Beta1-Adrenoceptor Polymorphism Predicts Flecainide Action in Patients with Atrial Fibrillation

Background

Antiarrhythmic action of flecainide is based on sodium channel blockade. Beta₁-adrenoceptor (β₁AR) activation induces sodium channel inhibition, too. The aim of the present study was to evaluate the impact of different β₁AR genotypes on antiarrhythmic action of flecainide in patients with structural heart disease and atrial fibrillation.

Methodology/Principal Findings

In 145 subjects, 87 with atrial fibrillation, genotyping was performed to identify the individual β₁AR Arg389Gly and Ser49Gly polymorphism. Resting heart rate during atrial fibrillation and success of flecainide-induced cardioversion were correlated with β₁AR genotype. The overall cardioversion rate with flecainide was 39%. The Arg389Arg genotype was associated with the highest cardioversion rate (55.5%; OR 3.30; 95% CI; 1.34–8.13; p = 0.003) compared to patients with Arg389Gly (29.5%; OR 0.44; 95% CI; 0.18–1.06; p = 0.066) and Gly389Gly (14%; OR 0.24; 95% CI 0.03–2.07; p = 0.17) variants. The single Ser49Gly polymorphism did not influence the conversion rate. In combination, patients with Arg389Gly-Ser49Gly genotype displayed the lowest conversion rate with 20.8% (OR 0.31; 95% CI; 0.10–0.93; p = 0.03). In patients with Arg389Arg variants the heart rate during atrial fibrillation was significantly higher (110±2.7 bpm; p = 0.03 vs. other variants) compared to Arg389Gly (104.8±2.4 bpm) and Gly389Gly (96.9±5.8 bpm) carriers. The Arg389Gly-Ser49Gly genotype was more common in patients with atrial fibrillation compared to patients without atrial fibrillation (27.6% vs. 5.2%; HR 6.98; 95% CI; 1.99–24.46; p<0.001).

Conclusions

The β₁AR Arg389Arg genotype is associated with increased flecainide potency and higher heart rate during atrial fibrillation. The Arg389Gly-Ser49Gly genotype might be of predictive value for atrial fibrillation.     

Convergence in plant traits between species within grassland communities simplifies their monitoring

Plant trait measurement is a very powerful and promising method for assessing the effects of land use change on ecosystem behavior in grasslands, but it is very time-consuming. Hence we pose the following questions for simplifying diagnosis and monitoring: (i) are plant traits (PTs) similar between plant life forms (PLF: grasses, rosettes, upright forbs, legumes) within a plant community? (ii) is it possible to define the main plant community characteristics by measuring traits on one PLF or a limited number of dominant species?Six PTs known for their ability to characterize the capacity of species to exploit resource-rich or -poor environments and for their competitive dominance in response to disturbance (specific leaf area (SLA), leaf dry matter content (LDMC), plant height (H), C and N contents, flowering time) were measured on the species of 18 plant communities located in Central Pyrenees. The experiment combined 2 fertility levels and 3 defoliation regimes (cutting, grazing). Comparisons were made between the weighted values at community, PLF and two dominant species levels. Regression analysis shows that there were significant correlations between grasses and rosettes for 4 PTs. For H, N and C:N ratio, data for both grass and rosette PLFs were close to the bisecting line. The largest difference in the intercept was observed for LDMC. On the basis of plant traits weighted for all the species, plant communities were ranked in similar ways for SLA and H (Spearman r > 0.93; p < 0.001) and to a lesser extent for LDMC (r = 0.72; p < 0.001). Convergence in weighted plant traits for different PLFs within a plant community mean that in the studied grasslands, defoliation regime and nutrient availability act as strong filters that impose, at least at PLF level, very similar PFTs. This determines a specific local community structure and composition. An application of this result in managed grasslands is the possibility of focusing on one PLF or a limited number of species for vegetation diagnosis and monitoring.     

The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells

Notch signalling is important for development and tissue homeostasis and activated in many human cancers. Nevertheless, mutations in Notch pathway components are rare in solid tumours. ZEB1 is an activator of an epithelial-mesenchymal transition (EMT) and has crucial roles in tumour progression towards metastasis. ZEB1 and miR-200 family members repress expression of each other in a reciprocal feedback loop. Since miR-200 members target stem cell factors, ZEB1 indirectly induces stemness maintenance and associated drug resistance. Here, we link ZEB1 and its cancer promoting properties to Notch activation. We show that miR-200 members target Notch pathway components, such as Jagged1 (Jag1) and the mastermind-like coactivators Maml2 and Maml3, thereby mediating enhanced Notch activation by ZEB1. We further detected a coordinated upregulation of Jag1 and ZEB1, associated with reduced miR-200 expression in two aggressive types of human cancer, pancreatic adenocarcinoma and basal type of breast cancer. These findings explain increased Notch signalling in some types of cancers, where mutations in Notch pathway genes are rare. Moreover, they indicate an additional way how ZEB1 exerts its tumour progressing functions.     

Relation between 3435C>T multidrug resistance 1 gene polymorphism with high dose methylprednisolone treatment of childhood acute idiopathic thrombocytopenic purpura

The current study was conducted to assess 3435C>T multidrug resistance 1 gene polymorphism and the efficacy of high dose methylprednisolone (HDMP) in childhood acute idiopathic thrombocytopenic purpura patients.

Methods

A total of 31 childhood acute Idiopathic thrombocytopenic purpura patients (17 females, 14 males) between the ages of 2 and 16 years of age were included in the study. High-dose methylprednisolone was given at a dose of 30 mg/kg/day for 3 days and 20 mg/kg/day for 4 days, consecutively and intravenously. Polymerase chain reaction-restriction fragment length polymorphism was used for the detection of C3435T single nucleotide polymorphism. Fragments obtained were 238 bp to T/T genotype, 172 bp and 60 bp fragments to the C/C genotype, and 238 bp, 172 bp and 60 bp to the C/T genotype.

Results

The distribution of CC, CT, and TT genotypes were 19.0%, 61.3%, and 19.4%, respectively. Both allele frequencies of C and T were the same — 50%. There was no significant difference in genotype and allele distribution between the patients with ITP and the control group (χ² = 0.84 p = 0.65, χ² = 0.2 p = 0.63, respectively). There were no significant differences in age, gender, and pre- and post-treatment platelet counts between CC, CT, and TT genotypes of the MDR gene. Response to treatment shows no significant difference between genotype and allele groups.

Conclusion

In our study, there was no difference in the HDMP treatment response between MDR1 gene genotypes. However, it should be noted that this study includes a small group of patients. Our data should therefore be considered preliminary, awaiting further confirmatory studies on an expanded patient base.     

Digestive enzyme activities in larvae of sharpsnout seabream (Diplodus puntazzo)

The ontogenesis and specific activities of pancreatic and intestinal enzymes were investigated in sharpsnout sea bream, Diplodus puntazzo, during larval development until the end of weaning on day 50. The green-water technique was carried out for larval rearing in triplicate. Trypsin was first detected as early as hatching and sharply increased related to age and exogenous feeding until day 25, but a sharp decrease was observed towards the end of the experiment. Amylase was determined 2 days after hatching (DAH) and sharply increased to 10 DAH. Afterwards, slight decreases were found between 10 and 20 DAH and then slow alterations were continued until end of the experiment. Lipase was measured for the first time on day 4, and then slight increase was found to 25 DAH. After this date, slow variations were maintained until end of the experiment. Pepsin was firstly assayed 32 DAH related with stomach formation and sharply increased to 40 DAH. Then it was fluctuated until end of the experiment. Enzymes of brush border membranes, alkaline phosphatase and aminopeptidase N, showed similar pattern on specific activities during the first 10 days. Thereafter, while specific activity of alkaline phosphatase slightly decreased to 15 DAH and fluctuated until 20 DAH, aminopeptidase N activity slowly declined to 20 DAH. Afterwards, activity of alkaline phosphatase and aminopeptidase N were sharply increased to 30 DAH, showing maturation of the intestinal digestive process and also these activities continued to slight increase until end of the experiment. The specific activity of cytosolic peptidase, leucine-alanine peptidase sharply increased to on day 8, then suddenly declined to 12 DAH and further decreased until 20 DAH. After this date, in contrast to enzymes of brush border membranes, it sharply decreased to 25 DAH and continued to gradually decline until the end of the experiment. These converse expressions were indicative of a maturation of enterocytes and the transition to an adult mode of digestion.