Pulmonary hypoxic vasoconstriction: how strong? How fast?

We have developed a minimally invasive technique for studying regional blood flow in conscious sheep, bypassing the complications of open-chest surgery, flow probes and tracer infusion. We quantitate regional perfusion continuously on the basis of regional clearance of methane (methane is produced in the sheep rumen, enters the circulation and is eliminated nearly completely (greater than 95%) in the lung). Tracheal intubation with a dual-lumen catheter isolates the gas exchange of the right apical lobe (RAL; less than 15% of the lung) from that of the remainder of the lung, which serves as a control (CL). We measure RAL and CL methane elimination by entraining expirates in constant flows, sampled continuously for methane. Results obtained with this technique and from regional oxygen uptake are in excellent agreement. We have found that hypoxic vasoconstriction is far more potent and stable during eucapnic hypoxia than during hypocapnic hypoxia. The time course of the vasoconstriction suggests that many of the data in the literature may have been obtained prior to steady state.     

The effect of indobufen on the thrombogenic potential of a Dacron prosthesis in an artificial circulation

We have evaluated the effect of indobufen on the potential thrombogenicity of a Dacron vascular prosthesis in an artificial circulation. In a randomised double blind crossover study, ten healthy volunteers received indobufen 200 mg or placebo twice daily for one week. The artificial circulation, incorporating a 15 cm length of 8 mm Dacron graft was perfused for 60 mins with volunteer blood containing autologous 111In labelled platelets. Graft thrombogenicity was assessed by changes in platelet function, isotope labelled platelet studies and scanning electron microscopy. Platelet count fell significantly during graft perfusion (P less than 0.05) and aggregation was significantly inhibited by treatment with indobufen pre perfusion compared with the placebo group (P less than 0.02). While deposition of labelled platelets was not statistically significant, consumption of these platelets was greater in the placebo group (P less than 0.01). Field counts of adherent platelets made from scanning electron micrographs of the indobufen treated group were significantly lower (P less than 0.01) compared with the placebo group. We conclude that indobufen can reduce the thrombogenic potential of Dacron vascular grafts and suggest that it may be an effective antiplatelet agent for use following Dacron bypass surgery.     

Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk

OBJECTIVE: The optimal prophylactic strategy and treatment regimen for deep venous thrombosis (DVT) in hospitalized pediatric patients is not clearly established. This study assessed the incidence, risk factors, and treatment patterns for DVT among pediatric patients admitted to a hospital ward. METHODS: Children (aged <17 years) admitted to a single tertiary-care hospital during a 14-year period who developed or presented with DVT were retrospectively identified. Patient demographic and clinical data were analyzed retrospectively. Patients who developed DVT in the hospital were stratified according to the Wells clinical probability scoring system from criteria noted before the diagnosis. Treatment patterns and outcomes were evaluated between the two time intervals of 1992 to 2001 (group I) and 2002 to 2005 (group II). RESULTS: Between 1992 and 2005, 358 children were evaluated for DVT, and 99 (52 boys, 47 girls) were admitted to the hospital and were determined to have DVT by confirmatory imaging. A prior DVT (12 total) was present in eight of the 21 patients admitted for DVT treatment; of the remaining, only seven received DVT prophylaxis on admission. In those developing a DVT, the inpatient clinical probability score was 21% (low), 40% (moderate), and 39% (high). The most common risk factor in those with prehospital DVT was a prior DVT (38%) or thrombophilic condition (33%), whereas inpatients had a central catheter (45%), with nearly 50% in the femoral vein. Children acquiring an inpatient DVT had concomitant severe respiratory (17%), oncologic (14%), and/or infectious (15%) diseases and required a prolonged intensive care unit (12.7 days) stay. Prehospital DVT was lower extremity predominant (90%) and statistically different from inpatient-acquired DVT (62%, P = .01). Treatment patterns between periods I and II revealed a trend to more low-molecular-weight heparin and less unfractionated heparin use (P = .09). Three patients died (one fatal pulmonary embolism). The number of recognized cases per 10,000 admissions increased from 0.3 to 28.8 from 1992 to 2005. CONCLUSION: The incidence of DVT in hospitalized children is increasing. Those presenting with DVT typically have prior DVT, thrombophilia, or lower extremity disease. Our study suggests that children admitted with severe medical conditions who require a prolonged intensive care unit stay in addition to central venous access (especially via the femoral vein) should be considered candidates for DVT prophylaxis. A clinical probability scoring system alone cannot stratify patients sufficiently to forgo prophylaxis in hopes of a rapid clinical diagnosis. Childhood-specific level 1 trials aimed at determining guidelines for DVT prophylaxis are urgently required.     

Neovascular Endothelial-Cell Activation: The Link Between Angiogenesis,Intimal Leukocyte Content,and Development of Symptomatic Carotid Occlusive Disease

New blood vessels in atherosclerotic lesions are postulated to be responsible for plaque instability by acting as conduits for inflammatory cells. This study assessed the association between macrophage content of plaque caps of carotid atherosclerotic lesions, plaque vascularity, and endothelial-cell activation within these blood vessels. Carotid endarterectomy specimens from patients who underwent endarterectomy for carotid occlusive disease (ten symptomatic, six asymptomatic) were examined. Sequential transverse sections were obtained and were stained conventionally and immunohistochemically with CD 34 (an endothelial-cell marker) and CD 68 (a macrophage marker), as well as VCAM-1 and ICAM-1 (markers of endothelial-cell activation). Microvessel and macrophage counts were performed for the whole plaque and the plaque cap respectively. The differences in microvessel density, macrophage content, and ICAM-1 and VCAM-1 expression, between symptomatic and asymptomatic patients and in different plaque types were examined, as was the association between microvessel density and microvessel content of atherosclerotic lesions. Higher microvessel counts were observed in patients with symptomatic carotid occlusive disease (p < 0.01). Higher ICAM-1 and VCAM-1 expression was noted in new blood vessels in plaques obtained from patients with symptomatic carotid occlusive disease, compared with asymptomatic patients (p < 0.001 and p < 0.01 respectively). A close association was observed between macrophage content of the plaque cap and microvessel counts in atherosclerotic lesions (p < 0.0001), as well as ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) expression, in these microvessels. This study highlights the significance of neovascularity and endothelial-cell activation in the evolution of symptomatic carotid occlusive disease. Furthermore, it points to a relationship between the inflammatory process and angiogenesis within the plaque, which may be mediated through endothelial-cell activation.     

Vitronectin-mediated inhibition of complement: evidence for different binding sites for C5b-7 and C9.

In the activated complement system, vitronectin (complement S-protein) occupies the metastable membrane binding site of the nascent precursor complex C5b-7, so that the newly formed SC5b-7 is unable to insert into cell membranes. Some evidence also indicates that vitronectin limits on-going membrane-associated pore formation by inhibiting C9 polymerization. It has been assumed that these two stages of terminal complement complex (TCC) inhibition take place through charge interactions between the heparin-binding region of vitronectin and homologous cysteine-rich sequences of the late complement proteins C6, C7, C8 and C9. We examined SC5b-7 formation and inhibition of C9 binding in the TCC using separate haemolytic assays. The mode of action of vitronectin in these assays was compared with two 15mer peptides which span residues 348-379 of the heparin-binding region, and a heparin-affinity polypeptide, protamine sulphate. The results showed that vitronectin acts predominantly through SC5b-7 production with a lesser effect on the inhibition of C9 lytic pore formation. In contrast, protamine sulphate did not prevent C5b-7 membrane attachment, but was a potent inhibitor of C9-mediated lysis. The peptides did not inhibit C5b-7 membrane insertion and only one affected C9 binding. These data suggest that the two stages of TCC inhibition involve separate binding sites on the vitronectin molecule. The site for association with nascent C5b-7 is unknown, whereas inhibition of C9 binding and pore formation takes place through the heparin-binding region.