The release of free arachidonic acid from membrane phospholipids is believed to be the rate-controlling step in the production of the prostaglandins, leukotrienes, and related metabolites in inflammatory cells such as the macrophage. We have previously identified several different phospholipases in the macrophage-like cell line P388D1 potentially capable of controlling arachidonic acid release. Among them, a membrane-bound, alkaline pH optimum, Ca2+-dependent phospholipase A2 is of particular interest because of the likelihood that the regulatory enzyme has these properties. This phospholipase A2 has now been solubilized from the membrane fraction with octyl glucoside and partially purified. The first two steps in this purification are butanol extractions that yield a lyophilized, stable preparation of phospholipase A2 lacking other phospholipase activities. This phospholipase A2 shows considerably more activity when assayed in the presence of glycerol, regardless of whether the substrate, dipalmitoylphosphatidylcholine, is in the form of sonicated vesicles or mixed micelles with the nonionic surfactant Triton X-100. Glycerol (70%) increases both the Vmax and the Km with both substrate forms, giving a Vmax of about 15 nmol min-1 mg-1 and an apparent Km of about 60 microM for vesicles and a Vmax of about 100 nmol min-1 mg-1 and an apparent Km of about 1 mM for mixed micelles. Vmax/Km is slightly greater for vesicles than for mixed micelles. The lyophilized preparation of the enzyme is routinely purified about 60-fold and is suitable for evaluating phospholipase A2 inhibitors such as manoalide analogues. Subsequent steps in the purification are acetonitrile extraction followed by high performance liquid chromatography on an Aquapore BU-300 column and a Superose 12 column. This yields a 2500-fold purification of the membrane-bound phospholipase A2 with a 25% recovery and a specific activity of about 800 nmol min-1 mg-1 toward 100 microM dipalmitoylphosphatidylcholine in mixed micelles. When this material was subjected to analysis on a Superose 12 sizing column, the molecular mass of the active fraction was approximately 18,000 daltons.

The objective of this study was to assess attitudes toward participation in dementia prevention trials among elderly women with a family history of Alzheimer's disease (AD). Prevention trials require the recruitment and retainment unaffected individuals. Many studies indicate that those with a family history of memory problems have increased risk of memory loss. As part of a study to determine the interest of participation a clinical trial of estrogen among women with a family history of AD, we assessed their perceptions about dementia and attitudes about several potential agents. Eighty-six women with a family history of dementia were asked three specific questions. If 10 represents the best of health and zero the worst, what number would you give to dementia? How would you compare your risk of getting dementia to other people your age? How worried are you about becoming demented? They were also asked about their current medication (Including nonprescription and nutritional supplements) use. Women were asked whether they were willing to participate in a randomized clinical trial of estrogen, vitamins, and nonsteroids. The mean age of women in the group was 71 years + 6 years and the mean education level was 13 years + 3 years). Seventy percent of the women interviewed rated AD as representing “the worst of health,” 44% reported feeling more at risk of becoming demented. Agreement to participate in a trail of vitamins was highest (48%). Willingness to participate in a trial of estrogen was 35% and that to participate in a trial of nonsteroidals was 29%. Ratings of worry, risk, and willingness to participate were increased among the 47 women who had personally cared for someone with dementia. These data of willingness to participate in clinical trials provide important information for estimating samples for prevention studies. Study supported by AG08702 and AG08031-0751.

Objective

A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes).

Methods

Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52.

Results

Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo.

Conclusions

Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment.

Classification of evidence

This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.

We present measurements of e+e- production at midrapidity in Au+Au collisions at sNN=200 GeV. The invariant yield is studied within the PHENIX detector acceptance over a wide range of mass (mee<5 GeV/c2) and pair transverse momentum (pT<5 GeV/c) for minimum bias and for five centrality classes. The e+e- yield is compared to the expectations from known sources. In the low-mass region (mee=0.30-0.76 GeV/c2) there is an enhancement that increases with centrality and is distributed over the entire pair pT range measured. It is significantly smaller than previously reported by the PHENIX experiment and amounts to 2.3±0.4(stat)±0.4(syst)±0.2(model) or to 1.7±0.3(stat)±0.3(syst)±0.2(model) for minimum bias collisions when the open heavy-flavor contribution is calculated with pythia or mc@nlo, respectively. The inclusive mass and pT distributions, as well as the centrality dependence, are well reproduced by model calculations where the enhancement mainly originates from the melting of the ρ meson resonance as the system approaches chiral symmetry restoration. In the intermediate-mass region (mee=1.2-2.8 GeV/c2), the data hint at a significant contribution in addition to the yield from the semileptonic decays of heavy-flavor mesons.

Introduction

There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.

Methods

Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.

Results

Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).

Discussion

Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.

The PHENIX experiment at the BNL Relativistic Heavy Ion Collider has measured second- and third-order Fourier coefficients of the azimuthal distributions of direct photons emitted at midrapidity in Au+Au collisions at sNN=200 GeV for various collision centralities. Combining two different analysis techniques, results were obtained in the transverse momentum range of 0.4

The PHENIX collaboration presents first measurements of low-momentum (0.41  GeV/c) direct-photon yield dN_{γ}^{dir}/dη is a smooth function of dN_{ch}/dη and can be well described as proportional to (dN_{ch}/dη)^{α} with α≈1.25. This scaling behavior holds for a wide range of beam energies at the Relativistic Heavy Ion Collider and the Large Hadron Collider, for centrality selected samples, as well as for different A+A collision systems. At a given beam energy, the scaling also holds for high p_{T} (>5  GeV/c), but when results from different collision energies are compared, an additional sqrt[s_{NN}]-dependent multiplicative factor is needed to describe the integrated-direct-photon yield.

We present results of a search for two hypothetical strange dibaryon states, i.e. the H-dibaryon and the possible Λn‾ bound state. The search is performed with the ALICE detector in central (0–10%) Pb–Pb collisions at sNN=2.76 TeV, by invariant mass analysis in the decay modes Λn‾→d‾π+ and H-dibaryon →Λpπ−. No evidence for these bound states is observed. Upper limits are determined at 99% confidence level for a wide range of lifetimes and for the full range of branching ratios. The results are compared to thermal, coalescence and hybrid UrQMD model expectations, which describe correctly the production of other loosely bound states, like the deuteron and the hypertriton.