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Biomedical subjects

D Hudson

Publications and source records attributed to D Hudson.

At least 19 recordsLinked to original sources
PubMed2003

Multidipole analysis of simulated epileptic spikes with real background activity.

This simulated magnetoencephalographic study was designed to determine the variability in source parameters with real subject background activity when applying multidipole spatial-temporal dipole analyses, for which the correct model was compared with undermodeled and overmodeled cases. The simulated sources were created from patches of the cortical surface of each subject's MRI. One- and two-source frontal lobe spikes were generated in two cortical regions seen commonly in frontal lobe epilepsy patients tested at our site (orbital frontal and premotor cortex). In general, the modeling results were adequate for the correct model order and the correct model order plus one. In addition, if the localization error was less than 10 mm from the simulated source, the peak latency of the spike and orientation were very reliable, but the peak amplitude was not. The additional source in the overmodeled condition, on the other hand, was not localized reliably across the different epochs within subjects. The results suggest that consistency of the spike localization and inconsistency of other sources will allow one to determine reliably the appropriate model order in real data, and therefore determine single and multifocal spike generators.

Action Potentials↗
PubMed2002

Predictions of extreme precipitation and sea-level rise under climate change.

Two aspects of global climate change are particularly relevant to river and coastal flooding: changes in extreme precipitation and changes in sea level. In this paper we summarize the relevant findings of the IPCC Third Assessment Report and illustrate some of the common results found by the current generation of coupled atmosphere-ocean general circulation models (AOGCMs), using the Hadley Centre models. Projections of changes in extreme precipitation, sea-level rise and storm surges affecting the UK will be shown from the Hadley Centre regional models and the Proudman Oceanographic Laboratory storm-surge model. A common finding from AOGCMs is that in a warmer climate the intensity of precipitation will increase due to a more intense hydrological cycle. This leads to reduced return periods (i.e. more frequent occurrences) of extreme precipitation in many locations. The Hadley Centre regional model simulates reduced return periods of extreme precipitation in a number of flood-sensitive areas of the UK. In addition, simulated changes in storminess and a rise in average sea level around the UK lead to reduced return periods of extreme high coastal water events. The confidence in all these results is limited by poor spatial resolution in global coupled models and by uncertainties in the physical processes in both global and regional models, and is specific to the climate change scenario used.

Altitude↗
PubMed2000

Paralysis of the marginal mandibular branch of the facial nerve: treatment options.

Isolated paralysis of the marginal mandibular branch of the facial nerve results in an asymmetrical smile with elevation of the lower lip on the affected side. We discuss the surgical options for its correction and present a series of 26 patients who underwent either botulinum toxin injection, anterior belly of digastric transfer or free extensor digitorum brevis transfer as treatment. Botulinum toxin injection provided satisfactory results although these were temporary. Anterior belly of digastric transfer was the surgical procedure of choice. It yielded superior cosmetic results, less donor-site morbidity and required a shorter operating time. In more complex congenital facial hypoplastic syndromes, or following extensive surgery in the digastric triangle, the anterior belly of the digastric muscle may be absent or damaged. Extensor digitorum brevis transfer is the preferred option in these cases.

Adolescent↗
PubMed1999

Isolation and characterization of human monoclonal antibodies to digoxin.

Fab preparations of sheep polyclonal anti-digoxin Abs have proven useful for reversal of the toxic effects of digoxin overdoses in patients. Unfortunately, the use of foreign species proteins in humans is limited because of the potential for immunological responses that include hypersensitivity reactions and acute anaphylaxis. Immunization of recently developed transgenic mice, whose endogenous micro heavy and kappa light chain Ig genes are inactivated and which carry human Ig gene segments, with a digoxin-protein conjugate has enabled us to generate and isolate eight hybridoma cell lines secreting human sequence anti-digoxin mAbs. Six of the mAbs have been partially characterized and shown to have high specificity and low nanomolar affinities for digoxin. In addition, detailed competition binding studies performed with three of these mAbs have shown them to have distinct differences in their digoxin binding, and that all three structural moieties of the drug, the primary digitoxose sugar, steroid, and five-member unsaturated lactone ring, contribute to Ab recognition.

Animals↗
PubMed1999

A phosphate bound universal linker for DNA synthesis.

A uridine-based linker immobilized onto polystyrene beads at the 5' terminus via a phosphodiester group and then used as a universal DNA synthesis support gives post synthesis DNA cleavage in 8 hrs or less without alkali metal salts. DNA produced with the new support was analyzed by HPLC, MALDI mass spectroscopy and PAGE. Each analysis showed DNA of equivalent quality to that produced with standard CPG supports, without contaminating materials resulting from linker or support backbone decomposition.

Chromatography, High Pressure Liquid↗
PubMed1996

A new universal linker for solid phase DNA synthesis.

A method is described as an alternative to the use of nucleoside pre-functionalized supports for DNA synthesis. The procedure should allow the generation of 3'-OH terminal moieties of any natural or modified DNA fragment using a single derivatized solid support material. The method utilizes 1-O-(4,4' dimethoxytrityl)-2- O-succinoyl-3-N-allyloxycarbonylpropane immobilized on amino-propyl CPG followed by subsequent coupling of unit phosphoramidites. Work up is accomplished by removal of the 3-N-allyloxycarbonyl group [Pd(0) at 50 degrees C for 15 min] followed by cleavage under very mild conditions (aqueous TEAA/NH3 buffer pH 10, room temperature) to release the desired product. The mechanism is believed to involve nucleophilic attack of the linker-derived amino group on the 3'-phosphate triester, followed by elimination of the desired product. DNA synthesis with the new support and with classical nucleotide synthesis supports have been performed, and the products shown to be identical. Further proof of product integrity was given by MALDI mass spectral studies and the efficacy of DNA primers made with the new support in PCR amplification.

Allyl Compounds↗
PubMed1994

A humanized antibody specific for the platelet integrin gpIIb/IIIa.

C4G1, a murine mAb reactive with the platelet gpIIb/IIIa integrin, was humanized for potential treatment of thrombosis-related disorders. The variable regions of light- and heavy-chain cDNAs from the C4G1 hybridoma were first cloned and sequenced. Humanized C4G1 Ab of the IgG1 isotype was constructed by combining the complementarity-determining regions of C4G1 with human framework and constant regions. The human framework was chosen to maximize homology with the C4G1 variable region sequence, and a computer model of C4G1 was used to aid design of the final framework sequence. Genetic constructs were also developed to produce Fab and F(ab')2 fragments of the humanized C4G1 Ab. The humanized IgG1 Ab as well as the Fab and F(ab')2 fragments showed equivalent binding affinities to their murine counterparts, indicating no loss in binding affinity during the humanization process. The humanized Ab and its fragments were also shown to inhibit platelet aggregation and to inhibit binding of fibrinogen to gpIIb/IIIa in vitro.

Amino Acid Sequence↗
PubMed1994

Cytotoxicity of recombinant Fab and Fv immunotoxins on adult T-cell leukemia lymph node and blood cells in the presence of soluble interleukin-2 receptor.

Single-chain immunotoxins anti-Tac(Fv)-PE40 and anti-Tac(Fv)-PE40KDEL, composed of variable domains of the anti-Tac monoclonal antibody and truncated forms of Pseudomonas exotoxin, have shown potent cytotoxic activity against malignant peripheral blood mononuclear cells (PBMCs) from adult T-cell leukemia (ATL) patients originating from the Caribbean. However, several clinically important issues have not previously been addressed. These include the potential of soluble interleukin 2 receptor in ATL patients to block immunotoxin effectiveness, the relative sensitivity of malignant lymph node cells (LNCs) versus PBMCs, the effect of an immunotoxin with a prolonged half-life, and finally whether ATL cells from patients in Japan have toxin sensitivity equal to those of the Caribbean patients. To resolve these questions, we studied 32 malignant PBMC and LNC samples from 30 ATL patients from Japan. PBMCs from 27 of 27 patients were very sensitive with 50% inhibition of protein synthesis achieved with 0.02-0.85 ng/ml (0.3-13 pM) of anti-Tac(Fv)-PE40KDEL or anti-Tac(Fv)-PE40. LNCs had sensitivity very similar to that of PBMCs in the five patients tested. The fully recombinant immunotoxin, anti-Tac(Fab)-PE40, which has 8-10 times the t1/2 alpha and beta compared to the Fv-immunotoxins, was also very cytotoxic toward cells from 27 of 27 patients tested with 50% inhibition of protein synthesis of 0.08-25 ng/ml. It was found that purified soluble interleukin 2 receptor added to the cytotoxicity assay decreased the cytotoxic activity of anti-Tac(Fv)-PE40KDEL or anti-Tac(Fab)-PE40, but that 1 x 10(4) units/ml or less had minimal competitive effects. It was found that ATL patients who have responded even incompletely to conventional chemotherapy have soluble interleukin 2 receptor levels lower than this at posttreatment. We conclude that recombinant immunotoxins containing anti-Tac(Fv) are effective against Japanese ATL PBMCs or LNCs and might be most effective if used in vivo after conventional chemotherapy. If it is found in humans that the effectiveness of single-chain recombinant toxins is limited by short half-life, anti-Tac(Fab)-PE40 should be considered as an alternative agent.

ADP Ribose Transferases↗
PubMed1993

RNA recognition by an isolated alpha helix.

A 17 amino acid peptide containing the arginine-rich region of the HIV Rev protein binds specifically to Rev response element (RRE) RNA. Even though it is highly charged, the peptide forms an alpha helix in solution, but only when its N- and C-termini are modified to provide favorable electrostatic interactions with the helix macrodipole. Binding affinity for IIB RNA (the primary binding site within the RRE) increases with alpha helix content, whereas nonspecific binding affinity is independent of helix content. Binding of mutant peptides demonstrates that one threonine, one asparagine, and four arginine side chains are important for sequence-specific recognition. Transactivation of the HIV LTR using Tat-Rev peptide hybrids and the RRE IIB site indicates that the peptide adopts an alpha-helical conformation in vivo. The results suggest that interactions with the RNA backbone may help to orient the alpha helix in the major groove of RNA.

Amino Acid Sequence↗
PubMed1992

Development of a monoclonal antibody to the conserved region of p34cdc2 protein kinase.

Mice and rabbits were injected with various forms of a 16 amino acid synthetic peptide representing PSTAIR, the evolutionarily conserved region of the protein kinase p34cdc2, for polyclonal antisera and hybridoma-monoclonal antibody production. Antisera from mice injected with an unconjugated monomeric form of the peptide showed no reaction to the peptide. Of four animals injected with the monomeric form of the peptide conjugated to keyhole limpet hemocyanin via m-maleimidobenzoyl-N-hydroxysulfosuccinimide (MBS), antisera from only one mouse had a very low titer to the peptide, and all four animals produced antibody to the MBS bridge. Both mice injected with an octameric multiple antigen peptide (MAP) of PSTAIR produced antisera reactive to the octameric MAP form of the peptide in ELISA and also to the cdc2 protein expressed in bacteria in an immunoblotting assay. Splenocytes from one mouse injected with the octameric MAP form of the peptide were successfully used for hybridoma-monoclonal antibody production. A monoclonal antibody was produced that reacted with octamer, monomer and cdc2-expressed protein and specifically with the carboxyl terminus of the 16 amino acid peptide.

Amino Acid Sequence↗
PubMed1991

Arginine-mediated RNA recognition: the arginine fork.

Short peptides that contain the basic region of the HIV-1 Tat protein bind specifically to a bulged region in TAR RNA. A peptide that contained nine arginines (R9) also bound specifically to TAR, and a mutant Tat protein that contained R9 was fully active for transactivation. In contrast, a peptide that contained nine lysines (K9) bound TAR poorly and the corresponding protein gave only marginal activity. By starting with the K9 mutant and replacing lysine residues with arginines, a single arginine was identified that is required for specific binding and transactivation. Ethylation interference experiments suggest that this arginine contacts two adjacent phosphates at the RNA bulge. Model building suggests that the arginine eta nitrogens and the epsilon nitrogen can form specific networks of hydrogen bonds with adjacent pairs of phosphates and that these arrangements are likely to occur near RNA loops and bulges and not within double-stranded A-form RNA. Thus, arginine side chains may be commonly used to recognize specific RNA structures.

Amino Acid Sequence↗
PubMed1991

Blocking of the receptor-mediated invasion of erythrocytes by Plasmodium knowlesi malaria with sulfated polysaccharides and glycosaminoglycans.

Invasion of human erythrocytes by Plasmodium knowlesi requires the Duffy blood group antigen. P. knowlesi merozoites synthesize a 135-kDa polypeptide which binds to the Duffy antigen with receptor-like specificity. In this study, we show that the sulfated polysaccharide fucoidan and the glycosaminoglycan dextran sulfate inhibit the binding of the 135-kDa polypeptide to human Duffy-positive and rhesus erythrocytes while the chondroitin sulfates do not. Fucoidan and dextran sulphate also blocked the in vitro invasion of human Duffy b and rhesus erythrocytes cells by P. knowlesi merozoites. These inhibitors were more effective at blocking the binding of the 135-kDa polypeptide to human Duffy b erythrocytes than to rhesus erythrocytes, which correlated with them having a greater inhibitory effect on invasion of merozoites into human than into rhesus erythrocytes. The blocking by these sulfated sugars is not related to charge density on the polysaccharides; fucoidan with a relatively low charge density blocks binding of the 135-kDa polypeptide at 4 micrograms/ml, while the highly negatively charged chondroitin sulfates do not block binding even at the concentration of 1 mg/ml. Furthermore, fucoidan-Sepharose bound and removed the 135-kDa polypeptide from parasite culture supernatants with a selectivity equal to that of the Duffy blood group antigen. The negatively charged sulfate groups on fucoidan and dextran sulfate and the conformation in which they are held possibly mimic similarly charged groups on the Duffy antigen which bind the 135-kDa P. knowlesi polypeptide.

Animals↗