemergent herbicides were examined in order to determine quantitative relationships between structure and activity against the following three weed species: switch grass (Panicum virgatum L.), barnyard grass (Echinochloa crusgalli L. Beauv.), and green foxtail (Setaria viridis L. Beauv.). Analogues were chosen to provide maximum parameter orthogonality. Regression analysis yielded structure-activity relationships wherein the most significant substituent parameters associated with herbicidal activity were found to be the partition coefficient (pi), the molar refractivity (MR), and two indicator variables, Z (denoting the presence of an alpha-methyl group) and H (denoting an ortho substituent capable of hydrogen bonding). For green foxtail, the structure-activity relationship was found to be: -log ED50 = 0.43 pi -0.052MR + 0.50H + 0.24Z + 0.61, where ED50 is expressed in moles per acre. The regression equations were found to explain 79-93% of the bioactivity for the three weed species studied. It was further shown that these equations represent the best possible correlations within the limitations of the biological data.

Cyclic N-Oxides↗