A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure

The objective of the study is to assess the role of cardiopulmonary exercise testing (CPX) variables, including peak oxygen consumption (VO₂), which is the most recognized CPX variable, the minute ventilation/carbon dioxide production (VE/VCO₂) slope, the oxygen uptake efficiency slope (OUES), and exercise oscillatory ventilation (EOV) in a current meta-analysis investigating the prognostic value of a broader list of CPX-derived variables for major adverse cardiovascular events in patients with HF. A search for relevant CPX articles was performed using standard meta-analysis methods. Of the initial 890 articles found, 30 met our inclusion criteria and were included in the final analysis. The total subject populations included were as follows: peak VO₂ (7,319), VE/VCO₂ slope (5,044), EOV (1,617), and OUES (584). Peak VO₂, the VE/VCO₂ slope and EOV were all highly significant prognostic markers (diagnostic odds ratios ≥ 4.10). The OUES also demonstrated promise as a prognostic marker (diagnostic odds ratio = 8.08) but only in a limited number of studies (n = 2). No other independent variables (including age, ejection fraction, and beta-blockade) had a significant effect on the meta-analysis results for peak VO₂ and the VE/VCO₂ slope. CPX is an important component in the prognostic assessment of patients with HF. The results of this meta-analysis strongly confirm this and support a multivariate approach to the application of CPX in this patient population.     

RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype

Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re‐expression. Furthermore, relapse‐free survival of non‐inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.     

Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation

Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the alpha7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor-kappaB nuclear entry in an inhibitor kappaB (IkappaB)alpha- and IkappaBepsilon-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.     

Oral health-related quality of life and caries experience of Hong Kong preschool children

Objective: This study aimed to investigate the association between oral health-related quality of life (OHRQoL) and caries experience of Hong Kong preschool children. Methods: Parents or primary caregivers of Hong Kong preschool children were invited to complete a self-administered dental health questionnaire. The study children were examined in their classrooms. The decayed, missing and filled primary teeth (dmft) index was used for documenting the caries status. The questionnaire included the Chinese Early Childhood Oral Health Impact Scale (ECOHIS) and collected sociodemographic information on the parents and children. Logistic regression analysis was used to determine the association between OHRQoL and caries experience of preschool children. Results: A total of 434 preschool children were invited to participate in the study; 336 (77.4%) received a dental examination and returned a parental questionnaire. The mean (SD) age of the study children was 4.7 (0.3) years. An OHRQoL impact (ECOHIS score of >0) for at least one item was reported by 236 (70.2%) parents/caregivers of the children included in the study. The overall mean (SD) ECOHIS score was 5.8 (6.2). A caries prevalence (dmft > 0) of 36.9% and a mean (SD) dmft score of 1.7 (3.2) were calculated for the study children. In the final logistic regression model, children with a higher dmft score had a significantly higher chance of having a poorer OHRQoL (OR = 1.20, 95% CI: 1.07–1.35, P = 0.002), whereas children’s sex, parent’s education levels and the respondent’s relationship to the child were not associated with OHRQoL (P > 0.05). Conclusion: Caries experience is associated with lower OHRQoL of Hong Kong preschool children.Key words: Child, dental caries, early childhood caries, oral health, quality of life     

Significant association between serum Wisteria floribunda agglutinin-positive Mac-2-binding protein and prognosis of hepatocellular carcinoma after surgical treatment

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA⁺-M2BP) is a novel marker for evaluating fibrosis and predicting the development of hepatocellular carcinoma (HCC). However, the role of WFA⁺-M2BP in the prognosis of HCC patients after curative surgery remains unknown. In this study, we aimed to evaluate the prognostic role of serum WFA⁺-M2BP in HCC patients after curative resection and liver transplantation. We enrolled 460 HCC patients (357 resection and 103 transplantation) to analyze the risk factors for HCC recurrence and patient’s survival. We employed time-to-event models using univariate and multivariable Cox proportional hazards regression analyses and calculated the hazard ratios (HRs) and adjusted HRs with their corresponding 95% confidence intervals (CIs). The levels of WFA⁺-M2BP were 0.19-14.51 COI (median 1.08) in patients of hepatectomy and 0.47-19.90 COI (median 6.0) in transplant patients. The levels of WFA⁺-M2BP in liver transplant patients is much higher than that of hepatectomy patients. Overall, liver fibrotic stage was positively correlated to WFA⁺-M2BP levels (P<0.0001). This study demonstrated that elevated WFA⁺-M2BP level (COI ≥0.75) was associated with a higher HCC recurrence rate in the resection group (P<0.001). Survival analysis showed that an elevated WFA⁺-M2BP level (COI ≥1.43) is associated with a higher mortality risk after surgical resection (P=0.0088) in the univariate analysis only. In liver transplant patients, WFA⁺-M2BP level (COI ≥3.81) did not predict HCC recurrence at all, but was associated poor survival after transplantation, with a borderline significance (P=0.0943). Serum WFA⁺-M2BP is a reliable marker for liver fibrosis in the present study. It is also reliable marker to predict prognosis of HCC after surgical resection. However, the prognostic role of WFA⁺-M2BP in HCC related transplants is equivocal, which is different from that of surgical resection.