Arteriopathy after transarterial chemo-lipiodolization for hepatocellular carcinoma.

OBJECTIVES: The purpose of this study was to investigate the incidence of and the risk factors for arteriopathy in hepatic arteries after transarterial chemo-lipiodolization in patients with hepatocellular carcinoma and the subsequent treatment strategy changes due to arteriopathy. PATIENTS AND METHODS: A total of 365 arteries in 167 patients (126 men and 41 women; mean age, 60.4±15.0 [SD] years [range: 18-87 years]) were evaluated for the development of arteriopathy after chemo-lipiodolization with epirubicin- or doxorubicin-Lipiodol® emulsion. The development of arteriopathy after chemo-lipiodolization was assessed on arteriograms performed during subsequent transarterial treatments. The treatment strategy changes due to arteriopathy, including change in the chemo-lipiodolization method and the application of alternative therapies was also investigated. Univariate and multivariate binary logistic regression models were used to identify risk factors for arteriopathy and subsequent treatment strategy change. RESULTS: One hundred two (27.9%) arteriopathies were detected in 62/167 (37.1%) patients (45 men, 17 women) with a mean age of 63.3±7.1 [SD] years (age range, 50-86 years). The incidence of arteriopathy was highly patient dependent, demonstrating significant correlation in a fully-adjusted multivariate regression model (P<0.0001). Multivariate-adjusted regression analysis with adjustment for the patient effect showed a statistically significant association of super-selective chemo-lipiodolization (P=0.003) with the incidence of arteriopathy. Thirty of the 102 arteriopathies (29.4%) caused a change in treatment strategy. No factors were found to be significantly associated with the treatment strategy change. CONCLUSION: The incidence of arteriopathy after chemo-lipiodolization is 27.9%. Among them, 29.4% result in a change in treatment strategy.

Mechanisms of Günther Tulip filter tilting during transfemoral placement.

OBJECTIVE: The purpose of this study was to characterize the mechanisms of Günther Tulip filter (GTF) tilting during transfemoral placement in an experimental model with further validation in a clinical series. MATERIALS AND METHODS: In an experimental study, 120 GTF placements in an inferior vena cava (IVC) model were performed using 6 configurations of pre-deployment filter position. The angle between the pre-deployment filter axis and IVC axis, and the proximity of the constrained filter legs to IVC wall prior to deployment were evaluated. The association of those pre-deployment factors with post-deployment filter tilting was analyzed. The association noted in the experimental study was then evaluated in a retrospective clinical series of 21 patients. RESULTS: In the experimental study, there was a significant association between the pre-deployment angle and post-deployment filter tilting (P<0.0001). With a low pre-deployment angle (≤5°), a significant association was noted between filter tilting and the proximity of the constrained filter legs to the far IVC wall (P=0.001). In a retrospective clinical study, a significant association between the pre-deployment angle and post-deployment filter tilting was also noted with a linear regression model (P=0.026). CONCLUSION: Significant association of the pre-deployment angle with post-deployment GTF tilting was shown in both the experimental and clinical studies. The experimental study also showed that proximity of filter legs is relevant when pre-deployment angle is small. Addressing these factors may result in a lower incidence of filter tilting.

Generation of high curvature membranes mediated by direct endophilin bilayer interactions.

Endophilin 1 is a presynaptically enriched protein which binds the GTPase dynamin and the polyphosphoinositide phosphatase synptojanin. Perturbation of endophilin function in cell-free systems and in a living synapse has implicated endophilin in endocytic vesicle budding (Ringstad, N., H. Gad, P. Low, G. Di Paolo, L. Brodin, O. Shupliakov, and P. De Camilli. 1999. Neuron. 24:143-154; Schmidt, A., M. Wolde, C. Thiele, W. Fest, H. Kratzin, A.V. Podtelejnikov, W. Witke, W.B. Huttner, and H.D. Soling. 1999. Nature. 401:133-141; Gad, H., N. Ringstad, P. Low, O. Kjaerulff, J. Gustafsson, M. Wenk, G. Di Paolo, Y. Nemoto, J. Crun, M.H. Ellisman, et al. 2000. Neuron. 27:301-312). Here, we show that purified endophilin can directly bind and evaginate lipid bilayers into narrow tubules similar in diameter to the neck of a clathrin-coated bud, providing new insight into the mechanisms through which endophilin may participate in membrane deformation and vesicle budding. This property of endophilin is independent of its putative lysophosphatydic acid acyl transferase activity, is mediated by its NH2-terminal region, and requires an amino acid stretch homologous to a corresponding region in amphiphysin, a protein previously shown to have similar effects on lipid bilayers (Takei, K., V.I. Slepnev, V. Haucke, and P. De Camilli. 1999. Nat. Cell Biol. 1:33-39). Endophilin cooligomerizes with dynamin rings on lipid tubules and inhibits dynamin's GTP-dependent vesiculating activity. Endophilin B, a protein with homology to endophilin 1, partially localizes to the Golgi complex and also deforms lipid bilayers into tubules, underscoring a potential role of endophilin family members in diverse tubulovesicular membrane-trafficking events in the cell.

Dual interaction of synaptotagmin with mu2- and alpha-adaptin facilitates clathrin-coated pit nucleation.

The synaptic vesicle protein synaptotagmin was proposed to act as a major docking site for the recruitment of clathrin coats implicated in endocytosis, including the recycling of synaptic vesicles. We show here that the C2B domain of synaptotagmin binds mu2- and alpha-adaptin, two of the four subunits of the endocytic adaptor complex AP-2. mu2 represents the major interacting subunit of AP-2 within this complex. Its binding to synaptotagmin is mediated by a site in subdomain B that is distinct from the binding site for tyrosine-based sorting motifs located in subdomain A. The presence of the C2B domain of synaptotagmin at the surface of liposomes enhances the recruitment of AP-2 and clathrin. Conversely, perturbation of the interaction between synaptotagmin and AP-2 by synprint, the cytoplasmic synaptotagmin-binding domain of N-type calcium channels, inhibits transferrin internalization in living cells. We conclude that a dual interaction of synaptotagmin with the clathrin adaptor AP-2 plays a key physiological role in the nucleation of endocytic clathrin-coated pits.

Generation of coated intermediates of clathrin-mediated endocytosis on protein-free liposomes.

Clathrin-coated buds and dynamin-coated tubules morphologically similar to corresponding structures observed in synaptic membranes can be generated on protein-free liposomes by incubation with cytosol, or with clathrin coat proteins and purified dynamin, respectively. Dynamin- and clathrin-coated intermediates may form independently of each other, despite the coupling between the two processes typically observed in synaptic membranes. Formation of both structures on liposomes can occur in the absence of nucleotides. These findings indicate that interfaces between lipids and cytosolic proteins are fully sufficient to deform lipids bilayers into buds and tubules. They suggest that a main function of membrane proteins is to act as positive and negative regulators of coat assembly, therefore controlling these processes in time and space.