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P Whittaker

Publications and source records attributed to P Whittaker.

At least 19 recordsLinked to original sources
PubMed2001

The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X.

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.

Chromosomes, Human, Pair 1↗
PubMed2001

Dissociation between improvement in angina pectoris and myocardial perfusion after transmyocardial revascularization with an excimer laser.

Xenon chloride excimer laser transmyocardial revascularization significantly reduced angina in all patients and increased regional myocardial perfusion in most patients; however, there was no correlation between symptomatic improvement and flow improvement. Patients' symptomatic improvement preceded improved perfusion by several months.

Angina Pectoris↗
PubMed2000

Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. UK Cancer Cytogenetics Group (UKCCG).

Deletion of the long arm of chromosome 20 represents the most common chromosomal abnormality associated with the myeloproliferative disorders (MPDs) and is also found in other myeloid malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Previous studies have identified a common deleted region (CDR) spanning approximately 8 Mb. We have now used G-banding, FISH or microsatellite PCR to analyse 113 patients with a 20q deletion associated with a myeloid malignancy. Our results define a new MPD CDR of 2.7 Mb, an MDS/AML CDR of 2.6 Mb and a combined 'myeloid' CDR of 1.7 Mb. We have also constructed the most detailed physical map of this region to date--a bacterial clone map spanning 5 Mb of the chromosome which contains 456 bacterial clones and 202 DNA markers. Fifty-one expressed sequences were localized within this contig of which 37 lie within the MPD CDR and 20 within the MDS/AML CDR. Of the 16 expressed sequences (six genes and 10 unique ESTs) within the 'myeloid' CDR, five were expressed in both normal bone marrow and purified CD34 positive cells. These data identify a set of genes which are both positional and expression candidates for the target gene(s) on 20q.

Antigens, CD34↗
PubMed2000

Brief antecedent ischemia enhances recombinant tissue plasminogen activator-induced coronary thrombolysis by adenosine-mediated mechanism.

BACKGROUND: Clinical studies have implicated preinfarct angina (brief antecedent ischemia/reperfusion [I/R]) as a predictor of more rapid thrombolysis and lower rates of reocclusion. However, the effects of antecedent ischemia on the efficacy of thrombolysis have not been rigorously assessed. Using a canine model of coronary thrombosis, we aimed to (1) reproduce these clinical findings and (2) determine whether release of adenosine (a potent inhibitor of platelet aggregation via stimulation of platelet A(2) receptors) during brief I/R contributes to this improved patency. METHODS AND RESULTS: To address our first objective, we compared the time required to achieve lysis with recombinant tissue plasminogen activator and patency during the first 2 hours after lysis in dogs in which 1-hour thrombotic occlusion was preceded by brief I/R (10-minute coronary occlusion/10-minute reperfusion) versus 20-minute uninterrupted perfusion (controls). Time to lysis was accelerated in the I/R group versus the control group (11+/-1 versus 35+/-6 minutes, P=0.004). In addition, the duration of subsequent reocclusion was reduced (17+/-12 versus 30+/-11 minutes), and the area of the flow-time profile (normalized to baseline flow x 120 minutes) was increased (64+/-12% versus 35+/-7%, P=0.04) in the I/R cohort. The protocol was then repeated, but all dogs were pretreated with the adenosine A(2)/A(1) antagonist CGS 15943 (CGS, 1.5 mg/kg). Time to lysis (38 versus 39 minutes) and subsequent patency were comparable in the CGS+control group versus the CGS+I/R group. CONCLUSIONS: Brief antecedent I/R enhances the efficacy of coronary thrombolysis in this canine model, which is due, at least in part, to an adenosine-mediated mechanism.

Adenosine↗
PubMed2000

Ventricular remodeling after acute myocardial infarction: effect of low-intensity laser irradiation.

BACKGROUND AND OBJECTIVE: Low-intensity laser irradiation is claimed to enhance wound healing. Healing after myocardial infarction results in ventricular enlargement and wall thinning. If laser treatment accelerated cardiac healing, we speculated that ventricular remodeling would be attenuated. STUDY DESIGN/MATERIALS AND METHODS: In vitro, fibroblasts were irradiated for 1 minute twice a day for 4 days (5 mW; wavelength, 780 nm). One day after infarction, rats were randomly assigned to 5 or 10 mW transdermal irradiation twice a day for 4 days or to sham. One week after infarction, we measured the remodeling parameters; cavity volume, infarct thickness, and vascular structure, and the healing parameters; collagen content and inflammation. RESULTS: Laser-treated fibroblasts occupied more area than controls. Hearts receiving the 10 mW treatment had smaller volumes than sham hearts. Laser treatment reduced infarct thinning and preserved arterial lumen area; however, collagen was not increased and inflammation was inhibited. CONCLUSIONS: Low-intensity irradiation attenuated infarct-associated remodeling. In contrast to expectations from in vitro study, these effects were not a result of enhanced healing.

Animals↗
PubMed2000

Histologic signatures of thermal injury: applications in transmyocardial laser revascularization and radiofrequency ablation.

BACKGROUND AND OBJECTIVE: Cardiac treatments such as transmyocardial laser revascularization and radiofrequency ablation cause thermal injury. We sought to provide quantitative histologic methods of assessing such injury by using the inherent birefringence of cardiac muscle and collagen; specifically, to exploit the connection between thermal injury and the loss of birefringence. STUDY DESIGN/MATERIALS AND METHODS: We quantified tissue birefringence changes in vitro for temperatures up to 130 degrees C. This information was used to assess thermal injury associated with myocardial channels made in vitro. We then measured in vivo cardiac injury 30 minutes and 3 days after radiofrequency exposure. RESULTS: Birefringence decreased above 60 degrees C for muscle and above 70 degrees C for collagen. Temperatures above 80 degrees C were associated with collagen fiber straightening and above 95 degrees C with little muscle birefringence. Injury adjacent to laser channels was greatest parallel to cell orientation. In vivo, muscle with reduced birefringence was surrounded by cells exhibiting focal birefringence increases (contraction bands). Early injury assessment marked by birefringence changes corresponded to lesion size at 3 days. CONCLUSION: Polarized light revealed histologic temperature signatures corresponding to irreversible muscle injury and collagen denaturation.

Animals↗
PubMed2000

Angiotensin II receptor blockade attenuates the deleterious effects of exercise training on post-MI ventricular remodelling in rats.

OBJECTIVES: The effects of exercise training on LV remodelling following large anterior myocardial infarction (MI) remains controversial. Blockade of the renin-angiotensin system has been shown to prevent ventricular dilation and deleterious remodeling. We therefore tested, in a rat model of chronic MI, whether any potentially deleterious effects of exercise on post-MI remodelling could be ameliorated by angiotensin II receptor blockade. METHODS: Male Wistar rats underwent coronary ligation or sham operation. Treatment with losartan (10 mg/kg/day) began 1 week post-MI and moderate treadmill exercise (25 m/min, 60 min/day, 5 days/week) was initiated 2 weeks post-MI. Systolic and diastolic pressure-volume relationships were measured in isolated, red-cell perfused, isovolumically beating hearts 8 weeks post-MI. Morphometric measurements were performed in trichrome stained cross sections of the heart. Five groups of animals were compared: sham (n=13), control MI (MI; n=11), MI plus losartan (MI-Los; n=13), MI plus exercise (MI-Ex; n=10) and MI plus exercise and losartan (MI-Ex-Los; n=12). RESULTS: Infarct size (% of left ventricle, LV) was similar among the infarcted groups [MI=43+/-4%, MI-Los=49+/-2%, MI-Ex=45+/-1%, MI-Ex-Los=48+/-2% (NS)]. Exercise, losartan and exercise+losartan treatments all attenuated LV dilation post-MI to a similar degree. Exercise training increased LV developed pressure in both untreated and losartan treated hearts (P<0.05 vs. other MI groups). In addition, exercise resulted in additional scar thinning in untreated hearts, while no additional scar thinning was seen in post-infarct hearts receiving both losartan and exercise. CONCLUSIONS: Following large anterior MI, losartan attenuated LV dilation and scar thinning. In untreated animals, exercise decreased dilation, but also contributed to scar thinning. Therefore, exercise concurrent with blockade of the renin-angiotensin system may provide optimal therapeutic benefit following large anterior MI.

Analysis of Variance↗
PubMed2000

Monophosphoryl lipid A: a novel nitric oxide-mediated therapy to attenuate platelet thrombosis?

Nitric oxide (NO) is a potent inhibitor of platelet aggregation. However, the benefits of NO-based therapies can be confounded by concomitant hypotension. Monophosphoryl lipid A (MLA) is a nontoxic derivative of endotoxin that purportedly increases nitric oxide synthase (NOS) activity and, presumably, NO production, yet has a hemodynamically benign profile. Thus our aims were to determine whether (a) MLA attenuates in vivo platelet aggregation in damaged and stenotic canine coronary arteries by a NO-mediated mechanism but without reductions in arterial pressure; and (b) the platelet inhibitory effects are manifest in vitro. To address the first aim, anesthetized dogs underwent coronary injury + stenosis, resulting in cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgement of platelet-rich thrombi. In protocol I, dogs received MLA (100 microg/kg + 40 microg/kg/h) or vehicle beginning 15 min before stenosis. Protocol II was identical, except the NOS inhibitor aminoguanidine was coadministered with MLA/vehicle. Coronary patency was assessed throughout the initial 3 h after injury + stenosis. Infusion of MLA did not result in hypotension. However, in protocol I, the median nadir of the CFVs was higher (2.1 vs. 0.8 ml/min; p < 0.05), median duration of total thrombotic occlusion tended to be reduced (0 vs. 10.4 min; p = 0.1), and mean flow-time area, expressed as a percentage of baseline flow, was increased (53 +/- 9% vs. 33 +/- 3%; p < 0.05) in MLA-treated versus vehicle-treated dogs. In contrast, in protocol II, vessel patency was comparable in both groups. Finally, whole blood impedance aggregometry (protocol HI) revealed a significant reduction in the in vitro platelet aggregation in blood samples receiving exogenous MLA, which was blocked by coadministration of exogenous aminoguanidine. Thus MLA attenuates platelet-mediated thrombosis in both damaged and stenotic canine coronary arteries and in vitro, possibly by an NO-mediated mechanism, but without concomitant hypotension.

Adjuvants, Immunologic↗
PubMed2000

Alkaline phosphatase isoenzymes and clinical features in hypophosphatasia.

Hypophosphatasia is an hereditary disease characterized by low activity of total serum alkaline phosphatase (TALP) accompanied by a range of skeletal diseases. We have measured the main circulating alkaline phosphatase isoenzymes--bone (BALP), liver (LALP), intestinal (IALP), placental (PALP)--in six families with hypophosphatasia, using kinetic and electrophorectic methods. Our observations show that patients with skeletal disease tend to have a very low BALP activity. Patients even with undetectable LALP activity do not appear to manifest any clinical complications. Patients also showed proportionately high IALP activity. Since the production of significant IALP activity is not a constant feature in all healthy individuals, it remains to be established whether the survival of one of these patients (IALP > 80% of TALP) depended on the presence of circulating IALP.

Adult↗
PubMed1999

Brief myocardial ischemia attenuates platelet thrombosis in remote, damaged, and stenotic carotid arteries.

BACKGROUND: Brief antecedent periods of coronary artery occlusion improve subsequent vessel patency in damaged and stenotic coronary arteries via release of adenosine from ischemic/reperfused myocardium and resultant adenosine receptor stimulation. However, the site of receptor stimulation-circulating blood-borne elements (ie, platelets) versus vessel-wall components of the culprit artery-remains unclear. If platelet adenosine receptors are involved, then the benefits of brief coronary occlusion (1) should be manifested systemically and improve patency at a remote site and (2) should be inhibited by an antagonist of adenosine A(2) receptors, whereas, in contrast, (3) brief vascular occlusion not associated with appreciable adenosine release should be ineffective in improving vessel patency. METHODS AND RESULTS: In Protocol 1, anesthetized rabbits received 5 minutes of transient coronary occlusion, 5 minutes of transient bilateral carotid occlusion (purported to cause negligible adenosine release from the brain), or no intervention. All rabbits then underwent injury plus stenosis of the left carotid artery, resulting in repeated cyclic variations in carotid blood flow (CFVs). Carotid patency during the initial 2 hours after stenosis (assessed by quantifying the nadir of the CFVs and area of the flow-time profile) was significantly enhanced with antecedent coronary-but not carotid-occlusion versus controls. In Protocol 2, improvement in carotid patency after brief coronary occlusion was corroborated in anesthetized dogs. However, the benefits of brief coronary occlusion were abrogated by the A(2)/A(1) antagonist CGS 15943. CONCLUSIONS: Brief antecedent coronary artery occlusion enhanced vessel patency in remote, damaged, and stenotic carotid arteries, largely due to adenosine receptor stimulation on circulating elements.

Adenosine↗
PubMed1999

Success of transmyocardial laser revascularization is determined by the amount and organization of scar tissue produced in response to initial injury: results of ultraviolet laser treatment.

BACKGROUND AND OBJECTIVE: Previous studies of transmyocardial laser revascularization have reported open channels after ultraviolet laser treatment and closed channels with infrared lasers. We speculated that differences in long-term channel patency were determined by the healing response to injury. METHODS: Channels were made in rat hearts with a frequency-tripled neodymium:YAG laser, at 5 and 10 mJ per pulse, by advancing an optic fiber through the myocardium, from the epicardium to the ventricular cavity. Several months later, we challenged the ability of the channel to supply blood by arterial occlusion and examined the channel structure with polarized light microscopy. RESULTS: Low-pulse energy was associated with lower patency, more fibrosis, and larger infarcts than was the higher energy. Open channels were surrounded by collagen fibers aligned parallel to the channel; in closed channels, fibers were aligned perpendicular to the original channel direction. CONCLUSION: The amount of initial injury and its repair determine channel patency and function.

Animals↗
PubMed1999

Laser-mediated reversal of cardiac expansion after myocardial infarction.

BACKGROUND AND OBJECTIVES: A complication of transmural myocardial infarction is infarct expansion, which can lead to the development of heart failure. However, the necrotic muscle is replaced by collagen, a material known to shrink when heated. Thus, the hypothesis was that thermally-induced scar shrinkage could reverse infarct expansion. STUDY DESIGN/MATERIALS AND METHODS: Four weeks after transmural infarcts were produced by coronary occlusion, rats were randomized to control or treatment with a neodymium:yttrium-aluminum-garnet laser. The epicardial scar surface was irradiated until shrinkage was observed. Thirty minutes later, hearts were excised and fixed at a distending pressure of 15 mm Hg, left ventricular cavity volume was measured, and histologic analysis was performed. RESULTS: Cavity volume was reduced by laser treatment (0.72 +/- 0.07 ml vs. 0.54 +/- 0.05 ml; P= 0.044). In addition, treatment resulted in thicker scars, a leftward shift of the heart's electrical axis, and straightening of collagen fibers. CONCLUSION: Laser treatment resulted in thermally-mediated scar shrinkage, which reversed infarct expansion and reduced cavity volume.

Animals↗
PubMed1999

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Journal Article↗
PubMed1999

Genotoxicity of iron compounds in Salmonella typhimurium and L5178Y mouse lymphoma cells.

The mutagenic activity of elemental and salt forms of iron (Fe), including compounds currently being used in dietary supplements and for food fortification, were evaluated for mutagenicity in Salmonella typhimurium and L5178Y mouse lymphoma cells. Except for the weak response obtained with ferrous fumarate, none of the compounds induced a mutagenic response in Salmonella. In the mouse lymphoma assay, responses were related to the Fe compound and/or reduction of ferric (Fe+3) to ferrous (Fe+2). Responses with the elemental forms of Fe were divergent. Electrolytic Fe with a relatively larger particle size and irregular shape was negative. The smaller-sized carbonyl Fe, which after 4 hr attached to and was taken up by the cells, induced mutagenic responses both with and without S9. With ferric chloride (FeCl3) and ferric phosphate (FePO4), there was an increase in mutant frequency only with S9. With the Fe+2 compounds, ferrous sulfate (FeSO4) and ferrous fumarate (FeC4H2O4), positive responses were observed without S9. The Fe chelate, sodium Fe(III)EDTA was positive in both the presence and absence of S9. The lowest effective doses (LED) for induction of mutagenicity were identified for these compounds and an LED ratio calculated. The LED ratio ranges from 1 for FeSO4 to 30 for carbonyl Fe, which are similar to oral LD50 values obtained in animal studies.

Animals↗
PubMed1999

Transmyocardial revascularization: the fate of myocardial channels.

Attempted cardiac revascularization through laser-made channels has gained considerable recent notoriety. Although the treatment reduces angina, its ability to enhance perfusion is unclear, and the mechanism of action unknown. The fate of the channels appears an obvious place to look for insight. Therefore, this review focuses on temporal and spatial changes in channel morphology. An appreciation of the natural history of the channels not only has potential to elucidate mechanisms, but also to provide the basis for optimization of channel-making.

Animals↗
PubMed1998

Brief antecedent ischemia attenuates platelet-mediated thrombosis in damaged and stenotic canine coronary arteries: role of adenosine.

BACKGROUND: Recent studies suggest that patients with angina before myocardial infarction exhibit improved recovery of coronary perfusion after thrombolysis by an as-yet-unknown mechanism. We therefore proposed that brief antecedent ischemia/reperfusion may, via release of adenosine, improve vessel patency in damaged and stenotic coronary arteries. METHODS AND RESULTS: Anesthetized dogs underwent coronary injury + stenosis, resulting in repeated cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgment of platelet-rich thrombi. Vessel patency was assessed for 3 hours after stenosis by quantification of the nadir of the CFVs, duration of total thrombotic occlusion (flow=0), and area of the flow-time profile (expressed as percent of baseline flow x 180 minutes). In protocol 1, dogs received 10 minutes of coronary occlusion + 10 minutes of reflow or a comparable 20-minute control period before injury + stenosis. The median nadir of the CFVs was higher (4.0 versus 0.3 mL/min), median zero flow duration per 30-minute time interval was shorter (0.4 versus 15.1 minutes), and mean percent flow-time area was greater (54+/-8% versus 28+/-9%) in dogs that received antecedent ischemia versus controls (P<.05). These benefits of antecedent ischemia/reperfusion were largely mimicked by a 10-minute intracoronary adenosine infusion (400 microg/min) in lieu of brief ischemia (protocol 2) and were abolished by administration of the adenosine A1/A2 receptor antagonist PD 115,199 (3 mg/kg i.v.) before brief antecedent coronary occlusion (protocol 3). CONCLUSIONS: Brief antecedent ischemia attenuates subsequent platelet-mediated thrombosis in damaged and stenotic canine coronary arteries, due, in large part, to an adenosine-mediated mechanism.

Adenosine↗
PubMed1998

Collagen organization in wound healing after myocardial injury.

Our understanding of what constitutes "normal" collagen organization in wound healing after myocardial injury and how such organization is achieved is still in its infancy. However, once this knowledge has been obtained, it may suggest methods of enhancing or even optimizing healing, and thus provide us with the possibility of modifying the structural problems responsible for infarct expansion and rupture.

Animals↗