Transposed Arteriovenous Fistulae: Do the Results Justify the Effort?

Transposed arteriovenous fistulae have been utilized in clinical scenarios where simple arteriovenous fistulae have failed or their construction was not possible for anatomical reasons. Despite variability in published reports, transposed arteriovenous fistulae have acceptable patency rates and outperform prosthetic arteriovenous grafts in patency, frequency of intervention to maintain patency, and complication rates.     

Bioactivation of phencyclidine in rat and human liver microsomes and recombinant P450 2B enzymes: evidence for the formation of a novel quinone methide intermediate

The hypothesis that the psychological side effects associated with the anesthetic phencyclidine (PCP) may be caused by irreversible binding of PCP or its reactive metabolite(s) to critical macromolecules in the brain has resulted in numerous in vitro studies aimed at characterizing pathways of PCP bioactivation. The studies described herein extend the current knowledge of PCP metabolism and provide details on a previously unknown metabolic activation pathway of PCP. Following incubations with NADPH- and GSH-supplemented human and rat liver microsomes and recombinant P450 2B enzymes, two sulfhydryl conjugates with MH+ ions at 547 and 482 Da, respectively, were detected by LC/MS/MS. Shebley et al. [(2006) Drug Metab. Dispos. 34, 375-383] have also observed the GSH conjugate 1 with MH+ at 547 Da in PCP incubations with rat P450 2B1 and rabbit P450 2B4 isoforms fortified with NADPH and GSH. The molecular weight of 1 is consistent with a bioactivation pathway involving Michael addition of the sulfhydryl nucleophile to the putative 2,3-dihydropyridinium metabolite of PCP obtained via a four-electron oxidation of the piperidine ring in the parent compound. The mass spectrum of the novel GSH adduct 2 with an MH+ ion at 482 Da was suggestive of a unique PCP bioactivation pathway involving initial ortho- or para-hydroxylation of the phenyl ring in PCP followed by spontaneous decomposition to piperidine and an electrophilic quinone methide intermediate, which upon reaction with GSH yielded adduct 2. The LC retention times and mass spectral properties of enzymatically generated 2 were identical to those of a reference standard obtained via reaction of GSH with synthetic p-hydroxyPCP in phosphate buffer (pH 7.4, 37 degrees C). 1H NMR and 13C-distortionless enhancement by polarization transfer (DEPT) NMR spectral studies on synthetically generated 2 suggested that the structural integrity of the p-hydroxyphenyl and cyclohexyl rings likely was preserved and that the site of GSH addition was the benzylic carbon joining the two scaffolds. The formation of 2 in human microsomes was reduced upon addition of the dual P450 2C19/P450 2B6 inhibitor (+)- N-3-benzylnirvanol. Consistent with this finding, both recombinant P450 2B6 and P450 2C19 catalyzed PCP bioactivation to 2. In the absence of GSH, synthetic p-hydroxyPCP underwent rapid decomposition (t1/2 approximately 5.2 min) to afford p-hydroxyphenylcyclohexanol and p-hydroxyphenylcyclohexene, presumably via the quinone methide intermediate. Overall, our findings on the facile degradation of synthetic p-hydroxyPCP to yield an electrophilic quinone methide intermediate capable of reacting with nucleophiles, including GSH and water, suggest an inherent instability of the putative phenolic PCP metabolite. Thus, if formed enzymatically in vivo, p-hydroxyPCP may not require further metabolism to liberate the quinone methide, which can then react with macromolecules. To our knowledge, this is the first report of a quinone methide reactive intermediate obtained in human-liver microsomal metabolism of PCP.     

Endovascular Repair of a Blunt Abdominal Aortic Injury

Blunt abdominal aortic injury is an uncommon traumatic finding. In the past, treatment options have traditionally consisted of open operative repair; however, the development of endovascular surgery has created new interventional possibilities. This case is presented to demonstrate the applications of endovascular abdominal aortic repair for a blunt traumatic injury.     

Exposure of fibrinogen receptors in human platelets by surface proteolysis with elastase.

Human platelets that were preincubated with porcine elastase aggregated spontaneously upon the addition of fibrinogen. Maximal aggregation to fibrinogen was observed with platelets pretreated with an elastase concentration of 111 micrograms/ml, and half-maximal aggregation occurred after treatment with 11 micrograms/ml elastase. Binding of radiolabeled fibrinogen to elastase-treated platelets was specific, saturable, and showed a single class of 48,400 +/- 9,697 fibrinogen-binding sites per platelet with a dissociation constant of 6.30 +/- 1.48 X 10(-7) M. ATP, apyrase, and the stimulators of platelet adenylate cyclase forskolin, prostaglandin E1, prostacyclin, and N6, 2''-O-dibutyryl cyclic AMP did not inhibit the fibrinogen-induced aggregation of elastase-treated platelets. EDTA completely blocked the initiation of aggregation and reversed the fibrinogen-induced aggregation of elastase-treated platelets. Monoclonal and polyclonal antibodies directed against glycoproteins (GP) IIb and IIIa completely blocked the fibrinogen-induced aggregation of elastase-treated platelets. Immunoprecipitates with these antibodies obtained from detergent extracts of surface-radiolabeled, intact, and elastase-treated platelets contained the glycoproteins IIb and IIIa. We conclude that surface proteolysis by low concentrations of elastase can expose fibrinogen-binding sites associated with GPIIb and GPIIIa on the platelet surface, resulting in spontaneous aggregation upon the addition of fibrinogen. These findings may be relevant to hemostatic changes observed in patients with increased levels of circulating elastase.     

Perioperative outcomes after reoperative carotid endarterectomy are worse than expected

Objective

Reoperative carotid endarterectomy (CEA) can be technically challenging because of significant scarring as a consequence of the initial CEA procedure. There are limited data that describe outcomes after reoperative CEA, and as such, our goal was to determine the effect of reoperative CEA on perioperative outcomes.

Association of plasma levels of F11 receptor/junctional adhesion molecule-A (F11R/JAM-A) with human atherosclerosis.

OBJECTIVES: The purpose of this study was to determine the association of the F11 receptor (F11R) with human vascular disease. BACKGROUND: A molecule identified as critical for platelet adhesion to a cytokine-inflamed endothelial surface in vitro is F11R. The F11R is known to be expressed in platelets and endothelium and reported recently to be overexpressed in atherosclerotic plaques. METHODS: A novel enzyme-linked immunosorbent assay was developed for the measurement of soluble F11R in human plasma. The F11R levels, along with a number of other biomarkers, were measured in 389 male patients with known or suspected coronary artery disease (CAD) undergoing coronary angiography at a Veterans Administration Medical Center. RESULTS: Patients with normal or nonobstructive disease (CAD angiographic score of 0), mild-to-moderate disease (score of 1 to 3), and severe disease (score of 4 to 6) had median F11R plasma levels of 38.6 pg/ml (mean 260 +/- 509.6 pg/ml), 45.2 pg/ml (mean 395.3 +/- 752.7 pg/ml), and 105.8 pg/ml (mean 629 +/- 831.7 pg/ml), respectively (p = 0.03). By multivariate analysis, the variables independently associated with CAD score were age, hyperlipidemia, chronic renal insufficiency, left ventricular function, and plasma F11R levels. The F11R was the only biomarker that was independently associated with CAD score. Consistent with the previously reported effects of tumor necrosis factor (TNF)-alpha on F11R expression in cultured endothelial cells, F11R levels correlated strongly with plasma TNF-alpha levels (r = 0.84; p < 0.0001). CONCLUSIONS: Plasma F11R is independently associated with the presence and severity of angiographically defined CAD. By virtue of its strong correlation to plasma TNF-alpha, F11R may be an important mediator of the effects of inflammation on the vessel wall. Strategies that block F11R may represent a novel approach to the treatment of human atherosclerosis.