Anti-phosphorylcholine IgM, an Anti-inflammatory Mediator, Predicts Peripheral Vein Graft Failure: A Prospective Observational Study.

OBJECTIVES: One third of infrainguinal vein bypasses may fail within the first 1.5 years. Pro- and anti-inflammatory mechanisms are thought to be involved in these graft stenoses and occlusions. In previous studies, low levels of anti-phosphorylcholine IgM (anti-PC IgM, an innate anti-inflammatory IgM) have been associated with increased cardiovascular events. In this study, the peri-operative dynamics of anti-PC IgM levels were established during leg bypass surgery, and associations assessed between anti-PC IgM levels and primary graft patency. DESIGN AND METHODS: This was a prospective, observational cohort study of infrainguinal autogenous vein bypass for peripheral arterial occlusive disease involving four university affiliated hospitals. Plasma cytokine and anti-PC IgM levels were measured pre- and post-operatively. The outcome of interest was loss of primary graft patency because of occlusion or intervention for graft stenosis. RESULTS: One hundred and forty-two consecutive patients were enrolled: mean age 66 (46-91); 91% white race and male; 72.5% critical limb ischaemia (Fontaine III or IV). Median pre-operative anti-PC IgM levels were 49 units/mL (IQR 32.3-107.7, mean 89.8 + 101 sd). During follow up of an average of 1.8 years (1 month-7.4 years), 50 (35.2%) grafts lost primary patency. Pre-operative levels of interleukin 6 or C-reactive protein did not predict graft failure. Patients with pre-operative anti-PC IgM values in the lowest quartile had a twofold increased risk of graft failure (multivariable Cox proportional hazard, p = .03, HR 2.11, 95% CI 1.09-4.07), even after accounting for the other significant factors of conduit diameter, distal anastomosis, smoking, and the severity of leg ischaemia. CONCLUSIONS: Low levels of anti-PC IgM are associated with vein bypass graft failure. This biological mediator may be a useful marker to identify patients at higher risk, and offers the potential for novel, directed therapies for vascular inflammation and its consequences.

Exploring modality switching effects in negated sentences: further evidence for grounded representations.

Theories of embodied cognition (e.g., Perceptual Symbol Systems Theory; Barsalou, 1999, 2009) suggest that modality specific simulations underlie the representation of concepts. Supporting evidence comes from modality switch costs: participants are slower to verify a property in one modality (e.g., auditory, BLENDER-loud) after verifying a property in a different modality (e.g., gustatory, CRANBERRIES-tart) compared to the same modality (e.g., LEAVES-rustling, Pecher et al., 2003). Similarly, modality switching costs lead to a modulation of the N400 effect in event-related potentials (ERPs; Collins et al., 2011; Hald et al., 2011). This effect of modality switching has also been shown to interact with the veracity of the sentence (Hald et al., 2011). The current ERP study further explores the role of modality match/mismatch on the processing of veracity as well as negation (sentences containing "not"). Our results indicate a modulation in the ERP based on modality and veracity, plus an interaction. The evidence supports the idea that modality specific simulations occur during language processing, and furthermore suggest that these simulations alter the processing of negation.

Dietary cholesterol increases paraoxonase 1 enzyme activity.

HDL-associated paraoxonase 1 (PON1) activity has been consistently associated with cardiovascular and other diseases. Vitamins C and E intake have previously been positively associated with PON1 in a subset of the Carotid Lesion Epidemiology and Risk (CLEAR) cohort. The goal of this study was to replicate these findings and determine whether other nutrient intake affected PON1 activity. To predict nutrient and mineral intake values, 1,402 subjects completed a standardized food frequency survey of their dietary habits over the past year. Stepwise regression was used to evaluate dietary and covariate effects on PON1 arylesterase activity. Five dietary components, cholesterol (P < 2.0 × 10(-16)), alcohol (P = 8.51 × 10(-8)), vitamin C (P = 7.97 × 10(-5)), iron (P = 0.0026), and folic acid (0.037) were independently predictive of PON1 activity. Dietary cholesterol was positively associated and predicted 5.5% of PON1 activity, second in variance explained. This study presents a novel finding of dietary cholesterol, iron, and folic acid predicting PON1 activity in humans and confirms prior reported associations, including that with vitamin C. Identifying and understanding environmental factors that affect PON1 activity is necessary to understand its role and that of HDL in human disease.

Additional Common Polymorphisms in the PON Gene Cluster Predict PON1 Activity but Not Vascular Disease.

Background. Paraoxonase 1 (PON1) enzymatic activity has been consistently predictive of cardiovascular disease, while the genotypes at the four functional polymorphisms at PON1 have not. The goal of this study was to identify additional variation at the PON gene cluster that improved prediction of PON1 activity and determine if these variants predict carotid artery disease (CAAD). Methods. We considered 1,328 males in a CAAD cohort. 51 tagging single-nucleotide polymorphisms (tag SNPs) across the PON cluster were evaluated to determine their effects on PON1 activity and CAAD status. Results. Six SNPs (four in PON1 and one each in PON2/3) predicted PON1 arylesterase (AREase) activity, in addition to the four previously known functional SNPs. In total, the 10 SNPs explained 30.1% of AREase activity, 5% of which was attributable to the six identified predictive SNPs. We replicate rs854567 prediction of 2.3% of AREase variance, the effects of rs3917510, and a PON3 haplotype that includes rs2375005. While AREase activity strongly predicted CAAD, none of the 10 SNPs predicting AREase predicted CAAD. Conclusions. This study identifies new genetic variants that predict additional PON1 AREase activity. Identification of SNPs associated with PON1 activity is required when evaluating the many phenotypes associated with genetic variation near PON1.

Switching Modalities in A Sentence Verification Task: ERP Evidence for Embodied Language Processing.

In an event related potential (ERP) experiment using written language materials only, we investigated a potential modulation of the N400 by the modality switch effect. The modality switch effect occurs when a first sentence, describing a fact grounded in one modality, is followed by a second sentence describing a second fact grounded in a different modality. For example, "A cellar is dark" (visual), was preceded by either another visual property "Ham is pink" or by a tactile property "A mitten is soft." We also investigated whether the modality switch effect occurs for false sentences ("A cellar is light"). We found that, for true sentences, the ERP at the critical word "dark" elicited a significantly greater frontal, early N400-like effect (270-370 ms) when there was a modality mismatch than when there was a modality-match. This pattern was not found for the critical word "light" in false sentences. Results similar to the frontal negativity were obtained in a late time window (500-700 ms). The obtained ERP effect is similar to one previously obtained for pictures. We conclude that in this paradigm we obtained fast access to conceptual properties for modality-matched pairs, which leads to embodiment effects similar to those previously obtained with pictorial stimuli.

Analysis of recently identified dyslipidemia alleles reveals two loci that contribute to risk for carotid artery disease.

BACKGROUND: Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) affecting high density lipoprotein (HDL) or low density lipoprotein (LDL) cholesterol levels; these SNPs may contribute to the genetic basis of vascular diseases. RESULTS: We assessed the impact of 34 SNPs at 23 loci on dyslipidemia, key lipid sub-phenotypes, and severe carotid artery disease (CAAD) in a case-control cohort. The effects of these SNPs on HDL and LDL were consistent with those previously reported, and we provide unbiased estimates of the percent variance in HDL (3.9%) and LDL (3.3%) explained by genetic risk scores. We assessed the effects of these SNPs on HDL subfractions, apolipoprotein A-1, LDL buoyancy, apolipoprotein B, and lipoprotein (a) and found that rs646776 predicts apolipoprotein B level while rs2075650 predicts LDL buoyancy. Finally, we tested the role of these SNPs in conferring risk for ultrasonographically documented CAAD stenosis status. We found that two loci, chromosome 1p13.3 near CELSR2 and PSRC1 which contains rs646776, and 19q13.2 near TOMM40 and APOE which contains rs2075650, harbor risk alleles for CAAD. CONCLUSION: Our analysis of 34 SNPs contributing to dyslipidemia at 23 loci suggests that genetic variation in the 1p13.3 region may increase risk of CAAD by increasing LDL particle number, whereas variation in the 19q13.2 region may increase CAAD risk by promoting formation of smaller, denser LDL particles.