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D Davidson

Publications and source records attributed to D Davidson.

At least 37 records · Page 2Linked to original sources
PubMed2001

FDG-PET sensitivity for melanoma lymph node metastases is dependent on tumor volume.

BACKGROUND AND OBJECTIVES: The purpose of this study is to determine the tumor volume threshold for successful positron emission tomography (PET) imaging of melanoma nodal metastases. METHODS: Review of a clinical series of patients who had FDG-PET imaging of regional lymph node basins followed by lymphadenectomy. Lymph node tumor volumes were calculated from direct measurements of metastatic nodule(s) in formalin fixed specimens. PET scan interpretations were correlated with histology to determine sensitivity. Sensitivity was correlated with the aggregate lymph node tumor volume in the nodal basin and with AJCC stage group. RESULTS: Forty-five patients with 49 pathologically positive regional nodal basins comprised the study group. Median total basin tumor volume was 28.3 mm(3)(range 0.004-22,879 mm(3)). FDG-PET sensitivity for detection of all tumor volumes was 0.49. The observed 90% sensitivity threshold for detection of nodal metastases was > or = 78 mm(3). PET sensitivity was 0.14 for detection of tumor volumes < 78 mm(3). PET sensitivity differed by prescan AJCC stage: I-0.0; II-0.24; III-0.81; IV-1.0 (P < 0.001). CONCLUSIONS: FDG-PET reliably detects lymph node tumor deposits greater than approximately 80 mm(3) volume, but sensitivity falls rapidly below this. This amount of tumor is most likely to occur in patients with AJCC stage III or IV disease.

Fluorodeoxyglucose F18↗
PubMed2001

Olanzapine reduces urge to drink after drinking cues and a priming dose of alcohol.

RATIONALE: Haloperidol, a D2 antagonist, has been shown to moderate the effects of alcohol consumption on craving. OBJECTIVE: The present study was designed to determine whether a single 5-mg dose of olanzapine (a D2/5-HT2 antagonist) would influence responses to alcohol cues or an alcohol challenge. It was hypothesized that olanzapine would attenuate cue-elicited urge to drink, attenuate the effects of alcohol consumption on urge to drink, and reduce the rewarding effects of alcohol. METHODS: To test these hypotheses, 26 heavy social drinkers were randomized to receive either 5 mg olanzapine or placebo approximately 8 h before each of two experimental sessions. Participants consumed a moderate dose of alcohol in one experimental session and a non-alcohol control beverage in another session. RESULTS: Results indicated that mere exposure to alcohol cues and consumption of alcohol increased urge to drink and that olanzapine attenuated these effects. Results also indicated that alcohol increased subjective stimulation and high while olanzapine did not moderate these effects. CONCLUSIONS: These results suggest that olanzapine did not influence the rewarding effects of alcohol but did attenuate the effects of alcohol cues and an alcohol challenge on urge to drink.

Adult↗
PubMed2001

Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively.

Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and safety of coadministration of colesevelam and atorvastatin, administration of these agents alone or in combination was examined in a double-blind study of 94 hypercholesterolemic men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the American Heart Association Step I diet, patients were randomized among five groups: placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8 g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 12-53% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin (38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%). Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05). Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected by colesevelam alone or in combination. The frequency of side effects did not differ among groups. At recommended starting doses of each agent, coadministration of colesevelam and atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol reductions comparable to those observed with the maximum atorvastatin dose.

Adult↗
PubMed2001

The effects of a mechanical thrombolytic device on normal canine vein valves.

PURPOSE: To determine if the Arrow-Trerotola Percutaneous Thrombolytic Device (PTD) causes damage to normal vein valves. MATERIALS AND METHODS: Ten lateral saphenous veins in five dogs were studied with descending venography with use of a wedge balloon catheter positioned above 48 valves (demonstrating 51 valves) before and after five antegrade passes each with an over-the-wire (0.025-inch), 6.5-F, 9-mm-diameter PTD. Vein diameters were 3.2-11.4 mm (mean, 5.9 mm). Contrast matter was injected at incremental rates from 3 to 15 mL/min during continuous pressure monitoring. Imaging was performed with digital subtraction angiography at a rate of 1 frame/sec. The time to valve reflux was determined by noting the frame at which reflux was first seen through the valve. The time to reflux and pressure required to reflux were compared before and after the PTD passes. All vessels were explanted and evaluated histologically for presence or absence of endothelial loss, thrombus formation, inflammation, or valve degeneration. Four veins in two animals were studied with venography to determine the variability of the venographic method. These veins thrombosed during venography and therefore served as positive pathologic controls. In two animals, one vein was studied with venography and one was not studied to provide pathologic controls. RESULTS: With use of two physiologic tests of valve function, 77% of valves had minimal or no damage as assessed by valve competency and 80% had minimal or no damage as demonstrated by the change in the pressures the valve can withstand before reflux. Twenty-six of 51 valves (51%) had no difference or later reflux after PTD use. Thirteen (26%) refluxed 1 second earlier after PTD use and 12 (23%) refluxed > or =2 seconds earlier (six at 2, four at 3, and two at 4). Four of the six valves with more than a 2-second difference in reflux times were in valves with diameters less than 4.2 mm. All these vessels were smaller than 7 mm in diameter. Twenty-one of 48 valve levels (44%) had no difference or sustained higher pressures before reflux after PTD use. Seventeen (36%) had a pressure drop of <10 mm Hg; five (10%) had drops of 12-24 mm Hg; and five (10%) had drops of more than 40 mm Hg. There was a significant difference in endothelial loss, thrombus formation, and inflammation between experimental veins, the veins with thrombus, the venography controls, and the normal vein controls. There was significant difference only in terms of inflammation when the experimental group was compared to the thrombosis group. CONCLUSION: The antegrade use of the PTD across normal canine vein valves does not cause physiologically significant damage in valves 7 mm or larger in diameter in this animal model.

Animals↗
PubMed2001

Preclinical in vivo testing of the Arrow-Trerotola percutaneous thrombolytic device for venous thrombosis.

PURPOSE: To test the safety and efficacy of using the Arrow-Trerotola percutaneous thrombolytic device (PTD) for treating deep vein thrombosis (DVT) in an animal model. MATERIALS AND METHODS: An established canine model of iliocaval subacute thrombosis was used. Thrombosis was caused by balloon occlusion of the infrarenal inferior vena cava (IVC) for 7 (n = 12), 10 (n = 1), or 17 (n = 1) days. Treatment was performed with use of an 8-F, over-the-wire (0.035-inch) PTD with a 15-mm-diameter basket. The procedure was performed without IVC filtration. Two acute procedures were performed and 12 procedures were intended as survival procedures with 30-day follow-up. Pulmonary arteriography, blood gases, and pulmonary artery pressure measurement were performed before and after the procedure, and at follow-up. The animals were killed after the follow-up procedure and their IVC, iliac veins, and lungs were removed and examined histologically. Heparin was used intraprocedurally but thrombolytic agents were not used. Low-molecular-weight heparin was given daily after the procedure. RESULTS: Thrombolysis was completely (12 of 13) or partially (one of 13) successful in all animals in the 7- and 10-day groups, but was unsuccessful in the animal in the 17-day group (n = 1). Variable amounts of segmental and subsegmental pulmonary emboli were found in all animals with small increases in pulmonary artery pressure. Two animals died within 6 days of the procedure, possibly due to pulmonary emboli. At 30-day follow-up, IVC patency was preserved in 80% (eight of 10) of animals, but significant caval narrowing due to intimal hyperplasia was noted at follow-up. All pulmonary emboli had resolved angiographically at follow-up, but evidence of recanalized or resolving pulmonary thromboemboli was found in seven of the 12 surviving animals. No acute vascular injury (eg, perforation) occurred. CONCLUSION: The modified PTD used in this study is effective in treating subacute (<7 days old) venous thrombosis, but temporary filtration will probably be necessary to keep pulmonary emboli to a minimum during the procedure. The 30-day patency is encouraging. The results in this animal model indicate that the Arrow-Trerotola PTD may be useful in the percutaneous treatment of DVT in humans.

Animals↗
PubMed2001

Mechanical thrombolysis of venous thrombosis in an animal model with use of temporary caval filtration.

PURPOSE: To test the effect of temporary caval filtration on pulmonary emboli when a mechanical thrombolytic device is used to treat venous thrombosis and to test the effects of a modified device on caval patency at 30-day follow-up. MATERIALS AND METHODS: In a canine model of iliocaval subacute thrombosis, mechanical thrombolysis was performed with use of an 8-F over-the-wire Arrow-Trerotola Percutaneous Thrombolytic Device (PTD) with a 9-mm (iliac) or 15-mm (inferior vena cava [IVC]) basket. In six procedures, the device was made of nitinol monofilament, and in another six, it was made of braided stainless steel. All procedures were performed with a nitinol expandable sheath (temporary filter) in the suprarenal IVC. Low-molecular-weight heparin was given daily after the procedure. Venography, pulmonary arteriography, measurement of blood gases, and pulmonary artery (PA) pressure measurement were performed before and after the procedure and at 30-day follow-up. Pulmonary arteriograms from the group treated with stainless-steel devices were compared to those from an earlier group of animals in which the identical procedure was performed without caval filtration. The IVC was examined histologically. RESULTS: Thrombolysis was successful in all animals. Rare segmental and subsegmental pulmonary emboli (PE) were seen arteriographically; compared to procedures without filters, there was a significant reduction in PE (P <.002). However, a mild increase in pulmonary artery pressure, decrease in pH, and increase in pCO(2) were observed postprocedurally. At 30-day follow-up (n = 11), IVC patency was preserved in 45% (n = 5) of animals overall. Caval patency was significantly better in animals in which the combination of stainless-steel devices was used (five of six = 83% vs zero with nitinol device; P =.015). Histologically, the stainless-steel device caused little intimal injury and fibrosis-less than that seen with the nitinol device. CONCLUSIONS: Temporary filtration reduces, but does not completely eliminate, PE during mechanical thrombolysis. The stainless-steel device results in less intimal injury and better caval patency than the nitinol device.

Animals↗
PubMed2001

Bioinformatics beyond sequence: mapping gene function in the embryo.

The spatio-temporal expression pattern of a gene during development is a valuable piece of information. But there is no way to compare precisely the patterns of expression of different genes, or the way the patterns are changed in a mutant. One way to solve this problem is to construct digital reference images of development (a bioinformatics framework), to which expression patterns can be mapped and stored, then compared. Such frameworks are under active development in several model systems. They will form the basis of powerful and integrated gene expression databases, which facilitate comparisons between genes, tissues and species.

Animals↗
PubMed2001

The Edinburgh Mouse Atlas: using the CD.

This paper provides a simple introduction to the reconstructions and data-handling tools stored on the Edinburgh Mouse Atlas CD, together with some of the ways in which the viewers and software can be used to understand mouse development and analyse data. The key aspect of the Mouse Atlas is that the underlying models are a complete representation of the histology, which has not been constrained to a particular interpretation. This means, for example, that the current anatomy domains can be further subdivided as required to any resolution up to the resolution of the models (2-7 microm). In the CD of the early embryos described here, virtually all tissues that can be usefully distinguished either by the histology or morphologically have been delineated.

Animals↗
PubMed2001

Synergistic regulation of immunoreceptor signaling by SLP-76-related adaptor Clnk and serine/threonine protein kinase HPK-1.

Recently, the identification of Clnk, a third member of the SLP-76 family of adaptors expressed exclusively in cytokine-stimulated hemopoietic cells, has been reported by us and by others. Like SLP-76 and Blnk, Clnk was shown to act as a positive regulator of immunoreceptor signaling. Interestingly, however, it did not detectably associate with known binding partners of SLP-76, including Vav, Nck, and GADS. In contrast, it became complexed in activated T cells and myeloid cells with an as yet unknown tyrosine-phosphorylated polypeptide of approximately 92 kDa (p92). In order to understand better the function of Clnk, we sought to identify the Clnk-associated p92. Using a yeast two-hybrid screen and cotransfection experiments with Cos-1 cells, evidence was adduced that p92 is HPK-1, a serine/threonine-specific protein kinase expressed in hemopoietic cells. Further studies showed that Clnk and HPK-1 were also associated in hemopoietic cells and that their interaction was augmented by immunoreceptor stimulation. A much weaker association was detected between HPK-1 and SLP-76. Transient transfections in Jurkat T cells revealed that Clnk and HPK-1 cooperated to increase immunoreceptor-mediated activation of the interleukin 2 (IL-2) promoter. Moreover, the ability of Clnk to stimulate IL-2 promoter activity could be blocked by expression of a kinase-defective version of HPK-1. Lastly we found that in spite of the differential ability of Clnk and SLP-76 to bind cellular proteins, Clnk was apt at rescuing immunoreceptor signaling in a Jurkat T-cell variant lacking SLP-76. Taken together, these results show that Clnk physically and functionally interacts with HPK-1 in hemopoietic cells. Moreover, they suggest that Clnk is capable of functionally substituting for SLP-76 in immunoreceptor signaling, albeit by using a distinct set of intracellular effectors.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Activation of nuclear factor-kappaB and its suppression by dexamethasone in polymorphonuclear leukocytes: newborn versus adult.

Polymorphonuclear leukocytes (PMN) of the newborn, to a greater extent than those of the adult, have the ability to amplify PMN recruitment to an inflammatory site by their own release of IL-8, and this process is inhibited by dexamethasone. The aim of the present study was to determine whether the regulation of nuclear factor-kappaB (NF-kappaB) could explain the previous observations. NF-kappaB is a transcription factor pivotal for expression of genes encoding inflammatory cytokines such as IL-8, but NF-kappaB has not been previously studied in the PMN of the newborn. NF-kappaB activation was measured by an electrophoretic mobility shift assay in nuclear extracts prepared from PMN isolated from adults and cord blood from newborns. Two distinct molecular forms of NF-kappaB were identified after tumor necrosis factor-alpha stimulation; this included the previously characterized p50/65 heterodimer and a newly identified p50/50 homodimer. Both NF-kappaB dimers were activated by tumor necrosis factor-alpha to significantly higher levels in the neutrophil of the newborn versus adult. An additional new finding was that pretreatment of PMN with dexamethasone (10(-7) M, therapeutic range) inhibited activation of both NF-kappaB complexes in both the newborn and the adult PMN. We conclude that the increased activation of NF-kappaB by the PMN of the newborn may play an important role in neonatal inflammatory reactions. Eventually, specific targeting of NF-kappaB activation in the neutrophil may be an effective molecular approach for the treatment of neutrophil-mediated disorders in the newborn.

Adult↗
PubMed2001

Analysis of the efficacy of pediatric day surgery.

OBJECTIVES: To assess the efficacy and safety of a pediatric day surgery program and its benefits to the child and family. DESIGN: A review and analysis of prospectively gathered data. SETTING: The Children's Hospital of Eastern Ontario (CHEO), a university-affiliated pediatric centre with a referral base of 2.5 million people. PATIENTS: All children undergoing day surgery at CHEO during the 5 years between 1992 and 1997. INTERVENTIONS: All surgical procedures performed on a day surgery basis. MAIN OUTCOME MEASURES: Procedures performed, complications and unexpected admissions. RESULTS: An average of 4,899 children per year underwent surgical procedures in the ambulatory day surgery program. The 4 commonest procedures performed were myringotomy, tonsillectomy and adenoidectomy, dental procedures, and inguinal hernia repair. The majority of children were between 2 and 7 years of age. Complications were few, averaging 1.6% per year, with postoperative bleeding, primarily secondary to tonsillectomy and adenoidectomy, being the most common. None resulted in permanent disability and there were no deaths. CONCLUSIONS: Pediatric day surgery is a safe and cost-effective program that benefits the child, the family and the pediatric surgical program.

Adolescent↗
PubMed2000

Identification of novel inhibitors of urokinase via NMR-based screening.

Using an NMR-based screen, a novel class of urokinase inhibitors were identified that contain a 2-aminobenzimidazole moiety. The inhibitory potency of this family of inhibitors is similar to that of inhibitors containing a guanidine or amidine group. However, unlike previously described guanidino- or amidino-based inhibitors which have pK(a) values greater than 9.0, urokinase inhibitors containing a 2-aminobenzimidazole have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved pharmacokinetic properties which could increase the bioavailability of inhibitors which contain this moiety. A crystal structure of one of the lead inhibitors, 2-amino-5-hydroxybenzimidazole, complexed with urokinase reveals the electrostatic and hydrophobic interactions that stabilize complex formation and suggests nearby subsites that may be accessed to increase the potency of this new series of urokinase inhibitors.

Benzimidazoles↗
PubMed2000

Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite.

BACKGROUND: Human urokinase-type plasminogen activator has been implicated in the regulation and control of basement membrane and interstitial protein degradation. Because of its role in tissue remodeling, urokinase is a central player in the disease progression of cancer, making it an attractive target for design of an anticancer clinical agent: Few urokinase inhibitors have been described, which suggests that discovery of such a compound is in the early stages. Towards integrating structural data into this process, a new human urokinase crystal form amenable to structure-based drug design has been used to discover potent urokinase inhibitors. RESULTS: On the basis of crystallographic data, 2-naphthamidine was chosen as the lead scaffold for structure-directed optimization. This co-crystal structure shows the compound binding at the primary specificity pocket of the trypsin-like protease and at a novel binding subsite that is accessible from the 8-position of 2-napthamidine. This novel subsite was characterized and used to design two compounds with very different 8-substituents that inhibit urokinase with K(i) values of 30-40 nM. CONCLUSIONS: Utilization of a novel subsite yielded two potent urokinase inhibitors even though this site has not been widely used in inhibitor optimization with other trypsin-like proteases, such as those reported for thrombin or factor Xa. The extensive binding pockets present at the substrate-binding groove of these other proteins are blocked by unique insertion loops in urokinase, thus necessitating the utilization of additional binding subsites. Successful implementation of this strategy and characterization of the novel site provides a significant step towards the discovery of an anticancer clinical agent.

Binding Sites↗
PubMed2000

Re-engineering of human urokinase provides a system for structure-based drug design at high resolution and reveals a novel structural subsite.

Inhibition of urokinase has been shown to slow tumor growth and metastasis. To utilize structure-based drug design, human urokinase was re-engineered to provide a more optimal crystal form. The redesigned protein consists of residues Ile(16)-Lys(243) (in the chymotrypsin numbering system; for the urokinase numbering system it is Ile(159)-Lys(404)) and two point mutations, C122A and N145Q (C279A and N302Q). The protein yields crystals that diffract to ultra-high resolution at a synchrotron source. The native structure has been refined to 1.5 A resolution. This new crystal form contains an accessible active site that facilitates compound soaking, which was used to determine the co-crystal structures of urokinase in complex with the small molecule inhibitors amiloride, 4-iodo-benzo(b)thiophene-2-carboxamidine and phenylguanidine at 2. 0-2.2 A resolution. All three inhibitors bind at the primary binding pocket of urokinase. The structures of amiloride and 4-iodo-benzo(b)thiophene-2-carboxamidine also reveal that each of their halogen atoms are bound at a novel structural subsite adjacent to the primary binding pocket. This site consists of residues Gly(218), Ser(146), and Cys(191)-Cys(220) and the side chain of Lys(143). This pocket could be utilized in future drug design efforts. Crystal structures of these three inhibitors in complex with urokinase reveal strategies for the design of more potent nonpeptidic urokinase inhibitors.

Amiloride↗
PubMed2000

The noncatalytic domain of protein-tyrosine phosphatase-PEST targets paxillin for dephosphorylation in vivo.

The noncatalytic domain of protein-tyrosine phosphatase (PTP)-PEST contains a binding site for the focal adhesion-associated protein paxillin. This binding site has been narrowed to a 52-residue sequence that is composed of two nonoverlapping, weak paxillin binding sites. The PTP-PEST binding site on paxillin has been mapped to the two carboxyl-terminal LIM (lin11, isl-1, and mec-3) domains. Transient expression of PTP-PEST reduced tyrosine phosphorylation of p130(cas), as anticipated. A PTP-PEST mutant defective for binding p130(cas) does not cause a reduction in its tyrosine phosphorylation in vivo. Expression of PTP-PEST also caused a reduction of phosphotyrosine on paxillin. Expression of mutants of PTP-PEST with deletions in the paxillin-binding site did not associate with paxillin in vivo and failed to cause a reduction in the phosphotyrosine content of paxillin. These results demonstrate that paxillin can serve as a PTP-PEST substrate in vivo and support the model that a noncatalytic domain interaction recruits paxillin to PTP-PEST to facilitate its dephosphorylation.

Animals↗
PubMed2000

Facet ridge end points in crystal shapes

We study equilibrium crystal shapes (ECS) near facet ridge end points (FRE) by means of a numerical study of a body-centered solid-on-solid model on a square lattice with an enhanced uniaxial interaction range. This tests the stability of the so-called stochastic FRE point where the model maps exactly onto one dimensional Kardar-Parisi-Zhang-type growth and where the local ECS is simple. We find that the generic shapes are more complex. They contain first-order faceted to rough boundaries terminating in Pokrovsky-Talapov-type end points, and first-order ridges inside the rounded part of the ECS where two rough surface orientations coexist.

Journal Article↗