Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease

Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.Mary M. Kavurma, Christina Bursill, Christopher P. Stanley, Freda Passam, Siân P. Cartland, Sanjay Patel, Jacky Loa, Gemma A. Figtree, Jonathan Golledge, Sarah Aitken, and David A. Robinso

Effect of different levels of pressure support and proportional assist ventilation on breathing pattern, work of breathing and gas exchange in mechanically ventilated hypercapnic COPD patients with acute respiratory failure

Background: Proportional assist ventilation (PAV) has been shown to maintain better patient-ventilator synchrony than pressure support ventilation (PSV); however, its clinical advantage regarding invasive ventilation of COPD patients has not been clarified. Objectives: To compare the effect of PAV and PSV on respiratory parameters of hypercapnic COPD patients with acute respiratory failure (ARF). Methods: Nine intubated hypercapnic COPD patients were placed on the PAV or PSV mode in random sequence. For each mode, four levels (L-1-L-4) of support were applied. At each level, blood gases, flow, tidal volume (V-T), airway pressure (Paw), esophageal pressure (Pes) (n = 7), patient respiratory rate (fp), ventilator rate (fv), missing efforts (ME = fp - fv) were measured. Results: We found increases in ME with increasing levels of PSV but not with PAV. PO2 and V-T increased whereas PCO2 decreased significantly with increasing levels of PSV (p < 0.05). With PAV, PCO2 decreased and V-T increased significantly only at L-4 whereas PO2 increased from L-1 to L-4. Runaways were observed at L-3 and L-4 of PAV. The pressure-time product (PTP) was determined for effective and missing breaths. The mean total PTP per minute (of effective plus missing breaths) was 160 +/- 57 cm H2O/s.min in PSV and 194 +/- 60 cm H2O/s.min in PAV. Conclusion: We conclude that in COPD patients with hypercapnic ARF, with increasing support, PSV causes the appearance of ME whereas PAV develops runaway phenomena, due to the different patient-ventilator interaction; however, these do not limit the improvement of blood gases with the application of both methods. Copyright (C) 2003 S. Karger AG, Basel

The relation between bone marrow angiogenesis and the proliferation index Ki-67 in multiple myeloma

Aim: Angiogenesis correlates with disease progression in various haematological malignancies. This study investigated the association between microvascular density (MVD) and the Ki-67 proliferation index (Ki-67 PI), bone marrow infiltration, and C reactive protein (CRP) in patients with multiple myeloma. Methods: Bone marrow MVD was examined in 44 biopsies at diagnosis and 15 in plateau phase by immunostaining the endothelial cells with a monoclonal antibody to CD34. The Ki-67 PI was evaluated by a double immunostaining technique using the monoclonal antibodies MIB-1 and CD38. Results: MVD, Ki-67 PI, bone marrow infiltration, and CRP were significantly higher in pretreatment patients than in controls and decreased in patients achieving plateau phase. MVD significantly correlated with Ki-67 PI and infiltration, and Ki-67 correlated with infiltration. Conclusion: In multiple myeloma, apart from being a marker of proliferative activity, Ki-67 is also associated with bone marrow angiogenesis and tumour burden

Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocytopenia and thrombosis. Here we show that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil-platelet association. HIT immune complexes induce formation of thrombi containing neutrophils, extracellular DNA, citrullinated histone H3 and platelets in a microfluidics system and in vivo, while neutrophil depletion abolishes thrombus formation. Absence of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation but not thrombocytopenia, suggesting they are induced by separate mechanisms. NETs markers and neutrophils undergoing NETosis are present in HIT patients. Our findings demonstrating the involvement of NETosis in thrombosis will modify the current concept of HIT pathogenesis and may lead to new therapeutic strategies

Βeta 2-glycoprotein i protects mice against gram-negative septicaemia in a sexually dimorphic manner

The immune responses of males and females to bacterial infections display differences. The mechanisms that underlie this sexual dimorphism are multifactorial. Lipopolysaccharide (LPS) contributes to the pathogenesis of endotoxaemia. We have previously demonstrated that the plasma protein beta-2 glycoprotein-1 (β2GPI) reduces LPS-induced inflammation in male mice. In the present study using a more robust infection model of septicaemia the role of β2GPI is examined in both male and female wild type (WT) and β2GPI deficient (β2GPI-/-) mice challenged with Escherichia coli (E. coli) intravenously. β2GPI deficiency led to an increase of E. coli colony forming units (CFU) in the circulation of both male and female mice. In male β2GPI-/- mice this was associated with a worse clinical severity score. This difference was not observed between female β2GPI-/- and female WT mice. Male WT mice had decreased levels of total and increased levels of free thiol β2GPI following administration of LPS or E. coli. This pattern of sexual dimorphic response was also observed in our cohort of humans with sepsis. These findings support a role for β2GPI in modulating the sex-specific susceptibility to gram-negative septicaemia