Acquired factor XIII deficiency: a therapeutic challenge

Less than 60 cases of acquired factor (F)XIII deficiencies have been reported, most having distinct clinical features. To illustrate the therapeutic challenges of acquired FXIII inhibitors, we report a case of a 65-year-old patient with no previous bleeding history who suddenly developed massive haemorrhages associated to a strong and isolated FXIII inhibitor. No underlying disorder has been detected till now after three years of follow-up. Despite aggressive treatment with prednisone, rituximab, cyclophosphamide, immunoglobulin, immunoadsorption and immune tolerance his inhibitor is still present, although at low titre and with a clinical benefit since the patient has no more bleed since more than one year. Moreover the patient had a venous thromboembolic complication. After a review of the management of acquired FXIII deficiency patients and based on the management of acquired haemophilia we discuss a possible strategy for such difficult cases.

Erythropoietin or darbepoetin for patients with cancer

Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoiesis stimulating agents (ESAs) and red blood cell transfusions.

Targeting landing zone 0 by total arch rerouting and TEVAR: midterm results of a transcontinental registry

Landing zone 0, defined as a proximal landing zone in the ascending aorta, remains the last frontier to be taken. Midterm results of total arch rerouting and thoracic endovascular aortic repair (TEVAR) extending into landing zone 0 remain to be determined.

Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis

The benefit of the coronary collateral circulation (natural bypass network) on survival is well established. However, data derived from smaller studies indicates that coronary collaterals may increase the risk for restenosis after percutaneous coronary interventions. The purpose of this systematic review and meta-analysis of observational studies was to explore the impact of the collateral circulation on the risk for restenosis.

Metabolomic markers for intestinal ischemia in a mouse model

Diagnosis of intestinal ischemia remains a clinical challenge. The aim of the present study was to use a metabolomic protocol to identify upregulated and downregulated small molecules (M(r) < 500) in the serum of mice with intestinal ischemia. Such molecules could have clinical utility when evaluated as biomarkers in human studies.

Endoscopic Image Overlay for the Targeting of Hidden Anatomy in Laparoscopic Visceral Surgery

Limitations associated with the visual information provided to surgeons during laparoscopic surgery increases the difficulty of procedures and thus, reduces clinical indications and increases training time. This work presents a novel augmented reality visualization approach that aims to improve visual data supplied for the targeting of non visible anatomical structures in laparoscopic visceral surgery. The approach aims to facilitate the localisation of hidden structures with minimal damage to surrounding structures and with minimal training requirements. The proposed augmented reality visualization approach incorporates endoscopic images overlaid with virtual 3D models of underlying critical structures in addition to targeting and depth information pertaining to targeted structures. Image overlay was achieved through the implementation of camera calibration techniques and integration of the optically tracked endoscope into an existing image guidance system for liver surgery. The approach was validated in accuracy, clinical integration and targeting experiments. Accuracy of the overlay was found to have a mean value of 3.5 mm ± 1.9 mm and 92.7% of targets within a liver phantom were successfully located laparoscopically by non trained subjects using the approach.

Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef function

Background The Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF) region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region. Results The dysfunctional HIV group O8 nef allele was restored to the consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2) and non-canonical (B2 and C1422) HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF→AAA) and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef’s association with the cellular p21-activated kinase 2 (PAK2), the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN) were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck. Conclusion Based on these findings, we propose that this highly conserved three amino acid VGF motif together with the acidic cluster and the proline-rich motif form a previously unrecognized amphipathic surface on Nef. This surface appears to be essential for the majority of Nef functions and thus represents a prime target for the pharmacological inhibition of Nef.

Intraperitoneal mesh implantation for fascial dehiscence and open abdomen

Postoperative fascial dehiscence and open abdomen are severe postoperative complications and are associated with surgical site infections, fistula, and hernia formation at long-term follow-up. This study was designed to investigate whether intraperitoneal implantation of a composite prosthetic mesh is feasible and safe.

Phosphoinositide 3-kinase C2β regulates RhoA and the actin cytoskeleton through an interaction with Dbl

The regulation of cell morphology is a dynamic process under the control of multiple protein complexes acting in a coordinated manner. Phosphoinositide 3-kinases (PI3K) and their lipid products are widely involved in cytoskeletal regulation by interacting with proteins regulating RhoGTPases. Class II PI3K isoforms have been implicated in the regulation of the actin cytoskeleton, although their exact role and mechanism of action remain to be established. In this report, we have identified Dbl, a Rho family guanine nucleotide exchange factor (RhoGEF) as an interaction partner of PI3KC2β. Dbl was co-immunoprecipitated with PI3KC2β in NIH3T3 cells and cancer cell lines. Over-expression of Class II phosphoinositide 3-kinase PI3KC2β in NIH3T3 fibroblasts led to increased stress fibres formation and cell spreading. Accordingly, we found high basal RhoA activity and increased serum response factor (SRF) activation downstream of RhoA upon serum stimulation. In contrast, the dominant-negative form of PI3KC2β strongly reduced cell spreading and stress fibres formation, as well as SRF response. Platelet-derived growth factor (PDGF) stimulation of wild-type PI3KC2β over-expressing NIH3T3 cells strongly increased Rac and c-Jun N-terminal kinase (JNK) activation, but failed to show similar effect in the cells with the dominant-negative enzyme. Interestingly, epidermal growth factor (EGF) and PDGF stimulation led to increased extracellular signal-regulated kinase (Erk) and Akt pathway activation in cells with elevated wild-type PI3KC2β expression. Furthermore, increased expression of PI3KC2β protected NIH3T3 from detachment-dependent death (anoikis) in a RhoA-dependent manner. Taken together, these findings suggest that PI3KC2β modulates the cell morphology and survival through a specific interaction with Dbl and the activation of RhoA.