WDR12, a Member of Nucleolar PeBoW-Complex,Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function

Aims

In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown.

Methods and Results

We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen–activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size.

Conclusions

WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects.     

Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma

Aim of the Study

Podocalyxin-like 1 is a transmembrane glyco-protein whose overexpression associates in many cancers with poor prognosis and unfavorable clinicopathological characteristics. Until now, its prognostic value has never been studied in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate podocalyxin expression in PDAC by a novel monoclonal antibody and a commercially available polyclonal antibody.

Patients and Materials

With tissue microarrays and immuno-histochemistry, podocalyxin expression evaluation involved 168 PDAC patients. The associa-tions of the podocalyxin tumor expression with clinicopathological variables were explored by Fisher’s exact test and the linear-by-linear test. Survival analyses were by Kaplan-Meier anal-ysis and the Cox proportional hazard model.

Results

The polyclonal antibody revealed membranous podocalyxin expression in 73 (44.0%) specimens and the monoclonal antibody was highly expressed in 36 (21.8%) cases. Membranous expression by the polyclonal antibody was associated with T classification (p=0.045) and perineural invasion (p=0.005), and high expression by the mono-clonal antibody with poor differentiation (p=0.033). High podocalyxin expression associated significantly with higher risk of death from PDAC by both the polyclonal antibody (hazard ratio (HR) = 1.62; 95% confidence interval (CI) 1.12-2.33; p=0.01) and the monoclonal antibody (HR = 2.10, 95% CI 1.38-3.20; p<0.001). The results remained significant in multivariate analysis, adjusted for age, gender, stage, lymph node ratio (≥/< 20%), and perivascular invasion (respectively as HR = 2.03; 95% CI 1.32-3.13, p=0.001; and as HR = 2.36; 95% CI 1.47-3.80, p<0.001).

Conclusion

We found podocalyxin to be an independent factor for poor prognosis in PDAC. To our knowledge, this is the first such report of its prognostic value.     

Recovery of cognitive performance from sleep debt: do a short rest pause and a single recovery night help?

We studied the recovery of multitask performance and sleepiness from acute partial sleep deprivation through rest pauses embedded in performance sessions and an 8 h recovery sleep opportunity the following night. Sixteen healthy men, aged 19-22 yrs, participated in normal sleep (two successive nights with 8 h sleep) and sleep debt (one 2 h night sleep followed by an 8 h sleep the following night) conditions. In both conditions, the participants performed four 70 min multitask sessions, with every other one containing a 10 min rest pause with light neck-shoulder exercise. The multitask consisted of four simultaneously active subtasks, with the level of difficulty set in relation to each participant's ability. Physiological sleepiness was assessed with continuous electroencephalography/electro-oculography recordings during themultitask sessions, and subjective sleepiness was self-rated with the Karolinska Sleepiness Scale. Results showed that multitask performance and physiological and subjective sleepiness were impaired by the sleep debt ( p > .001). The rest pause improved performance and subjective sleepiness for about 15 min, regardless of the amount of prior sleep ( p > .01-.05). Following recovery sleep, all outcome measures showed marked improvement ( p < .001), but they failed to reach the levels observed in the control condition ( p < .001-.05). A correlation analysis showed the participants whose multitask performance deteriorated the most following the night of sleep loss tended to be the same persons whose performance was most impaired following the night of the recovery sleep ( p < .001). Taken together, our results suggest that a short rest pause with light exercise is not an effective countermeasure in itself for sleep debt-induced impairments when long-term effects are sought. In addition, it seems that shift arrangements that lead to at least a moderate sleep debt should be followed by more than one recovery night to ensure full recovery. Persons whose cognitive performance is most affected by sleep debt are likely to require the most sleep to recover.     

Association of Serum 25-Hydroxyvitamin D with Lifestyle Factors and Metabolic and Cardiovascular Disease Markers: Population-Based Cross-Sectional Study (FIN-D2D)

Objectives

Low serum 25-hydroxyvitamin D (25OHD) level has been associated with an increased risk of several chronic diseases. Our aim was to determine lifestyle and clinical factors that are associated with 25OHD level and to investigate connection of 25OHD level with metabolic and cardiovascular disease markers.

Design

In total, 2868 Finnish men and women aged 45–74 years participated in FIN-D2D population-based health survey in 2007. Participants that had a serum sample available (98.4%; n = 2822) were included in this study. 25OHD was measured with chemiluminescent microparticle immunoassay method.

Results

The mean 25OHD level was 58.2 nmol/l in men (n = 1348) and 57.1 nmol/l in women (n = 1474). Mean 25OHD level was lower in the younger age groups than in the older ones (p<0.0001 both in men and women). This study confirmed that low physical activity (p<0.0001 both in men and women), smoking (p = 0.0002 in men and p = 0.03 in women) and high BMI (p<0.0001 in women) are factors that independently associate with low 25OHD level. Of the metabolic and cardiovascular disease markers high triglyceride concentration (p = 0.02 in men and p = 0.001 in women) and high apolipoprotein B/apolipoprotein A1 ratio (p = 0.04 in men and p = 0.03 in women) were independently associated with low 25OHD level.

Conclusions

Higher age did not predict lower 25OHD level in this study population of aged 45–74 years which may derive from a healthy life-style of “active pensioners”. Low physical activity and smoking came up as independent lifestyle factors associated with low 25OHD level. Defining the molecular mechanisms behind the associations of 25OHD with low physical activity and smoking are important objective in future studies. The association of 25OHD with BMI, high triglyceride concentration and apolipoprotein B/apolipoprotein A1 ratio may be related to the role of vitamin D in inflammation, but more detailed studies are needed.     

Job strain and alcohol intake: a collaborative meta-analysis of individual-participant data from 140,000 men and women

Background

The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake.

Methodology and Principal Findings

We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1–14, men: 1–21 drinks/week), intermediate (women: 15–20, men: 22–27 drinks/week) and heavy (women: >20, men: >27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake.

Conclusions

Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.     

Interaction with Intestinal Epithelial Cells Promotes an Immunosuppressive Phenotype in Lactobacillus casei

Maintenance of the immunological tolerance and homeostasis in the gut is associated with the composition of the intestinal microbiota. We here report that cultivation of Lactobacillus casei ATCC 334 in the presence of human intestinal epithelial cells promotes functional changes in bacteria. In particular, the interaction enhanced the immunosuppressive phenotype of L. casei as demonstrated by the ability of L. casei to generate functional regulatory T cells (CD4+CD25+FoxP3+) and production of the anti-inflammatory cytokine interleukin-10 by human peripheral blood mononuclear cells. The results indicate microbe-host cross-talk that changes features of microbes, and suggest that in vitro simulation of epithelial cell interaction can reveal functional properties of gut microbes more accurately than conventional cultivation.     

Molecular approaches for the detection and identification of bifidobacteria and lactobacilli in the human gastrointestinal tract

In this review an overview of various molecular techniques and their application for the detection and identification of bifidobacteria and lactobacilli in the gastrointestinal (GI) tract is presented. The techniques include molecular typing techniques such as amplified ribosomal DNA restriction analysis (ARDRA), randomly amplified polymorphic DNA (RAPD), pulsed field gel electrophoresis (PFGE), ribotyping and community profiling techniques such as PCR coupled to temperature and denaturing gradient gel electrophoresis (PCR-TGGE and PCR-DGGE, respectively). Special attention is given to oligonucleotide probes and primers that target the ribosomal RNA (rRNA) sequences and their use in PCR and different hybridisation techniques such as DNA microarrays and fluorescent in situ hybridisation (FISH). In addition, recent findings based on the molecular studies of bifidobacteria and lactobacilli in the GI-tract are reviewed.     

Geographical and environmental controls of palm beta diversity in paleo-riverine terrace forests in Amazonian Peru

The palm (Arecaceae) community on low paleo-riverine terraces (terrace forest) in the north-western Amazon, is described, and we assessed the importance of environmental differences and geographic distance as drivers of its local (25² grain and 0–500 extent) and regional scale (500² grain and 0.3–143 km extent) beta diversity using ordination, multiple regressions on distance matrices and Indicator Species Analysis. A total of 15,869 individuals and 37 species of palm were sampled in 10 terrace forest transects, while 3758 individuals and 21 species were sampled in two adjacent floodplain forest transects for comparison. The terrace and floodplain forest were clearly different in their diversity and floristic composition. The relative importance of geographical distance and environmental difference as controls of terrace forest beta diversity was scale dependent, with environmental differences, notably in soil moisture, dominating at local scales and geographical distance dominating at regional scales. In fact, none of the environmental factors had a significant influence on regional-scale beta diversity. The geographical distance decay in floristic similarity was markedly steeper at local scale ( −0.25 km ⁻¹) than at regional scale ( −0.003 km⁻¹). Such a nonlinear decay is expected if simple dispersal limitation controls beta diversity. However, the absent flattening of the distance decay at the largest distances and the sub-Andean affinities of the westernmost palm communities suggest that large-scale biogeographical processes also contribute to the regional-scale beta diversity. Hereby our results indicate that not only local environment, but also dispersal limitation and biogeographical history can be important controls of the diversity and composition of local plant communities.