Plasma concentration of folate as a biomarker for the intake of fruit and vegetables: the Hordaland Homocysteine Study

BACKGROUND: Nutritional biomarkers may be used to assess dietary exposure without the errors commonly associated with self-reported dietary data. OBJECTIVE: The objective was to examine the association between plasma folate and intake of folate, fruit, and vegetables in a large cohort of healthy adults consuming foods that had not been fortified with folic acid. DESIGN: The present study population included 5533 middle-aged (47-49 y) and old (71-74 y) subjects from the Hordaland Homocysteine Study. The participants completed a food-frequency questionnaire and provided blood samples for chemical analyses. RESULTS: We observed a significant difference in plasma concentrations of folate across increasing quartiles of fruit, vegetable, and orange juice consumption. The difference in plasma folate between the highest and lowest quartiles was 1.97 (95% CI: 1.86, 2.07) nmol/L for fruit intake, 1.79 (95% CI: 1.69, 1.89) nmol/L for vegetable intake, and 2.69 (95% CI: 2.51, 2.87) nmol/L for orange juice intake. A significant inverse relation was observed across increasing quartiles of milk and bread intakes. The difference between the highest and lowest quartiles was -1.03 (95% CI: -1.13, -0.92) nmol/L for milk and -1.60 (95% CI: -1.69, -1.50) nmol/L for bread. CONCLUSION: Plasma folate concentration may be a useful biomarker for the intake of fruit and vegetables in populations consuming unfortified food products. The association can be attenuated by and should be corrected for individual intake of folic acid supplements.     

A study of phosphorylated ERK1/2 and COX‐2 in early stage (T1–T2) oral squamous cell carcinomas

Background: Histomorphological grading at the invasive front of oral squamous cell carcinomas (OSCCs) may provide useful prognostic information. In the present study, we investigated the presence and prognostic value of activated phosphorylated extracellular signal‐regulated kinases 1 and 2 (p‐ERK1/2) and cyclo‐oxygenase‐2 (COX‐2) both at the invasive front and in central/superficial parts of OSCCs. Methods: Using immunohistochemistry, we assessed the presence of p‐ERK1/2 and COX‐2 in 53 early stage OSCCs. Clinical data were recorded prospectively. The end point was disease‐free survival. Results: p‐ERK1/2 staining was present in almost all tumours. The staining was mostly nuclear in the cells of the invasive front and either nuclear or nuclear/cytoplasmic in central/superficial tumour parts. COX‐2 was observed in almost all tumours (98%) and the staining was often restricted to focal areas. Most tumours were COX‐2 negative at the invasive front. The lowest P‐value in survival analyses was P = 0.06 for p‐ERK1/2 at the invasive front. COX‐2, the histomorphological grading systems and TNM stage were of no prognostic value. Conclusion: p‐ERK1/2 was present in almost all tumours and p‐ERK1/2 may be a prognostic marker at the invasive front of OSCCs. In early stage OSCCs, most tumours did not express COX‐2 at the invasive front.     

Global test for high-dimensional mediation: Testing groups of potential mediators

We address the problem of testing whether a possibly high-dimensional vector may act as a mediator between some exposure variable and the outcome of interest. We propose a global test for mediation, which combines a global test with the intersection-union principle. We discuss theoretical properties of our approach and conduct simulation studies that demonstrate that it performs equally well or better than its competitor. We also propose a multiple testing procedure, ScreenMin, that provides asymptotic control of either familywise error rate or false discovery rate when multiple groups of potential mediators are tested simultaneously. We apply our approach to data from a large Norwegian cohort study, where we look at the hypothesis that smoking increases the risk of lung cancer by modifying the level of DNA methylation.     

Usefulness and Limitation of Dobutamine Stress Echocardiography to Predict Acute Response to Cardiac Resynchronization Therapy

Background: It has been hypothesized that a long-term response to cardiac resynchronization therapy (CRT) could correlate with myocardial viability in patients with left ventricular (LV) dysfunction. Contractile reserve and viability in the region of the pacing lead have not been investigated in regard to acute response after CRT. Methods: Fifty-one consecutive patients with advanced heart failure, LV ejection fraction ≤ 35%, QRS duration > 120 ms, and intraventricular asynchronism ≥ 50 ms were prospectively included. The week before CRT implantation, the presence of viability was evaluated using dobutamine stress echocardiography. Acute responders were defined as a ≥15% increase in LV stroke volume. Results: The average of viable segments was 5.8 ± 1.9 in responders and 3.9 ± 3 in nonresponders (P = 0.03). Viability in the region of the pacing lead had an excellent sensitivity (96%), but a low specificity (56%) to predict acute response to CRT. Mitral regurgitation (MR) was reduced in 21 patients (84%) with acute response. The presence of MR was a poor predictor of response (sensibility 93% and specificity 17%). However, combining the presence of MR and viability in the region of the pacing lead yields a sensibility (89%) and a specificity (70%) to predict acute response to CRT. Conclusion: Myocardial viability is an important factor influencing acute hemodynamic response to CRT. In acute responders, significant MR reduction is frequent. The combined presence of MR and viability in the region of the pacing lead predicts acute response to CRT with the best accuracy. (Echocardiography 2010;27:50-57)     

Phosphate stimulates matrix Gla protein expression in chondrocytes through the extracellular signal regulated kinase signaling pathway

Whereas increasing evidence suggests that inorganic phosphate (Pi) may act as a signaling molecule in mineralization-competent cells, its mechanisms of action remain largely unknown. The aims of the present work were to determine whether Pi regulates expression of matrix Gla protein (MGP), a mineralization inhibitor, in growth plate chondrocytes and to identify the involved signaling pathways. Chondrogenic ATDC5 cells and primary growth plate chondrocytes were used. Messenger RNA and protein analyses were performed by quantitative PCR and Western blotting, respectively. The activation and role of MAPKs were, respectively, determined by Western blotting and the use of specific inhibitors. Immunohistological detection of ERK1/2 was performed in rib organ cultures from newborn mice. The results indicate that Pi markedly stimulates expression of MGP in ATDC5 cells and primary growth plate chondrocytes. Investigation of the involved intracellular signaling pathways reveals that Pi activates ERK1/2 in a cell-specific manner, because the stimulation was observed in ATDC5 and primary chondrocytes, MC3T3-E1 osteoblasts, and ST2 stromal cells, but not in L929 fibroblasts or C2C12 myogenic cells. Accordingly, immunohistological detection of ERK1/2 phosphorylation in rib growth plates revealed a marked signal in chondrocytes. Finally, a specific ERK1/2 inhibitor, UO126, blocks Pi-stimulated MGP expression in ATDC5 cells, indicating that ERK1/2 mediates, mainly, the effects of Pi. These data demonstrate, for the first time, that Pi regulates MGP expression in growth plate chondrocytes, thereby suggesting a key role for Pi and ERK1/2 in the regulation of bone formation.