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Biomedical subjects

D Anderson

Publications and source records attributed to D Anderson.

At least 55 records · Page 3Linked to original sources
PubMed2001

Electromagnetic energy penetration in the self-induced transparency regime of relativistic laser-plasma interactions.

Two qualitatively different scenarios for the penetration of relativistically intense laser radiation into an overdense plasma, accessible by self-induced transparency, are presented. In the first one, penetration of laser energy occurs by solitonlike structures moving into the plasma. This scenario occurs at plasma densities less than approximately 1.5 times the critical one (depending on ion mass). At higher background densities, laser light penetrates only over a finite length which increases with incident intensity. In this regime the plasma-field structures represent alternating electron (and, on longer time scales, ion) layers separated by about half a wavelength of cavitation with concomitant strong charge separation.

Journal Article↗
PubMed2001

Factors that contribute to biomarker responses in humans including a study in individuals taking Vitamin C supplementation.

It is possible in many situations to identify humans exposed to potentially toxic materials in the workplace and in the environment. As in most human studies, there tends to be a high degree of interindividual variability in response to chemical insults. Some non-exposed control individuals exhibit as high a level of damage as some exposed individuals and some of these have levels of damage as low as many of the controls. Thus, it is only the mean values of the groups that can substantiate an exposure-related problem; the data on an individual basis are still of limited use. While human lymphocytes remain the most popular cell type for monitoring purposes, sperm, buccal, nasal, epithelial and placental cells are also used. However, for interpretation of responses, the issue of confounding factors must be addressed. There are endogenous confounding factors, such as age, gender, and genetic make-up and exogenous ones, including lifestyle habits (smoking, drinking, etc.) There are biomarkers of exposure, effect/response and susceptibility and the last may be influenced by the genotype and polymorphism genes existing in a population. From our own studies, confounding effects on cytogenetic damage and ras oncoproteins will be considered in relation to workers exposed to vinyl chloride and petroleum emissions and to volunteers taking Vitamin C supplementation. Smoking history, exposure and duration of employment affected the worker studies. For petroleum emissions, so did gender and season of exposure. For the non-smoking volunteer Vitamin C supplementation study, cholesterol levels, plasma Vitamin C levels, lipid peroxidation products and DNA damage in the Comet assay were also measured. Gender affected differences in Vitamin C levels, antioxidant capacity and the number of chromosome aberrations induced by bleomycin challenge in vitro. The results were the same for both high and low cholesterol subjects. The relationship between biomarkers and the various factors which affect them is complex. Sometimes the variables are not completely independent of each other.

Antioxidants↗
PubMed2001

Expression of GnTIII in a recombinant anti-CD20 CHO production cell line: Expression of antibodies with altered glycoforms leads to an increase in ADCC through higher affinity for FC gamma RIII.

The gene encoding the rat glycosylation enzyme beta1-4-N-acetylglucosaminyltransferase III (GnTIII) was cloned and coexpressed in a recombinant production Chinese hamster ovary (CHO) cell line expressing a chimeric mouse/human anti-CD20 IgG1 antibody. The new cell lines expressed high levels of antibody and have growth kinetics similar to that of the parent. Relative QPCR showed the cell lines to express varying levels of mRNA. High-performance liquid chromatography (HPLC) analysis showed the enzyme to have added bisecting N-acetylglucosamine (GlcNAc) residues in most (48% to 71%) of the N-linked oligosaccharides isolated from antibody preparations purified from the cell lines. In an ADCC assay the new antibody preparations promoted killing of CD20-positive target cells at approximately 10- to 20-fold lower concentrations than the parent. This activity was blocked using an anti-Fc gamma RIII antibody, supporting the role of Fc gamma RIII binding in this increase. In addition, cell binding assays showed the modified antibody bound better to Fc gamma RIII-expressing cells. The increase in ADCC activity is therefore likely due to an increased affinity of the modified antibody for the Fc gamma RIII receptor.

Animals↗
PubMed2001

Multifilament structures in relativistic self-focusing.

A simple model is derived to prove the multifilament structure of relativistic self-focusing with ultraintense lasers. Exact analytical solutions describing the transverse structure of waveguide channels with electron cavitation, for which both the relativistic and ponderomotive nonlinearities are taken into account, are presented.

Journal Article↗
PubMed2001

Coatings.

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Chromatography, Gas↗
PubMed2001

Genetic and reproductive toxicity of butadiene and isoprene.

Butadiene (BD) and its 2-methyl analogue, isoprene, have been extensively studied in animals and BD in population studies. Both chemicals are metabolised by liver cytochrome P450 dependent monogenases to monoepoxide and diepoxide intermediates. The diepoxide intermediates of both compounds were mutagenic in Salmonella typhimurium. However, unlike the monoepoxide of BD, the monoepoxides of isoprene were not mutagenic. It appears that they have no alkylating capacity. BD did not induce somatic cell mutation and recombination or sex-linked recessive lethal mutation in Drosophila melanogaster and isoprene produced no increase in chromosomal aberrations in CHO cells in vitro. Comparative concentrations of haemoglobin adducts in the blood of mice and rats after exposure to BD indicated that reaction with blood may decrease the levels of reactive intermediates available to tissues in rats, but not in mice contributing to greater potency of BD in the mouse. For isoprene, the adducts reach approximately the same concentrations in both species. DNA adducts have also been detected in testicular and lung cells of mice after BD exposure. The level of epoxybutene haemoglobin adducts was significantly elevated in BD-exposed workers, but lower than in rats and mice. In conjunction with the toxicology and carcinogenesis studies for BD and isoprene, additional mice were included for the evaluation of cytogenetic effects. Both chemicals produced increases in sister chromatid exchanges in bone marrow cells and in the frequency of micronuclei in normochromatic and polychromatic erythrocytes, but only BD produced an increase in the percent of bone marrow cells with chromosomal aberrations. At similar doses, the effects with BD were 2-3 times larger than with isoprene. There were also increased hprt mutation frequencies in rats and mice after BD exposure. Biomonitoring studies with hprt mutations in lymphocytes showed conflicting results, with both positive and negative findings. BD has been shown to be positive in one human cytogenetic biomonitoring study and not in three others, but chromosomal aberrations were increased in BD-exposed workers after challenge with gamma rays. Re-analysis of GSTTI null individuals showed positive results. There was an increase in spermatid micronuclei in mice by BD and its metabolites and in rats only by its metabolites. The cytotoxic response of germ cells in mice is greater than in rats. Dominant lethal mutations have been induced by BD and diepoxybutane, but not by epoxybutene. There was some evidence of congenital malformations in mice after BD exposure and there was a linear concentration-related induction of heritable translocations in mice. There was no induction of dominant lethal mutations or congenital malformations in rats. Using the heritable translocation data in mice, it has been determined that if a worker is continually exposed over 5 or 6 weeks to 20-25 ppm of BD, the risk of producing a child with a balanced reciprocal translocation is twice as high as the background risk. Since genetic damage cannot be measured directly in human germ cells, risk to such cells can also be estimated from germ cells and somatic cells of the mouse and human somatic cells using the parallelogram approach. Using doubling doses, the fourth corner of the parallelogram was calculated as a doubling dose for human germ cells of 4390 ppm/h. However, it is still questioned if man is more like rat than mouse in terms of sensitivity to exposure. Similar germ cell data do not exist for isoprene. In conventional developmental studies, where rats and mice were exposed to BD, maternal toxicity was shown in rats but there was no evidence of developmental toxicity or teratogenic effects and there was a small effect on sperm morphology. After exposure to isoprene, there was no adverse effect on rat dams or other reproductive indices. In mice, there was reduced foetal body weight and decreased maternal weight gain and isoprene also affected ovarian follicles. There was a reduction in testicular function parameters such as testicular weight and sperm motility.

Animals↗
PubMed2001

Composition and mass of the bacteriophage phi29 prohead and virion.

The protein composition of the Bacillus subtilis bacteriophage phi29 prohead and virion was determined by combustion of gel bands of (3)H-labeled proteins. Copy numbers of individual proteins were calculated relative to the 12 copies of the head-tail connector protein. The mean numbers of copies of the major capsid protein in the prohead and virion were 241 and 218, respectively, approaching the 235 copies determined previously by cryoelectron microscopy. The mean numbers of copies of the dimeric head fiber on the prohead and virion were 24 and 31, respectively, demonstrating partial occupancy of the 55 fiber binding sites. Measured copies of neck and tail proteins in the virion included 11 of the lower collar, 58 of the appendage, and 9 of the tail; if the true copies of these proteins are 12, 60, and 9, respectively, the entire neck and tail of phi29 has quasi-sixfold symmetry. The mass of the fiberless prohead with pRNA was about 14.2 MDa, and the mass of the prohead determined by scanning transmission electron microscopy was consistent with the biochemical data. The mass of the fiberless virion containing the 12.8-MDa DNA genome was about 30.4 MDa. A full complement of dimeric fibers on the prohead or virion would increase the mass of the particle by about 3.2 MDa. The data complement studies relating the structure of phi29 components to dynamic functions in morphogenesis and infection.

Bacillus Phages↗
PubMed2001

Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy.

PURPOSE: The optimal management of patients who have recurrent thromboembolism while being treated with oral anticoagulation therapy is unknown. This study reports managing such patients with extended duration low molecular weight heparin therapy. SUBJECTS AND METHODS: This study was a retrospective review of the prospective databases of three tertiary care teaching hospitals over a 27-month period. All patients who had recurrent symptomatic thromboembolism while being treated with warfarin were identified. All patients were treated with low molecular weight heparin (dalteparin), 200 U/kg daily. Data were collected for recurrent venous thromboembolism, bleeding, and survival. RESULTS: Eight hundred eighty-seven patients were managed for acute thromboembolism. In 32 patients, symptomatic, objectively documented thromboembolism recurred while they were taking warfarin; 63% of the patients with recurrence had cancer, compared with 30% of patients without recurrence. All recurrences were treated with dalteparin. In 3 patients (9% [95% confidence interval: 2% to 25%]), symptomatic recurrence developed while they were being treated with low molecular weight heparin. Nineteen patients (59%) died while receiving anticoagulation therapy; all deaths but 1 were due to malignancy, and none was due to pulmonary embolism or bleeding. CONCLUSIONS: These results suggest that recurrent venous thromboembolism is more likely to develop in cancer patients while being treated with warfarin and that long-term therapy with low molecular weight heparin may be effective in managing warfarin-failure thromboembolic disease.

Adolescent↗
PubMed2001

Evaluation of the role of RANK and OPG genes in Paget's disease of bone.

Paget's disease of bone (PDB) is one of the most common bone disorders in the western world. PDB is characterized by focal areas of increased osteoclastic bone resorption and bone formation, which leads to the formation of poorly structured bone. These abnormalities of bone turnover and structure predispose affected individuals to various complications including bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. One of the main mechanisms of osteoclast formation and activation involves the receptor activator of nuclear factor -kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway, where binding of RANKL to RANK results in the differentiation of osteoclast precursors. OPG, on the other hand, acts as an inhibitor of osteoclastogenesis by serving as a decoy receptor for RANKL. Recently, mutations in the RANK gene have been shown to cause familial expansile osteolysis, a rare bone disorder showing great similarity to PDB. We performed mutation analysis in the RANK and OPG genes in 28 PDB patients to investigate whether mutations in these genes could be responsible for PDB. Our data suggest that RANK is not directly involved in PDB in our set of patients, as no mutations in the RANK coding region could be identified and allele frequencies of RANK polymorphisms did not differ in PDB patients as compared with the random population. Also, in the OPG gene, we could not detect PDB-causing mutations. However, of the several polymorphisms identified, one (400 + 4 C/T in intron 2), showed a statistically significant increased frequency for the C allele in PDB patients, suggesting that individuals harboring this allele may be more susceptible for developing PDB.

Carrier Proteins↗
PubMed2001

Takayasu disease masquarading as interruption of the aortic arch in a 2-year-old child.

Takayasu disease is a chronic, progressive inflammatory vasculitis of large and medium-sized vessels, which commonly presents in adulthood. This case report describes a 2 year old girl who presented with acute heart failure and complete occlusion of the aortic arch and was subsequently diagnosed with Takayasu disease. As far as we can determine, this is the first report of such an acute and atypical presentation of Takayasu disease at such a young age.

Cardiac Output, Low↗
PubMed2001

Anti-endomysial antibody negative celiac disease: does additional serological testing help?

Anti-endomysium antibodies (AEM) fail to identify all untreated celiac disease (CD) patients. This study aims to determine if additional serology, in particular, IgA anti-tissue transglutaminase (tTG) antibodies, increases detection. Fifty-three biopsy-proven untreated CD patients (39 women, 14 men; median age 51 years) and 65 control patients with normal duodenal histology (46 women, 19 men; age range 17-90 years, median 45 years) were prospectively studied. Serum total IgA, IgA anti-tTG, IgA AEM, IgA anti-gliadin (AGA) and IgG AGA antibodies were measured. Thirteen (25%) CD patients were AEM negative. None were IgA deficient. Three AEM-negative CD patients had a raised IgA anti-tTG and IgA AGA. IgG AGA was raised in 10 AEM-negative CD patients, but also in 14/65 (22%) of controls. In conclusion, AEM-negative CD is common and detection is only modestly enhanced by testing for IgA anti-tTG antibodies. Duodenal biopsy is still recommended for the accurate diagnosis of CD.

Adult↗
PubMed2001

Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin.

BACKGROUND: Quercetin is a naturally occurring flavonoid with many biological activities including inhibition of a number of tyrosine kinases. A phase I, dose-escalation trial of quercetin defined the maximum tolerated dose (MTD) as 1700 mg/m2 three weekly, but the vehicle, dimethyl sulphoxide (DMSO) is unsuitable for further clinical development of quercetin. PATIENTS AND METHODS: A water-soluble, pro-drug of quercetin (3'(N-carboxymethyl)carbomyl-3,4',5,7-tetrahydroxyflavone), QC12 has been synthesised. Six cancer patients received 400 mg of QC12 (equivalent to 298 mg of quercetin), orally on day 1 and intravenously (i.v.) in normal saline on day 14. RESULTS: Following oral administration of QC12 we were unable to detect QC12 or quercetin in plasma. After i.v. administration, we detected peak plasma concentrations of QC12 of 108.7 +/- 41.67 microMolar (microM). A two-compartment model with mean t(1/2)alpha of 0.31 +/- 0.27 hours and mean t(1/2)beta of 0.86 +/- 0.78 hours best described the concentration-time curves for QC12. The mean AUC was 44.54 +/- 13.0 microM.hour and mean volume of distribution (Vd) of 10.0 +/- 6.2 litres (l). Quercetin was found in all patients following i.v. infusion of QC12, with peak levels of quercetin 19.9 +/- 11.8 microM. The relative bioavailability of quercetin was estimated to be 20%-25% quercetin released from QC12. CONCLUSIONS: QC12 is not orally bioavailable. This water-soluble pro-drug warrants further clinical investigation; starting with a formal phase I, IV, dose-escalation study.

Adult↗
PubMed2001

Extracts of Flourensia cernua reduce consumption of alfalfa pellets by sheep.

Effects of three extracts (hexanes, ether, and ethanol) from tarbush (Flourensia cernua) on intake of alfalfa pellets by lambs were examined. Forty-five ewe lambs were fed one of five treatments for five days (randomized complete block, three lambs per block on each treatment). Treatments were alfalfa pellets (CON) or alfalfa pellets plus ethanol carrier (CAR), hexanes extract (HEX), ether extract (ETH), or ethanol extract (ETOH). Extracts were applied to alfalfa pellets at the same concentration as in an equivalent amount of tarbush (as fed basis) in experiment 1 and at 10-fold dilutions of that concentration in experiment 2. Treatments were isolated from tarbush leaves by using a sequential extraction with hexanes, diethyl ether, and 100% ethanol. Lambs received 640 g of alfalfa pellets (dry matter basis) each morning and intake was monitored during a 20-min interval. Lambs were maintained and fed alfalfa pellets (4.7% of body weight) as one group except during this interval. In experiment 1, mean intake by lambs during the 20-min interval was 361, 393, 204, 212, and 228 g for CON, CAR, HEX, ETH, and ETOH, respectively (SEM = 28.9). All three extracts decreased intake (P < 0.001) compared to CON or CAR. Intake did not differ among the three extracts (HEX, ETH, and ETOH) or between the two controls (CON and CAR). Mean intake did not differ among treatments in experiment 2 (468, 455, 389, 381, and 431 g for CON, CAR, HEX, ETH, and ETOH, respectively; SEN = 30.5; P = 0. 187). Several compounds are probably responsible for the low palatability and differential use of tarbush typically exhibited by livestock.

Animal Feed↗
PubMed2001

In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase.

Virus-directed enzyme prodrug therapy (VDEPT) utilising cytosine deaminase (CD) converts 5-fluorocytosine (5-FC) into the chemotherapy agent, 5-fluorouracil (5-FU), and has entered into a clinical trial for metastatic colon cancer. To improve this system, a replication-deficient adenovirus, containing a bifunctional fusion gene, CD:uracil phosphoribosyltransferase (UPRT), was constructed (AdCDUPRT). UPRT enhances the conversion of 5-FU into its active metabolites, which inhibit DNA and RNA synthesis. In vitro, AdCDUPRT infection of colon cancer cells resulted in a marked increase in sensitisation to 5-FU, compared with AdCD-infected or uninfected cells. The corollary is a approximately 100-fold and approximately 10 000-fold increase in sensitisation to 5-FC in AdCDUPRT-infected cells, compared to AdCD-infected and uninfected cells, respectively. There was a strong bystander effect in vitro, 70% of tumour cells were killed by 5-FC when only 10% of cells expressed CDUPRT. In vivo, athymic mice with colon cancer xenografts treated with intratumoral AdCDUPRT and intraperitoneal 5-FC, significantly reduced tumour growth rates compared with untreated controls (P = 0.02), whereas AdCD/5-FC treated mice did not. At higher AdCDUPRT virus doses, 5-FC and 5-FU were equally effective at delaying tumour growth compared with controls. In summary, VDEPT for colon cancer utilising AdCDUPRT is more effective than AdCD and the bifunctional CDUPRT gene enables the use of either 5-FC or 5-FU as prodrugs.

Adenoviridae↗
PubMed2001

PARP determines the mode of cell death in skin fibroblasts, but not keratinocytes, exposed to sulfur mustard.

Sulfur mustard is cytotoxic to dermal fibroblasts as well as epidermal keratinocytes. We demonstrated that poly(ADP-ribose) polymerase (PARP) modulates Fas-mediated apoptosis, and other groups and we have shown that PARP plays a role in the modulation of other types of apoptotic and necrotic cell death. We have now utilized primary dermal fibroblasts, immortalized fibroblasts, and keratinocytes derived from PARP(-/-) mice and their wildtype littermates (PARP(+/+)) to determine the contribution of PARP to sulfur mustard toxicity. Following sulfur mustard exposure, primary skin fibroblasts from PARP-deficient mice demonstrated increased internucleosomal DNA cleavage, caspase-3 processing and activity, and annexin V positivity, compared to those derived from PARP(+/+) animals. Conversely, propidium iodide staining, PARP cleavage patterns, and random DNA fragmentation revealed a dose-dependent increase in necrosis in PARP(+/+) but not PARP(-/-) cells. Using immortalized PARP(-/-) fibroblasts stably transfected with the human PARP cDNA or with empty vector alone, we show that PARP inhibits markers of apoptosis in these cells as well. Finally, primary keratinocytes were derived from newborn PARP(+/+) and PARP(-/-) mice and immortalized with the E6 and E7 genes of human papilloma virus. In contrast to fibroblasts, keratinocytes from both PARP(-/-) and PARP(+/+) mice express markers of apoptosis in response to sulfur mustard exposure. The effects of PARP on the mode of cell death in different skin cell types may determine the severity of vesication in vivo, and thus have implications for the design of PARP inhibitors to reduce sulfur mustard pathology.

Apoptosis↗