Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-α) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-α in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-α contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastas

Segregation of Fluorescent Membrane Lipids into Distinct Micrometric Domains: Evidence for Phase Compartmentation of Natural Lipids?

Background: We recently reported that sphingomyelin (SM) analogs substituted on the alkyl chain by various fluorophores (e.g. BODIPY) readily inserted at trace levels into the plasma membrane of living erythrocytes or CHO cells and spontaneously concentrated into micrometric domains. Despite sharing the same fluorescent ceramide backbone, BODIPY-SM domains segregated from similar domains labelled by BODIPY-D-e-lactosylceramide (D-e-LacCer) and depended on endogenous SM. Methodology/Principal Findings. We show here that BODIPY-SM further differed from BODIPY-D-e-LacCer or -glucosylceramide (GlcCer) domains in temperature dependence, propensity to excimer formation, association with a glycosylphosphatidylinositol (GPI)-anchored fluorescent protein reporter, and lateral diffusion by FRAP, thus demonstrating different lipid phases and boundaries. Whereas BODIPY-D-e-LacCer behaved like BODIPY-GlcCer, its artificial stereoisomer, BODIPY-L-t-LacCer, behaved like BODIPY- and NBD-phosphatidylcholine (PC). Surprisingly, these two PC analogs also formed micrometric patches yet preferably at low temperature, did not show excimer, never associated with the GPI reporter and showed major restriction to lateral diffusion when photobleached in large fields. This functional comparison supported a three-phase micrometric compartmentation, of decreasing order: BODIPY-GSLs > -SM > -PC (or artificial L-t-LacCer). Co-existence of three segregated compartments was further supported by double labelling experiments and was confirmed by additive occupancy, up to ~70% cell surface coverage. Specific alterations of BODIPY-analogs domains by manipulation of corresponding endogenous sphingolipids suggested that distinct fluorescent lipid partition might reflect differential intrinsic propensity of endogenous membrane lipids to form large assemblies. Conclusions/Significance. We conclude that fluorescent membrane lipids spontaneously concentrate into distinct micrometric assemblies. We hypothesize that these might reflect preexisting compartmentation of endogenous PM lipids into non-overlapping domains of differential order: GSLs > SM > PC, resulting into differential self-adhesion of the two former, with exclusion of the latter

Non-technical Skills in Healthcare

AbstractNon-technical Skills (NTS) are a set of generic cognitive and social skills, exhibited by individuals and teams, that support technical skills when performing complex tasks. Typical NTS training topics include performance shaping factors, planning and preparation for complex tasks, situation awareness, perception of risk, decision-making, communication, teamwork and leadership. This chapter provides a framework for understanding these skills in theory and practice, how they interact, and how they have been applied in healthcare, as well as avenues for future research

Haplotypes of the NR4A2/NURR1 Gene and Cardiovascular Disease. The Rotterdam Study

Nuclear receptor subfamily 4, group A, member 2 (NR4A2, also called Nurr1) has lately become of interest with regard to atherogenesis. We examined the association between common variation in the NR4A2 gene and cardiovascular disease in the Rotterdam Study, a prospective population-based study among persons aged >= 55 years. Three SNPs that tag common haplotypes across a 36-kb region surrounding the NR4A2 gene were determined. Four haplotypes with frequencies > 1% covered 96% of the genetic variation. In 5,650 participants without history of coronary heart disease, 729 coronary heart disease events occurred during a median follow-up time of 11.9 years. NR4A2 haplotypes were neither associated with coronary events nor with intima-media thickness (IMT), carotid plaques, or ankle-arm index (AAI). NR4A2 haplotypes showed a tendency toward associations with aortic and coronary calcification (haplo.score global simulation P values 0.076 and 0.075, respectively), which seemed to be based on haplotype 2 (individual P values were both P = 0.015). Furthermore, NR4A2 haplotype 3 was associated with higher high-density lipoprotein (HDL) cholesterol and haplotype 4 with lower systolic blood pressure. In conclusion, NR4A2/NURR1 haplotypes were not associated with coronary events, carotid IMT, carotid plaques, or AAI. There was a tendency toward associations with aortic calcification and coronary calcification. Associations for NR4A2 were found with both HDL levels and blood pressure. It remains to be investigated which pathophysiological mechanisms pertain to NR4A2 function in cardiovascular disease. Hum Mutat 30, 417-423, 2009. (C) 2009 Wiley-Liss, Inc

Lipid pickup and delivery

Intracellular organelles have specific lipid and protein compositions. Although great progress has been made concerning the mechanisms that govern the transport of proteins between organelles, little information is available about the mechanisms of inter-organellar lipid transport. New work identifies a protein that specifically transports ceramide, a precursor of sphingolipid synthesis, between intracellular organelles

Basal cell carcinomas without histological confirmation and their treatment: an audit in four European regions.

BACKGROUND: Limited data are available on how often basal cell carcinomas (BCCs) are clinically diagnosed without histological confirmation and how they are treated. OBJECTIVES: Within the framework of the EPIDERM project, an audit was conducted in four European countries to study the occurrence of clinically diagnosed BCCs without histological confirmation and to investigate how these are treated. METHODS: In the Netherlands, Scotland, Finland and Malta studies were performed within different timeframes. Patients with one or more BCC(s) were selected and the number of clinically diagnosed BCCs without histological confirmation and their treatment was investigated by (manually) reviewing the (electronic) patient records and checking the (hospital) pathology databases to find evidence of histological confirmation. RESULTS: In the Netherlands, 1089 patients with a first histologically confirmed BCC developed 1974 BCCs of which 1833 (92·9%) were histologically confirmed and 141 (7·1%) were not. A 4-month retrospective study conducted in Scotland selected 294 patients with 344 BCCs; 306 (89·0%) were histologically confirmed and 38 (11·0%) were not. A 3-month prospective study performed at the same centre in Scotland identified 44 patients who developed 58 BCCs; 44 (75·9%) of these were histologically confirmed and 14 (24·1%) were not. In Finland, there were 701 patients who developed 977 BCCs, of which 807 (82·6%) were histologically and 170 (17·4%) nonhistologically confirmed. In Malta, there were 420 patients with 477 BCCs. Only three (0·7%) of them were clinically diagnosed without histological confirmation. In the Netherlands and Finland, clinically diagnosed BCCs without histological confirmation were most often treated with cryotherapy, whereas in Scotland 5% imiquimod cream was the preferred treatment modality. CONCLUSIONS: Although the frequency of clinically diagnosed BCCs without histological confirmation differed between the four European regions (range 0·7-24·1%), this confirms that the burden of BCC in Europe is underestimated when based on data from pathology and/or cancer registries