Nimodipine prior to alcohol withdrawal prevents memory deficits during the abstinence phase

Effects of the dihydropyridine, nimodipine, an antagonist at L-type calcium channels, on the memory loss in rats caused by long term alcohol consumption were examined. Either a single dose of nimodipine or 2 weeks of repeated administration was given prior to withdrawal from 8 months of alcohol consumption. Memory was measured by the object recognition test and the T maze. Both nimodipine treatments prevented the memory deficits when these were measured between 1 and 2 months after alcohol withdrawal. At the end of the memory testing, 2 months after cessation of chronic alcohol consumption, glucocorticoid concentrations were increased in specific regions of rat brain without changes in plasma concentrations. Both nimodipine treatment schedules substantially reduced these rises in brain glucocorticoid. The data indicate that blockade of L-type calcium channels prior to alcohol withdrawal protects against the memory deficits caused by prolonged alcohol intake. This shows that specific drug treatments, such as nimodipine, given over the acute withdrawal phase, can prevented the neuronal changes responsible for subsequent adverse effects of long term consumption of alcohol. The results also suggest the possibility that regional brain glucocorticoid increases may be involved in the adverse effects of long term alcohol intake on memory. Such local changes in brain glucocorticoid levels would have major effects on neuronal function. The studies indicate that L-type calcium channels and brain glucocorticoid levels could form new targets for the treatment of cognitive deficits in alcoholics.

Intracellular Ca(2+) operates a switch between repair and lysis of streptolysin O-perforated cells

Pore-forming (poly)peptides originating from invading pathogens cause plasma membrane damage in target cells, with consequences as diverse as proliferation or cell death. However, the factors that define the outcome remain unknown. We show that in cells maintaining an intracellular Ca(2+) concentration [Ca(2+)](i) below a critical threshold of 10 microM, repair mechanisms seal off 'hot spots' of Ca(2+) entry and shed them in the form of microparticles, leading to [Ca(2+)](i) reduction and cell recovery. Cells that are capable of preventing an elevation of [Ca(2+)](i) above the critical concentration, yet are unable to complete plasma membrane repair, enter a prolonged phase of [Ca(2+)](i) oscillations, accompanied by a continuous shedding of microparticles. When [Ca(2+)](i) exceeds the critical concentration, an irreversible formation of ceramide platforms within the plasma membrane and their internalisation drives the dying cells beyond the 'point of no return'. These findings show that the extent of [Ca(2+)](i) elevation determines the fate of targeted cells and establishes how different Ca(2+)-dependent mechanisms facilitate either cell survival or death.

In vitro allergy tests compared to intradermal testing in horses with recurrent airway obstruction

Recurrent airway obstruction (RAO) is a common condition in stabled horses characterised by small airway inflammation, airway neutrophilia and obstruction following exposure of susceptible horses to mouldy hay and straw and is thus regarded as a hypersensitivity reaction to mould spores. However, the role of IgE-mediated reactions in RAO remains unclear. The aim of the study was to investigate with a serological IgE ELISA test (Allercept), an in vitro sulfidoleukotriene (sLT) release assay (CAST) and with intradermal testing (IDT) whether serum IgE and IgE-mediated reactions against various mould, mite and pollen extracts are associated with RAO. IDT reactions were evaluated at different times in order to detect IgE-mediated immediate type reactions (type I hypersensitivity reactions, 0.5-1 h), immune complex-mediated late type reactions (type III reactions, 4-10 h) and cell-mediated delayed type reactions (type IV hypersensitivity reactions 24-48 h). In the serological test, overall the control horses displayed more positive reactions than the RAO-affected horses but the difference was not significant. Comparison of the measured IgE levels showed that the RAO-affected horses had slightly higher IgE levels against Aspergillus fumigatus than controls (35 and 16 AU, respectively, p<0.05), but all values were below the cut off (150 AU) of the test. In the sLT release assay, seven positive reactions were observed in the RAO-affected horses and four in the controls but this difference was not significant. A significantly higher proportion of late type IDT reactions was observed in RAO-affected horses compared to controls (25 of 238 possible reactions versus 12 of 238 possible reactions, respectively, p<0.05). Interestingly, four RAO-affected but none of the control horses reacted with the recombinant mould allergen A. fumigatus 8 (rAsp f 8, p<0.05), but only late phase and delayed type reactions were observed. In all three tests the majority of the positive reactions was observed with the mite extracts (64%, 74% and 88% of all positive reactions, respectively) but none of the tests showed a significant difference between RAO-affected and control animals. Our findings do not support that IgE-mediated reactions are important in the pathogenesis of RAO. Further studies are needed to investigate whether sensitisation to mite allergens is of clinical relevance in the horse and to understand the role of immune reactions against rAsp f 8.

Switching on the fluorescence of 2-aminopurine by site-selective microhydration

​2-Aminopurine (​2AP) is a fluorescent isomer of ​adenine and has a fluorescence lifetime of ~11 ns in water. It is widely used in biochemical settings as a site-specific fluorescent probe of DNA and RNA structure and base-flipping and -folding. These assays assume that ​2AP is intrinsically strongly fluorescent. Here, we show this not to be the case, observing that gas-phase, jet-cooled ​2-aminopurine and ​9-methyl-2-aminopurine have very short fluorescence lifetimes (156 ps and 210 ps, respectively); they are, to all intents and purposes, non-fluorescent. We find that the lifetime of ​2-aminopurine increases dramatically when it is part of a hydrate cluster, 2AP·(H2O)n, where n = 1–3. Not only does it depend on the presence of water molecules, it also depends on the specific hydrogen-bonding site to which they attach and on the number of H2O molecules at that site. We selectively microhydrate ​2-aminopurine at its sugar-edge, cis-amino or trans-amino sites and see that its fluorescence lifetime increases by 4, 50 and 95 times (to 14.5 ns), respectively.

MR imaging of the adrenal glands: 1.5T versus 3T

MR imaging at 1.5T is considered the prime cross-sectional imaging modality for characterization of adrenal lesions. This is of utmost clinical importance, because non-functioning adenoma and adrenal metastasis are fairly common. The differentiation of these two tumor entities primarily is based on chemical shift imaging, also known as dual echo in-phase and opposed-phase imaging. At 3.0 T, the echo time pairs for in-phase and opposed-phase MR imaging need to be adjusted because the frequency difference is double that of standard 1.5T MR systems. Unfortunately, the acquisition of the first opposed-phase echo at 1.1 milliseconds and the first in-phase echo at 2.2 milliseconds within the same breath-hold requires unacceptably high receiver bandwidths at 3.0 T. Therefore, alternative data collection schemes have been implemented. This article reviews the current literature regarding adrenal imaging at 3.0 T with a focus on the chemical shift technique.

Right-handed neutrino production rate at T > 160 GeV

The production rate of right-handed neutrinos from a Standard Model plasma at a temperature above a hundred GeV has previously been evaluated up to NLO in Standard Model couplings (g ~ 2/3) in relativistic (M ~ πT) and non-relativistic regimes (M ≫ πT), and up to LO in an ultrarelativistic regime (M ≲ gT). The last result necessitates an all-orders resummation of the loop expansion, accounting for multiple soft scatterings of the nearly light-like particles participating in 1↔2 reactions. In this paper we suggest how the regimes can be interpolated into a result applicable for any right-handed neutrino mass and at all temperatures above 160GeV. The results can also be used for determining the lepton number washout rate in models containing right-handed neutrinos. Numerical results are given in a tabulated form permitting for their incorporation into leptogenesis codes. We note that due to effects from soft Higgs bosons there is a narrow intermediate regime around M ~g 1/2 T in which our interpolation is phenomenological and a more precise study would be welcome.

Measurement of the muon reconstruction performance of the ATLAS detector using 2011 and 2012 LHC proton-proton collision data

This paper presents the performance of the ATLAS muon reconstruction during the LHC run with pp collisions at √s = 7–8 TeV in 2011–2012, focusing mainly on data collected in 2012. Measurements of the reconstruction efficiency and of the momentum scale and resolution, based on large reference samples of J/ψ → μμ, Z → μμ and ϒ → μμ decays, are presented and compared to Monte Carlo simulations. Corrections to the simulation, to be used in physics analysis, are provided. Over most of the covered phase space (muon |η| < 2.7 and 5 ≲ pT ≲ 100 GeV) the efficiency is above 99% and is measured with per-mille precision. The momentum resolution ranges from 1.7% at central rapidity and for transverse momentum pT ≅ 10 GeV, to 4% at large rapidity and pT ≅ 100 GeV. The momentum scale is known with an uncertainty of 0.05% to 0.2% depending on rapidity. A method for the recovery of final state radiation from the muons is also presented.

Insulin activates Na(+)/H(+) exchanger 3: biphasic response and glucocorticoid dependence.

Insulin is an important regulator of renal salt and water excretion, and hyperinsulinemia has been implicated to play a role in hypertension. One of the target proteins of insulin action in the kidney is Na(+)/H(+) exchanger 3 (NHE3), a principal Na(+) transporter responsible for salt absorption in the mammalian proximal tubule. The molecular mechanisms involved in activation of NHE3 by insulin have not been studied so far. In opossum kidney (OK) cells, insulin increased Na(+)/H(+) exchange activity in a time- and concentration-dependent manner. This effect is due to activation of NHE3 as it persisted after pharmacological inhibition of NHE1 and NHE2. In the early phase of stimulation (2-12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, enhanced NHE3 activity was accompanied by an increase in total and cell surface NHE3 protein and NHE3 mRNA abundance. All the effects of insulin on NHE3 activity, protein, and mRNA were amplified in the presence of hydrocortisone. These results suggest that insulin stimulates renal tubular NHE3 activity via a biphasic mechanism involving posttranslational factors and an increase in NHE3 gene expression and the effects are dependent on the permissive action of hydrocortisone.

Effectiveness of tooth wipes in removing babies' dental biofilm

PURPOSE To assess the effectiveness of tooth wipes in removing dental biofilm from babies' anterior teeth, as well as to evaluate the babies' behaviour and the guardians' preference concerning hygiene methods. MATERIALS AND METHODS In this random blind cross-over study, 50 high caries risk babies, from 8 to 15 months old, were divided into two groups: babies with oral hygiene performed by caregivers (n = 25) or by their mothers (n = 25). The caregivers and mothers removed biofilm using three methods of oral hygiene (tooth wipes, toothbrushes and gauze), one in each experimental phase. Professional cleaning was done before each phase, which had 2 days of biofilm accumulation and 1 experimental day, when caregivers and mothers used one method to remove biofilm. Examiners blinded to the study design assessed the biofilm index at baseline, prior to and following biofilm removal using each method. The babies' behaviour and the mothers'/caregivers' preference were assessed. RESULTS The tooth wipes, toothbrushes and gauze significantly reduced the amount of biofilm (P < 0.001). The mothers' group removed more biofilm than the caregivers' group, using toothbrushes or tooth wipes (P < 0.05). Babies in the mothers' group had better behaviour using tooth wipes than toothbrushes (P < 0.05). Mothers and caregivers preferred to use tooth wipes. CONCLUSIONS Tooth wipes are effective in removing biofilm from babies' anterior teeth and are the method best accepted by mothers, caregivers and babies.

Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06)

pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients.

Effect of the Addition of a Fused Donor-Acceptor Ligand on a Ru(II) Complex: Synthesis, Characterization, and Photoinduced Electron Transfer Reactions of Ru(TTF-dppz)(2)(Aqphen) (2+)

The synthesis and the photophysical properties of the complex [Ru(TTF-dppz)(2)(Aqphen)](2+) (TTF = tetrathiafulvalene, dppz = dipyrido-[3,2-a:2',3'-c]phenazine, Aqphen = anthraquinone fused to phenanthroline via a pyrazine bridge) are described. In this molecular triad excitation into the metal ligand charge transfer bands results in the creation of a long-lived charge separated state with TTF acting as electron donor and anthraquinone as terminal acceptor. The lifetime of the charge-separated state is 400 ns in dichloromethane at room temperature. A mechanism for the charge separation involving an intermediate charge-separated state is proposed based on transient absorption spectroscopy.

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial

In cirrhosis, hepatic endothelial dysfunction as a result of oxidative stress contributes to the postprandial increase in hepatic venous pressure gradient (HVPG).

FLAG phase 2: Status and prospects

In this talk I presented the FLAG initiative, discussed the history of the project, its aim and scope. After completing the first review in 2010, we decided to extend the review to more quantities and to involve a larger group of people. I have illustrated the phase 2 of the project, its new structure and the schedule for the release of the next review.