Lipoprotein-Associated Phospholipase A2 Activity Predicts Cardiovascular Events in High Risk Coronary Artery Disease Patients

Objective

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is deemed to play a role in atherosclerosis and plaque destabilization as demonstrated in animal models and in prospective clinical studies. However, most of the literature is either focused on high-risk, apparently healthy patients, or is based on cross sectional studies. Therefore, we tested the hypothesis that serum Lp-PLA2 mass and activity are useful for predicting cardiovascular (CV) events over the coronary atherosclerotic burden and conventional risk factors in high-risk coronary artery disease patients.

Methods and Results

In a prospective cohort study of 712 Caucasian patients, who underwent coronary angiography and measurement of both Lp-PLA2 mass and activity at baseline, we determined incident CV events at follow-up after splitting the patients into a high and a low Lp-PLA2 mass and activity groups based on ROC analysis and Youden index. Kaplan-Meier and propensity score matching analysis were used to compare CV event-free survival between groups. Follow-up data were obtained in 75% of the cohort after a median of 7.2 years (range 1–12.7 years) during which 129 (25.5%) CV events were observed. The high Lp-PLA2 activity patients showed worse CV event-free survival (66.7% vs. 79.5%, p = 0.023) and acute coronary syndrome-free survival (75.4% vs. 85.6%, p = 0.04) than those in low Lp-PLA2 group.

Conclusions

A high Lp-PLA2 activity implies a worse CV prognosis at long term follow up in high-risk Caucasian patients referred for coronary angiography.     

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia

Background

Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.

Methods

Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.

Results

Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.

Conclusions

The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research.     

Long chain polyunsaturated fatty acids alter membrane-bound RANK-L expression and osteoprotegerin secretion by MC3T3-E1 osteoblast-like cells

Inflammation triggers an increase in osteoclast (bone resorbing cell) number and activity. Osteoclastogenesis is largely controlled by a triad of proteins consisting of a receptor (RANK), a ligand (RANK-L) and a decoy receptor (osteoprotegerin, OPG). Whilst RANK is expressed by osteoclasts, RANK-L and OPG are expressed by osteoblasts. The long chain polyunsaturated fatty acid (LCPUFA) arachidonic acid (AA, 20:4n-6) and its metabolite prostaglandin E2 (PGE2), are pro-inflammatory and PGE2 is a potent stimulator of RANKL expression. Various LCPUFAs such as eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3) and gamma-linolenic acid (GLA, 18:3n-6) have anti-inflammatory activity. We aimed to determine if AA itself can stimulate RANKL expression and whether EPA, DHA and GLA inhibit RANKL expression in osteoblasts. MC3T3-E1/4 osteoblast-like cells were cultured under standard conditions with each of the LCPUFAs (5microg/ml) for 48h. Membrane-bound RANKL expression was measured by flow cytometry and OPG secretion measured by ELISA. In a second experiment, RANKL expression in MC3T3-E1/4 cells was stimulated by PGE2 treatment and the effect of EPA, DHA and GLA on membrane-bound RANKL expression and OPG secretion determined. The percentage of RANKL-positive cells was higher (p<0.05) than controls following treatment with AA or GLA but not after co-treatment with the cyclooxygenase inhibitor, indomethacin. DHA and EPA had no effect on membrane-bound RANKL expression under standard cell culture conditions. Secretion of OPG was lower (p<0.05) in AA-treated cells but not significantly different from controls in GLA, EPA or DHA treated cells. Treatment with prostaglandin E2 (PGE2) resulted in an increase (p<0.05) in the percentage of RANK-L positive cells and a decrease (p<0.05) in mean OPG secretion. The percentage of RANKL positive cells was significantly lower following co-treatment with PGE2 and either DHA or EPA compared to treatment with PGE2 alone. Mean OPG secretion remained lower than controls in cells treated with PGE2 regardless of co-treatment with EPA or DHA. Results from this study suggest COX products of GLA and AA induce membrane-bound RANKL expression in MC3T3-E1/4 cells. EPA and DHA have no effect on membrane-bound RANKL expression in cells cultured under standard conditions however both EPA and DHA inhibit the PGE2-induced increase in RANKL expression in MC3T3-E1/4 cells.     

Revision of <Emphasis Type="Italic">Plasmopara</Emphasis> (Oomycota,Peronosporales) parasitic to <Emphasis Type="Italic">Impatiens</Emphasis>

The oomycete Plasmopara obducens was first described on wild Impatiens noli-tangere in Germany in 1877. About 125 years later the first occurrence of P. obducens on cultivated I. walleriana in the United Kingdom was reported, and a worldwide epidemic followed. Although this pathogen is a major threat for ornamental busy lizzy, the identity of the pathogen remained unconfirmed and the high host specificity observed for the genus Plasmopara cast doubts regarding its determination as P. obducens. In this study, using multigene phylogenies and morphological investigation, it is revealed that P. obducens on I. noli-tangere is not the conspecific with the pathogen affecting I. walleriana and another ornamental balsam, I. balsamina. As a consequence, the new names P. destructor and P. velutina are introduced for the pathogens of I. walleriana and I. balsamina, respectively.     

Early and Late Pathomechanisms in Alzheimer’s Disease: From Zinc to Amyloid-β Neurotoxicity

There are several systemic and intracerebral pathologic conditions, which limit provision and utilization of energy precursor metabolites in neuronal cells. Energy deficits cause excessive depolarization of neuronal cells triggering glutamate-zinc evoked excitotoxic cascade. The intracellular zinc excess hits several intraneuronal targets yielding collapse of energy balance and impairment functional and structural impairments cholinergic neurons. Disturbances in metabolism of acetyl-CoA, which is a direct precursor for energy, acetylcholine, N-acetyl-l-aspartate and acetylated proteins synthesis, play an important role in these pathomechanisms. Disruption of brain homeostasis activates slow accumulation of amyloid-β _1?42 , which extra and intracellular oligomeric deposits disrupt diverse transporting and signaling processes in all membrane structures of the cell. Both neurotoxic signals may combine aggravating detrimental effects on neuronal cell. Different neuroglial and neuronal cell types may display differential susceptibility to similar pathogenic insults depending on specific features of their energy and functional parameters. This review, basing on findings gained from cellular and animal models of Alzheimer’s disease, discusses putative energy/acetyl-CoA dependent mechanism in early and late stages of neurodegeneration.     

A closer look at the phosphorus-phosphorus double bond lengths in meta-terphenyl substituted diphosphenes

The single crystal X-ray structure of DmpPPDmp (1, Dmp = 2,6-Mes₂C₆H₃), which was previously reported to have a relatively short PP bond distance of 1.985(2) Å at room temperature, has been reexamined at variable temperatures. Crystallographic analyses of 1 at 100 K allow for resolution of disorder of the two phosphorus atoms (which is unresolvable from room temperature diffraction data), and for determination of a more conventional PP bond length of 2.029(1) Å. Single crystals of the closely related diphosphene DxpPPDxp (2, Dxp = 2,6-(2,6-Me₂C₆H₃)₂C₆H₃) show similar disorder in one of two crystallographically independent molecules in the unit cell. A value of 2.0276(4) Å is found for the non-disordered PP bonds at 100 K for 2. A new diphosphene Ar′PPAr′ (3, Ar′ = 2,6-Mes₂-4-OMe-C₆H₃) has been prepared and its structure has also been examined. The PP bond length for 3 was determined to be 2.0326(9) Å and relatively free of the effects of disorder.     

Microarray analyses of peripheral blood cells identifies unique gene expression signature in psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic and erosive form of arthritis of unknown cause. We aimed to characterize the PsA phenotype using gene expression profiling and comparing it with healthy control subjects and patients rheumatoid arthritis (RA). Peripheral blood cells (PBCs) of 19 patients with active PsA and 19 age- and sex-matched control subjects were used in the analyses of PsA, with blood samples collected in PaxGene tubes. A significant alteration in the pattern of expression of 313 genes was noted in the PBCs of PsA patients on Affymetrix U133A arrays: 257 genes were expressed at reduced levels in PsA, and 56 genes were expressed at increased levels, compared with controls. Downregulated genes tended to cluster to certain chromosomal regions, including those containing the psoriasis susceptibility loci PSORS1 and PSORS2. Among the genes with the most significantly reduced expression were those involved in downregulation or suppression of innate and acquired immune responses, such as SIGIRR, STAT3, SHP1, IKBKB, IL-11RA, and TCF7, suggesting inappropriate control that favors proin-flammatory responses. Several members of the MAPK signaling pathway and tumor suppressor genes showed reduced expression. Three proinflammatory genes--S100A8, S100A12, and thioredoxin--showed increased expression. Logistic regression and recursive partitioning analysis determined that one gene, nucleoporin 62 kDa, could correctly classify all controls and 94.7% of the PsA patients. Using a dataset of 48 RA samples for comparison, the combination of two genes, MAP3K3 followed by CACNA1S, was enough to correctly classify all RA and PsA patients. Thus, PBC gene expression profiling identified a gene expression signature that differentiated PsA from RA, and PsA from controls. Several novel genes were differentially expressed in PsA and may prove to be diagnostic biomarkers or serve as new targets for the development of therapies.