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Biomedical subjects

W Martin

Publications and source records attributed to W Martin.

At least 73 records · Page 4Linked to original sources
PubMed2000

Evaluation of four blood pump geometries: the optical tracer technique.

Artificial blood pump assistance of the failing human heart can allow it to recover. Analysis of blood pump fluid flow is a useful tool for design development and thrombosis minimization. The aim of this study was to investigate fluid flow, particularly ventricular clearance rate and stagnation areas, in four different blood pump geometries and to determine the best design. The blood pumps consisted of a polyurethane ventricle, and combinations of inlet/outlet pipe angles and compression plate shapes. A video camera recorded the motion of fluid labelled with an optical tracer (Methyl Blue histological dye). A novel processing method was developed to produce colour maps of tracer concentration, experimentally calibrated. An overall picture of fluid flow in each pump geometry was generated by considering clearance curves, tracer concentration maps and inflow jet animations. Overall and local mixing coefficients are calculated for each pump. The best geometry featured straight inlet/outlet pipes and a domed compression plate. This optical tracer technique has proven convenient, economical, sensitive to low concentrations of tracer and provides instantaneous pictures of tracer distribution in a ventricle.

Benzenesulfonates↗
PubMed1999

Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial.

OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.

Adult↗
PubMed1999

Decreased basal despite enhanced agonist-stimulated effects of nitric oxide in 12-week-old stroke-prone spontaneously hypertensive rat.

This study examined both basal and agonist-stimulated effects of nitric oxide in rings of thoracic aorta and carotid artery from 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and compared them to those found in rings from normotensive Wistar Kyoto (WKY) controls. Acetylcholine-induced endothelium-dependent relaxation was found to be five-fold more sensitive in both male and female SHRSP when compared with those from age- and sex-matched WKY rats. In contrast, we found a reduction in the effects of basal nitric oxide in the SHRSP rat. Specifically, the ability of basal nitric oxide to depress contractile responses to phenylephrine was found to be reduced in vessels from SHRSP when compared with those from WKY rats. In addition, the endothelium-dependent depression of vasodilator responses to the nitric oxide donor, glyceryl trinitrate, was reduced in vessels from SHRSP when compared to those from WKY rats. Thus, we have shown that the effects of basal nitric oxide are impaired in the SHRSP rat at an age when the effects of agonist-stimulated nitric oxide are actually enhanced. This impairment may be related to the greater susceptibility of basal nitric oxide to destruction by superoxide anion which is known to be produced in excess in this model of hypertension.

Acetylcholine↗
PubMed1999

Gene transfer of endothelial nitric oxide synthase improves nitric oxide-dependent endothelial function in a hypertensive rat model.

OBJECTIVE: We have shown previously that there is a relative nitric oxide deficiency at the level of vascular endothelium in the stroke-prone spontaneously hypertensive rat (SHRSP), a model of human essential hypertension, as compared to its normotensive reference strain Wistar Kyoto (WKY) rat. The aim of the current study was to investigate whether adenoviral-mediated gene transfer of an endothelial nitric oxide synthase (eNOS) cDNA (AdCMVeNOS) into carotid arteries of the SHRSP may improve endothelial function. METHODS: Enzyme activity of the recombinant eNOS protein encoded by AdCMVeNOS was tested using a Griess assay in endothelial cells in culture. Left carotid arteries of SHRSP were surgically isolated and exposed to either the AdCMVeNOS or control beta-galactosidase-containing virus, (2 x 10(9) pfu/ml) ex vivo and in vivo. The vessels were harvested 24 h after surgery and analysed by Western blotting, immunohistochemistry and by examining endothelial function ex vivo. RESULTS: Cultured endothelial cells showed almost 100% transduction with both viruses and a dose response of eNOS expression showed a five-fold increase in nitrite production for AdCMVeNOS with no change for beta-galactosidase-containing virus. Western blotting demonstrated a significant increase of eNOS expression in vessels infused with AdCMVeNOS when compared to controls. Immunohistochemistry showed highly positive staining with monoclonal antibodies against eNOS in the intact endothelial cells of the AdCMVeNOS infused vessels. The areas under the curve of the concentration responses to phenylephrine (10(-9) to 3 x 10(-6) M) in the absence and presence of NG-nitroarginine methyl ester (100 microM) showed increased basal nitric oxide bioavailability in the carotid arteries infused with AdCMVeNOS compared to the control (n = 6 for each; P = 0.0069; 95% CI, 0.864 to 3.277). CONCLUSIONS: Our results show that AdCMVeNOS is an effective tool for vascular gene transfer and that it can improve endothelial NO availability in the SHRSP, a genetic model of essential hypertension and endothelial dysfunction.

Animals↗
PubMed1999

Mosaic bacterial chromosomes: a challenge en route to a tree of genomes.

In a recent analysis J.G. Lawrence and H. Ochman [Proc Natl Acad Sci USA 1998;95:9413-9417 (Reference 1)] surmised that about 10% of the current E. coli genome consists of genes that were acquired in over 200 events of lateral gene transfer, which occurred subsequent to the divergence of E. coli and Salmonella some 100 million years ago. Overall, the data suggest that no less than 18% of E. coli's genes might be relatively recent foreign acquisitions, and that the average rate of acquisition may be close to about 16 kb per million years. These quantitative estimates of comparatively recent genome flux have profound impact on evolutionary genome comparisons. They tend to suggest that a search should be on to identify principles that might ultimately govern gene distribution patterns across prokaryotic genomes.

Biological Evolution↗
PubMed1999

The genome of Rickettsia prowazekii and some thoughts on the origin of mitochondria and hydrogenosomes.

The sequence of an alpha-proteobacterial genome, that of Rickettsia prowazekii, is a substantial advance in microbial and evolutionary biology. The genome of this obligately aerobic intracellular parasite is small and is apparently still undergoing reduction, reflecting gene losses attributable to its intracellular parasitic lifestyle. Evolutionary analyses of proteins encoded in the genome contain the strongest phylogenetic evidence to date for the view that mitochondria descend from alpha-proteobacteria. Although both Rickettsia and mitochondrial genomes are highly reduced, it appears that genome reduction in these lineages has occurred independently. Rickettsia's genome encodes an ATP-generating machinery that is strikingly similar to that of aerobic mitochondria. But it does not encode homologues for the ATP-producing pathways of anaerobic mitochondria or hydrogenosomes, leaving an important issue regarding the origin and nature of the ancestral mitochondrial symbiont unresolved.

Animals↗
PubMed1999

Can technetium 99m pyrophosphate be used to quantify myocardial injury in donor hearts?

BACKGROUND: There are no prospective methods available to quantify the myocyte injury in hearts prior to transplantation. The potential of the isotope labeled infarct marker 99m Technetium pyrophosphate (TcPPT) being used in this role was investigated. METHODS: Brain death was induced by creating an extradural space occupying lesion in young adult swine after which hemodynamic changes were monitored and myocyte injury was quantified by histochemistry. TcPPT was administered 5 hours after induction of intracranial hypertension, and after hearts were harvested myocardial uptake was measured. These latter measurements were related to the histochemical assessment of myocyte injury. RESULTS: Sham animals (n = 4) maintained cardiovascular stability and experienced minimal myocyte injury, grades 0 to 3. BD animals (n = 10) exhibited varying patterns of hemodynamic change and myocyte injury, the latter was significant in 6, graded 4 to 11, p less than 0.05. Uptake of TcPPT by BD hearts was greater than twice the 90th centile sham value in 6. The sensitivity and specificity of greater uptake indicating the presence of myocyte injury was 83.3% and 75% respectively. CONCLUSIONS: TcPPT has the potential to quantify myocardial injury induced by brain death and its potential utility merits further investigation.

Animals↗
PubMed1999

Why have organelles retained genomes?

The observation that chloroplasts and mitochondria have retained relics of eubacterial genomes and a protein-synthesizing machinery has long puzzled biologists. If most genes have been transferred from organelles to the nucleus during evolution, why not all? What selective pressure maintains genomes in organelles? Electron transport through the photosynthetic and respiratory membranes is a powerful - but dangerous - source of energy. Recent evidence suggests that organelle genomes have persisted because structural proteins that maintain redox balance within bioenergetic membranes must be synthesized when and where they are needed, to counteract the potentially deadly side effects of ATP-generating electron transport.

Biological Evolution↗
PubMed1999

Regiochemical control of monolignol radical coupling: a new paradigm for lignin and lignan biosynthesis.

BACKGROUND: Although the lignins and lignans, both monolignol-derived coupling products, account for nearly 30% of the organic carbon circulating in the biosphere, the biosynthetic mechanism of their formation has been poorly understood. The prevailing view has been that lignins and lignans are produced by random free-radical polymerization and coupling, respectively. This view is challenged, mechanistically, by the recent discovery of dirigent proteins that precisely determine both the regiochemical and stereoselective outcome of monolignol radical coupling. RESULTS: To understand further the regulation and control of monolignol coupling, leading to both lignan and lignin formation, we sought to clone the first genes encoding dirigent proteins from several species. The encoding genes, described here, have no sequence homology with any other protein of known function. When expressed in a heterologous system, the recombinant protein was able to confer strict regiochemical and stereochemical control on monolignol free-radical coupling. The expression in plants of dirigent proteins and proposed dirigent protein arrays in developing xylem and in other lignified tissues indicates roles for these proteins in both lignan formation and lignification. CONCLUSIONS: The first understanding of regiochemical and stereochemical control of monolignol coupling in lignan biosynthesis has been established via the participation of a new class of dirigent proteins. Immunological studies have also implicated the involvement of potential corresponding arrays of dirigent protein sites in controlling lignin biopolymer assembly.

Amino Acid Sequence↗
PubMed1999

Effects of superoxide dismutase mimetics on the activity of nitric oxide in rat aorta.

A number of structurally distinct superoxide dismutase (SOD) mimetics were examined to determine if they shared the ability of authentic Cu/Zn SOD to produce endothelium-dependent relaxation of rings of rat aorta by protecting basal nitric oxide from destruction by endogenously produced superoxide anion. MnCl2 (10 nM-100 microM), CuSO4 (100 nM-1 mM) and CuDIPS (Cu [II]-[diisopropylsalicylate]2; 100 nM-30 microM) each mimicked the ability of Cu/Zn SOD (0.1-300 u ml(-1)) to produce relaxation of phenylephrine-precontracted aortic rings in a manner inhibited by endothelial removal or treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM). In contrast, MnTMPyP (Mn [III] tetrakis [1-methyl-4-pyridyl] porphyrin; 10 nM-30 microM) augmented phenylephrine-induced contraction and this was blocked by endothelial removal or treatment with L-NAME (100 microM), consistent with destruction rather than protection of basal nitric oxide activity. Pretreatment with Cu/Zn SOD (250 u ml(-1)) blocked this augmentation suggesting that it arose paradoxically through destruction of nitric oxide by superoxide anion. The spin trap agents tiron (100 nM-1 mM), tempol (100 nM-1 mM) and PTIYO (4-phenyl-2,2,5,5-tetramethyl imidazolin-1-yloxy-5-oxide; 100 nM-300 microM) all failed to promote endothelium-dependent relaxation. In fact, the last two augmented phenylephrine-induced tone and this was blocked by endothelial removal or treatment with L-NAME (100 microM), consistent with destruction of basal nitric oxide activity. This destruction was unaffected by pretreatment with Cu/Zn SOD (250 u ml(-1)) and probably reflected the direct ability of tempol and PTIYO to destroy nitric oxide. Thus, the ideal SOD mimetic for protection of nitric oxide activity in conditions of oxidant stress still awaits development.

Animals↗
PubMed1999

Bioavailability investigation of a new tilidine/naloxone liquid formulation compared to a reference formulation.

An oral solution available as ethanol-free droplets of the fixed drug combination tilidine-HCl 50 mg/naloxone-HCl 4 mg (CAS 27107-79-5 and CAS 465-65-6, respectively; Tilidin-ratiopharm plus Tropfen) was investigated in 12 healthy volunteers together with an ethanol-containing reference preparation for comparable bioavailability. The study was conducted in an open, randomized, two-way cross-over design applying single doses of 20 droplets (equivalent to 50 mg tilidine-HCl/4 mg naloxone-HCl) of either formulation in the fasting state. The drug plasma profiles were monitored for a period of 48 h by means of LC-MS/MS for tilidine and its active metabolite nortilidine, whereas GC-MS was employed in order to determine naloxone and its phase I metabolite, 6-beta-naloxole. Maximum concentrations (Cmax) achieved were 22.28 ng/ml (tilidine) and 92.78 ng/ml (nortilidine) for the test preparation. Corresponding values for the reference preparation were 24.95 ng/ml (tilidine) and 100.73 ng/ml (nortilidine). The extent of drug absorption (AUC0-infinity) amounted to 38.83 ng h/ml and 467.63 ng h/ml for the prodrug tilidine and the metabolite nortilidine of the test preparation and corresponded well to 43.81 ng h/ml and 493.85 ng h/ml of the reference. Regarding the rate of drug absorption, essentially identical tmax and Rabs values for both tilidine and nortilidine of either preparation in addition pointed to well comparable liquid formulations and equipotent analgesia may be inferred from opioid pharmakokinetic profiles. Pharmacokinetics of the opioid antagonist naloxone and 6-beta-naloxole were also determined and resulted in well coinciding profiles for both preparations. Thus despite the fact that only minimum oral naloxone bioavailabilities were observed, plasma level monitoring of naloxone and 6-beta-naloxole allowed for demonstration of systemic exposure of opioid antagonistic compounds throughout a period of 2-3 h after oral drug administration. Due to the limited number of subjects involved, the primary aim of the study did not consist in demonstration of drug bioequivalence. Rather a comparable bioavailability between preparations was assumed if AUC and Cmax point estimators of 90% confidence intervals would be contained within a 0.80-1.20 range. The study outcome revealed that all four investigated analytes met this requirement, whilst nortilidine pharmacokinetic parameters even fulfilled commonly accepted bioequivalence criteria, i.e. inclusion of 90% confidence intervals of AUC- and Cmax-ratios within acceptance limits of 80% and 125%. Increased data variation observed with bioavailability parameters of tilidine, naloxone and 6-beta-naloxole prevented their bioequivalence demonstration based on only 12 study participants. In conclusion, single doses of two different tilidine/naloxone 50 mg/4 mg liquid formulations revealed well comparable bioavailability for all 4 analytes investigated. Both treatments were fairly well tolerated. Most frequently reported adverse events were dizziness, headache and nausea, which all recovered without sequelae and necessity of concomitant treatment.

Adult↗
PubMed1999

Imaging of adenosine bolus transit following intravenous administration: insights into antiarrhythmic efficacy.

OBJECTIVE: To study the effects of the site of intravenous injection of adenosine and to assess the site of action of adenosine in the heart by correlating cardiac effects with bolus transit. METHODS: Ten patients undergoing routine technetium (Tc-99m) gated blood pool ventriculography consented to the coadministration of intravenous adenosine. The dose of adenosine required to produce heart block during sinus rhythm was determined following antecubital vein administration. This dose (6-18 mg) was mixed with Tc-99m and given first into the same antecubital vein (proximal injection) and then repeated into a hand vein (distal injection). The ECG was recorded and the transit of the bolus was imaged using a gamma camera. RESULTS: Heart block occurred in all 10 patients (second degree in seven, first degree in three) at (mean (SEM)) 17.5 (1.0) seconds after the proximal injection of adenosine. Distal injection produced heart block in six patients (second degree in two, first degree in four) at 21.9 (4.4) seconds (p < 0.01). In eight of 10 patients the electrophysiological effects were less with distal injection. The onset of heart block was close to the time of peak bolus Tc-99m activity in the left ventricle. Peak bolus activity was delayed (by about three seconds) and the duration of bolus activity in the left ventricle was increased with distal injection compared with proximal injection, at 17.2 (4.2) v 9.2 (3.1) seconds, p < 0.01. CONCLUSIONS: The lesser electrophysiological effects of adenosine following distal intravenous injections were associated with delay in transit time and dispersion of the bolus. The correlation of adenosine induced heart block with bolus activity in the left heart indicated dependence on coronary arterial delivery of adenosine to the atrioventricular node.

Adenosine↗
PubMed1999

Oral health and the older diabetic.

Older diabetics are at high risk for developing certain oral complications. Conversely, these oral health problems can complicate overall diabetic management, potentially undermining good blood-glucose control and impairing mastication of nutritionally appropriate foods. This article reviews the oral complications associated with diabetes. Additionally, special considerations in dental treatment of the older diabetic patient are discussed, including management of diabetic emergencies.

Aged↗
PubMed1998

Eubacterial origin of nuclear genes for chloroplast and cytosolic glucose-6-phosphate isomerase from spinach: sampling eubacterial gene diversity in eukaryotic chromosomes through symbiosis.

Higher plants possess two distinct nuclear-encoded glucose-6-phosphate isomerase (GPI) isoenzymes, a cytosolic enzmye of the Embden-Meyerhof pathway and a chloroplast enzyme essential to storage and mobilization of carbohydrate fixed by the Calvin cycle. We have purified spinach chloroplast GPI to homogeneity, determined amino acid sequences from the active enzyme, and cloned cDNAs for chloroplast and cytosolic GPI isoenzymes from spinach. Sequence comparisons reveal three distantly related families of GPI genes that are non-uniformly distributed among contemporary eubacteria and archaebacteria, suggesting that ancient gene diversity existed for this glycolytic enzyme. Spinach chloroplast GPI is much more similar to its homologue from the cyanobacterium Synechocystis PCC6803 than it is to the enzyme from any other source, providing strong evidence that the gene for chloroplast GPI was acquired by the nucleus via endosymbiotic gene transfer from the cyanobacterial antecedants of chloroplasts. Eukaryotic nuclear genes for cytosolic GPI are more similar to eubacterial than to archaebacterial homologues, suggesting that these too were acquired by eukaryotes from eubacteria, probably during the course of the endosymbiotic origin of mitochondria. Chloroplast and cytosolic GPI provide evidence for a eubacterial origin of yet another component of the eukaryotic glycolytic pathway.

Amino Acid Sequence↗
PubMed1998

Gene transfer to the nucleus and the evolution of chloroplasts.

Photosynthetic eukaryotes, particularly unicellular forms, possess a fossil record that is either wrought with gaps or difficult to interpret, or both. Attempts to reconstruct their evolution have focused on plastid phylogeny, but were limited by the amount and type of phylogenetic information contained within single genes. Among the 210 different protein-coding genes contained in the completely sequenced chloroplast genomes from a glaucocystophyte, a rhodophyte, a diatom, a euglenophyte and five land plants, we have now identified the set of 45 common to each and to a cyanobacterial outgroup genome. Phylogenetic inference with an alignment of 11,039 amino-acid positions per genome indicates that this information is sufficient--but just rarely so--to identify the rooted nine-taxon topology. We mapped the process of gene loss from chloroplast genomes across the inferred tree and found that, surprisingly, independent parallel gene losses in multiple lineages outnumber phylogenetically unique losses by more that 4:1. We identified homologues of 44 different plastid-encoded proteins as functional nuclear genes of chloroplast origin, providing evidence for endosymbiotic gene transfer to the nucleus in plants.

Cell Nucleus↗
PubMed1998

Gene structure, expression in Escherichia coli and biochemical properties of the NAD+ -dependent glyceraldehyde-3-phosphate dehydrogenase from Pinus sylvestris chloroplasts.

Photosynthetic eukaryotes typically possess two distinct glyceraldehyde-3-phosphate dehydrogenases, an NAD+ -specific enzyme in the cytosol (GapC: EC 1.2.1.12) and an NADP+ -dependent enzyme in the chloroplast (GapAB: EC 1.2.1.13). The gymnosperm Pinus sylvestris is an exception in that it is known to express a gene encoding a transit peptide-bearing GapC-like subunit that is imported into chloroplasts (GapCp), but the enzymatic properties of this novel GAPDH have not been described from any source. We have expressed the mature GapCp unit from Pinus in Escherichia coli and have characterized the active enzyme. GapCp has a specific activity of 89 units per milligram and is strictly NAD+ -dependent, showing no detectable activity with NADP+. Values of the apparent Km for NAD+ and glyceraldehyde-3-phosphate were determined as 62 and 344 microM, respectively. The Pinus GapCpl gene possesses 12 introns, two in the region encoding the transit peptide and ten in the region encoding the mature subunit, all of which are found at positions strictly conserved across genes for higher plant GapC. A cDNA encoding a homologue of GapCp was isolated from the heterosporous fern Marsilea quadrifolia, indicating that NAD+ -dependent chloroplast GAPDH also occurs in other higher plants.

Amino Acid Sequence↗
PubMed1998

Interaction between peroxynitrite and L-cysteine: effects on rat aorta.

In rings of rat aorta previously exposed to peroxynitrite (1 mM), L-cysteine and its analogues containing, but not those lacking, a thiol group produced a powerful transient relaxation. This relaxation is likely to result from the release of nitric oxide from a nitrated/nitrosated compound formed following reaction of peroxynitrite with a component of the tissue or bathing medium. Furthermore, when peroxynitrite was pre-mixed with L-cysteine a new relaxant species was formed. Analogues of L-cysteine with a free thiol reacted with peroxynitrite to form species with similar relaxant potencies. Analogues lacking a thiol formed products with relaxant activity, but less than with L-cysteine. Analogues with a free amino but no thiol or carboxylic functions formed products with potencies similar to those lacking only the thiol. If the amino is substituted and the thiol removed, no relaxant activity was generated. Thus, peroxynitrite reacts with L-cysteine to form a novel relaxant whose activity derives mainly from formation of its S-nitrosothiol, with a lesser component perhaps from an N-nitroso derivative.

Animals↗