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Acetaminophen (APAP) or paracetamol is a commonly encountered medicine in poisonings. We studied the changes in APAP related calls to the Finnish poison information centre (FPIC), and serious intoxications, involving hepatotoxicity or death in 2001-2014. These data were compared with paracetamol sales in Finland.This is a retrospective analysis of the FPIC database calls, national cause of death registry, registries of liver transplantations and molecular adsorbent recycling system (MARS)-treated patients from Helsinki University Hospital together with the National Institute of Health and Welfare registry of patients hospitalized. Data on APAP sales were obtained from the Finnish Medicines Agency.Between 2001 and 2014, the number of calls/year related to human APAP exposures to the FPIC increased from 227 to 1058. No change in the age distribution of enquiries was seen. Most calls involved minors: 58% (range 52-64%) for children under 6 years old, and 9% (range 6-14%) for children of 6-15 years. In Finland, APAP related fatalities have gradually increased from an average of 7/year (range 4-10) in 2000-2005 to an average of 11/year (range 6-17) in 2010-2013, whereas the number of liver transplantations remained low, average 0.6/year (range 0-2). For patients in need of MARS-treatment, a slight decrease was seen. Total APAP sales increased from 5.6 (47% prescription, 53% OTC) to 29.7 (81% prescription, 19% OTC). DDD/1000 inhabitants/day from 2001 to 2014 is recorded. Best linear relationship (RDuring the study period, we see an increase in FPIC exposure calls accompanied by an increase in APAP sales. Changes in the chosen indicators for serious poisonings show only a weak association. Despite an evident trend between sales and fatalities, the correlation with fatality remains weak due to the small number of fatalities.

Nicotine intoxication is a rare cause of death and can lead to brain death after respiratory arrest and hypoxic-ischemic encephalopathy. To our knowledge, no previous reports regarding organ donation after nicotine intoxication have been described. We present a successful case of kidney donation after brain death caused by subcutaneous nicotine overdose from liquid nicotine from an e-cigarette cartridge in an attempted suicide. Both kidneys were transplanted successfully with immediate graft function, and both recipients were discharged at postoperative day 9 with normal plasma creatinine levels. Graft function has remained excellent in follow-up. This case suggests that kidneys from a donor with fatal nicotine intoxication may be successfully used for kidney transplantation in the absence of other contraindications for donation.

1,2-Dimyristoyl-sn-glycero-3-phospho-rac-glycerol (DMPG) at low salt concentrations has a complex endotherm with at least four components and extending over the span of 20 degrees. During this ongoing melting, the solution becomes viscous and scatters light poorly. This multipeak endotherm was suggested to result from the effects of curvature on the relative free energies of gel and fluid DMPG bilayers, further relating to the formation of an intermediate sponge phase between the lamellar gel and fluid phases. Although later studies appear to exclude a connected bilayer network, the relation of the endotherm peaks to curvature remains an appealing hypothesis. This was tested by including in the system both water-soluble small molecules (dimethyl sulfoxide, ethanol, and urea) as well as amphiphiles (myristoyl-lyso-PG, cholesterol, cholesterol-3-sulfate, and dimyristoylglycerol) known to alter the spontaneous curvature of bilayers. All compounds increasing the monolayer positive spontaneous curvature (ethanol, urea, myristoyl-lyso-PG, cholesterol-3-sulfate) increased the temperature span of the intermediate state and elevated the temperature of its dissolution, while all compounds increasing the negative spontaneous curvature (dimethyl sulfoxide, cholesterol, dimyristoylglycerol) had the opposite effect, implying that the intermediate state contains a structure with positive curvature. The results support the view that the intermediate state consists of vesicles with a large number of holes. The viscosity increase could be related to vesicle expansion needed to accommodate the numerous holes.

Siramesine (SRM) is a sigma-2 receptor agonist which has been recently shown to inhibit growth of cancer cells. Fluorescence spectroscopy experiments revealed two distinct binding sites for this drug in phospholipid membranes. More specifically, acidic phospholipids retain siramesine on the bilayer surface due to a high-affinity interaction, reaching saturation at an apparent 1:1 drug-acidic phospholipid stoichiometry, where after the drug penetrates into the hydrocarbon core of the membrane. This behavior was confirmed using Langmuir films. Of the anionic phospholipids, the highest affinity, comparable to the affinities for the binding of small molecule ligands to proteins, was measured for phosphatidic acid (PA, mole fraction of X(PA) = 0.2 in phosphatidylcholine vesicles), yielding a molecular partition coefficient of 240 +/- 80 x 10(6). An MD simulation on the siramesine:PA interaction was in agreement with the above data. Taking into account the key role of PA as a signaling molecule promoting cell growth our results suggest a new paradigm for the development of anticancer drugs, viz. design of small molecules specifically scavenging phospholipids involved in the signaling cascades controlling cell behavior.

A novel method for the quantitative assessment of the membrane partitioning of a ligand from the aqueous phase is described, demonstrated here with the thoroughly studied antipsychotic chlorpromazine (CPZ). More specifically, collisional quenching of the fluorescence of a pyrene labeled fluorescent lipid analog 1-palmitoyl-2[10-(pyren-1-yl)]decanoyl-sn-glycero-3-phosphocholine (PPDPC) by CPZ was utilized, using 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine and -serine (POPC and POPS) liposomes as model membranes. The molar partition coefficient is obtained from two series of titrations, one with constant [phospholipid] and increasing [drug] and the other with constant [drug] and varying total [phospholipid], the latter further comprising of large unilamellar vesicles (LUVs) of POPC/POPS/PPDPC at a constant concentration of 10 microM and indicated concentrations of POPC/POPS LUVs. Notably, the approach described is generic and can be employed in screening for the membrane partitioning of compounds, providing that a suitable fluorescence parameter can be incorporated into one population of liposomes utilized as model membranes.

One of the most prominent hallmarks of apoptotic cells is the altered characteristics of their plasma membrane, with its blebbing and exposure of the anionic phospholipid, phosphatidylserine (PS), in the outer leaflet of the lipid bilayer. The latter feature provides the basis of distinguishing apoptotic cells from most normal cells due to staining with fluorescently labeled annexin V, binding specifically to PS. In this article, we report on the binding to apoptotic leukemic T cells (Jurkat cell line, treated with different apoptotic inducers) of cationic liposomes (CLs) composed of the cationic gemini surfactant SS-1 ((2S,3S)-2,3-dimethoxy-1,4-bis(N-hexadecyl-N,N-dimethylammonium)butane dibromide), the fluorescent lipid analog DOPRho (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl)), and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine). Control cells showed negligible and irregular binding patterns of CLs, whereas apoptotic cells revealed a strongly augmented staining of their plasma membrane. Morphological observations and comparison with standard procedures for detecting apoptotic cells further demonstrated the binding of CLs to be intense for cells undergoing apoptosis. In addition, some apoptotic cells with higher caspase-3 activity also revealed more pronounced staining by CLs. Our data suggest that the binding of CLs to apoptotic cells is mediated through an electrostatic interaction between the positively charged head group of SS-1 and the translocated anionic phospholipid PS in the plasma membrane. Because the fluorescent lipid tracer can be freely selected, this approach provides convenient and versatile means for the fluorescence detection of apoptotic cells.

The thermal phase behaviors of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs) were compared by fluorescence spectroscopy, using PPDPC (1-palmitoyl-2[10-(pyren-1-yl)]decanoyl-sn-glycero-3-phosphocholine) as a reporter, in parallel with differential scanning calorimetry (DSC). A striking difference is seen between MLVs and LUVs in the lateral organizational dynamics of PPDPC, in particular, below the main phase transition temperature T(m), with efficient clustering of PPDPC into fluid microdomains in the L(beta') and P(beta') (ripple) phases of DPPC MLVs. In the P(beta') phase of MLVs, the probe is likely to become enriched in linear line defects, restricting intermolecular collisions to occur in a quasi one-dimensional system. In contrast, fluorescence and DSC data both suggest that the P(beta') phase is not well-defined in LUVs. Fluorescence anisotropy for 1-palmitoyl-2-[3-(diphenylhexatrienyl)propanoyl]-sn-glycero-3-phosphocholine (DPH-PC) revealed similar acyl chain order for both LUVs and MLVs in the L(beta') and P(beta') phases. However, for MLVs with this probe, T(m) determined from anisotropy was elevated by 0.7 degrees, with higher anisotropy evident in the L(alpha) phase compared to LUVs. These differences in the thermal phase behavior of the two types of liposomes are likely to derive from the augmented acyl chain order due to cooperative coupling of the lamellae of DPPC MLVs, thus manifesting in new, emerging material properties in the latter type of bilayer membrane assembly, as reflected in the organizational dynamics of the pyrene-labeled analogue.

The properties of a novel disulfide-bond-containing gemini surfactant bis[N,N-dimethyl-N-hexadecyl-N-(2-mercaptoethyl)ammonium bromide] disulfide (DSP) were studied using a Langmuir balance, supported monolayers, differential scanning calorimetry, giant vesicles, and LUVs. In 150 mM NaCl the cmc for DSP was 7.5 microM whereas that of the monomer N,N-dimethyl-N-hexadecyl-N-(2-mercaptoethyl)ammonium bromide (MSP) was 12.1 microM. Both surfactants exhibited single endotherms upon DSC, with peak temperatures Tm at 21.7 and 20.1 degrees C for DSP and MSP, respectively. The endotherm for MSP was significantly broader indicating less cooperative melting. Both in monolayers and in vesicles reductive cleavage of the disulfide bond of DSP could be obtained by glutathione (GSH). For Langmuir films of DSP the addition of GSH into the subphase led to a decrease in surface pressure pi as well as surface dipole potential psi. Although the cleavage by GSH was significantly slower in the presence of a charge saturating concentration of DNA, it did not prevent the reaction. The resulting monomers detached from supported monolayers, leading to loss of affinity of the surface for DNA. Disruption of giant vesicles containing DSP within approximately 30 s following a local injection of GSH was observed, revealing membrane destabilization.

While much is known about the self-assembly of lipids on nanoscale, our understanding of their biologically relevant mesoscale organization remains incomplete. Here, we show for a cationic gemini lipid a sharp and reversible transition from small vesicles with an average diameter of approximately 40 nm to giant vesicles (GVs) with an average diameter of approximately 11 microm. This transition is dependent on proper [NaCl] and specific temperature. Below this transition and in the vicinity of the air/water interface, a series of mesoscale morphological transitions was observed, revealing complex structures resembling biological membranes. On the basis of microscopy experiments, a tentative [NaCl] versus temperature shape/size phase diagram was constructed. To explain this unprecedented transition, we propose a novel mechanism whereby a specific interaction of Cl(-) counterion with the cationic gemini surfactant initiates the formation of a commensurate solute counterion lattice with low spontaneous curvature. In keeping with the high bending rigidity of NaCl crystal, this tightly associated ionic lattice enslaves membrane curvature and the mesoscale 3-D organization of this lipid.

International audience; Activation of kainate receptors depresses excitatory synaptic transmission in the hippocampus. In the present study, we have utilised a GluR5 selective agonist, ATPA [(RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid], and a GluR5 selective antagonist, LY294486 [(3SR,4aRS,6SR,8aRS)-6-([[(1H-tetrazol-5-y l)methyl]oxy]methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3 -carboxylic acid], to determine whether GluR5 subunits are involved in this effect. ATPA mimicked the presynaptic depressant effects of kainate in the CA1 region of the hippocampus. It depressed reversibly AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor-mediated field excitatory postsynaptic potentials (field EPSPs) with an IC50 value of approximately 0.60 microM. The dual-component excitatory postsynaptic current (EPSC) and the pharmacologically isolated NMDA (N-methyl-D-aspartate) receptor-mediated EPSC were depressed to a similar extent by 2 microM ATPA (61 +/- 7% and 58 +/- 6%, respectively). Depressions were associated with an increase in the paired-pulse facilitation ratio suggesting a presynaptic locus of action. LY294486 (20 microM) blocked the effects of 2 microM ATPA on NMDA receptor-mediated EPSCs in a reversible manner. In area CA3, 1 microM ATPA depressed reversibly mossy fibre-evoked synaptic transmission (by 82 +/- 10%). The effects of ATPA were not accompanied by any changes in the passive properties of CA1 or CA3 neurones. However, in experiments where K+, rather than Cs+, containing electrodes were used, a small outward current was observed. These results show that GluR5 subunits comprise or contribute to a kainate receptor that regulates excitatory synaptic transmission in both the CA1 and CA3 regions of the hippocampus.