Predictors of the voltage derived left atrial fibrosis in patients with long-standing persistent atrial fibrillation

Background: Left atrial (LA) arrhythmogenic substrate beyond the pulmonary veins (PV) seems to play a crucial role in the maintenance of atrial fibrillation (AF). The aim of this study was to evaluate the association of selected parameters with the presence and extent of voltage-defined LA fibrosis in patients with long-standing persistent AF (LSPAF) undergoing catheter ablation. Methods: One hundred and sixteen consecutive patients underwent high density-high resolution voltage mapping of the LA with a multielectrode catheter following PV isolation and restoration of sinus rhythm with cardioversion. A non-invasive dataset, such as clinical variables, two-and three-dimensional echocardiography determined LA size and function and fibrillatory-wave amplitude on a standard surface electrocardiogram were obtained during AF before ablation. Results: Low-voltage areas (LVA; 15 cm2 [IQR 8–31]) were detected in 56% of patients. Twenty nine percent of them presented mild, 43% moderate and 28% severe global LVA burden. In univariate analysis, age ≥ 57 years old, female sex, body surface area ≤ 1.76 m2, valvular heart disease, moderate mitral regurgitation, chronic coronary syndrome, hypothyroidism, CHA2DS2-VASc score ≥ 3 and ≥ 4 predicted the presence of LVA. In multivariate analysis only female sex, valvular heart disease and CHA2DS2-VASc ≥ 4 remained statistically significant. AF duration, LA size and function and fibrillatory-waves amplitude were neither associated with the prediction of the LVA, nor severe LVA burden. Conclusions: A LSPAF diagnosis does not indicate the presence of voltage defined fibrosis in many cases. Simple non-invasive screening of the LSPAF population could predict LVA prevalence

Anti-TNF antibodies do not induce the apoptosis of lamina propria mononuclear cells in uninflamed intestinal tissue in patients with Crohn’s disease

It is not known if anti-tumor necrosis factor (anti-TNF) agents provoke only apoptosis of lamina propria mononuclear cells (LPMC) engaged in inflammatory processes or whether it’s a general phenomenon concerning all LPMC. In this study we carried out an immunohistochemical analysis of the expression of several apoptosis-related proteins (active caspase-3, Bax, Bcl-2, Fas, TNFR1, CD4, and CD8) in uninflamed mucosa in Crohn’s disease (CD) patients treated with anti-TNF agents. 16 CD patients (mean age 34 ± 11, mean disease duration 7 ± 5 years) were included in the study. 10 patients were treated with infliximab and 6 — with adalimumab. The expression of active caspase 3, Bax, Bcl-2, Fas, TNFR1 and CD8 in LPMC did not change significantly after the therapy. We concluded that anti-TNF antibodies did not promote LPMC apoptosis in uninflamed tissues. This is in contrast to the phenomena observed in inflamed tissues. These data show that anti-TNF antibodies rather restore the susceptibility to apoptosis of LPMC in inflamed areas of the gut in CD, than directly induce LPMC apoptosis; otherwise the anti-TNF antibodies should have also induced apoptosis in the uninflamed mucosa

Transcript-Level Dysregulation of BCL2 Family Genes in Acute Myeloblastic Leukemia

The expression of apoptosis-related BCL2 family genes, fine-tuned in normal cells, is dysregulated in many neoplasms. In acute myeloid leukemia (AML), this problem has not been studied comprehensively. To address this issue, RNA-seq data were used to analyze the expression of 26 BCL2 family members in 27 AML FAB M1 and M2 patients, divided into subgroups differently responding to chemotherapy. A correlation analysis, analysis of variance, and Kaplan-Meier analysis were applied to associate the expression of particular genes with other gene expression, clinical features, and the presence of mutations detected by exome sequencing. The expression of BCL2 family genes was dysregulated in AML, as compared to healthy controls. An upregulation of anti-apoptotic and downregulation of pro-apoptotic genes was observed, though only a decrease in BMF, BNIP1, and HRK was statistically significant. In a group of patients resistant to chemotherapy, overexpression of BCL2L1 was manifested. In agreement with the literature data, our results reveal that BCL2L1 is one of the key players in apoptosis regulation in different types of tumors. An exome sequencing data analysis indicates that BCL2 family genes are not mutated in AML, but their expression is correlated with the mutational status of other genes, including those recurrently mutated in AML and splicing-related. High levels of some BCL2 family members, in particular BIK and BCL2L13, were associated with poor outcome

Does a Vagal Response Indicate Cardiac Autonomic Modulation and Improve the Therapeutic Effect of Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation? Insights from Cryoballoon Ablation

Background: The incidence and influence of vagal response (VR) observed during cryoballoon-based pulmonary vein isolation (CBA-based PVI) on the cardiac autonomic nervous system (CANS) and ablation outcomes in paroxysmal atrial fibrillation (PAF) remain unknown. Methods: 296 patients were treated with a 28 mm second-generation cryoballoon (Medtronic). A total of 74 patients without structural heart disease and concomitant diseases were chosen for a detailed CANS assessment with a heart rate variability (HRV) analysis. All patients were screened over a 2-year post-ablation period. Results: VR was detected in 30% of patients and included sinus arrest (64%) or severe sinus bradycardia (46%). The presence of VR was not related to PV ostial dimension, patient clinical characteristics or intraprocedural ablation details. CANS modulation, manifesting as increased median HR and decreased HRV parameters with intact sympatho-vagal balance occurred independently of VR presence or absence and sustained for at least 12 months following ablation. VR was not related with more intensive CANS modulation and did not translate into better ablation outcomes when compared to the non-VR group (74% vs. 71% at 12 months and 69% vs. 65% at 24 months respectively). Conclusions: VR is frequent during CBA-based PVI for PAF and unrelated to any additional clinical benefit

NPM1 alternative transcripts are upregulated in acute myeloid and lymphoblastic leukemia and their expression level affects patient outcome

Abstract Background Expression of the NPM1 gene, encoding nucleophosmin, is upregulated in cancers. Although more than ten NPM1 transcripts are known, the reports were usually limited to one predominant transcript. In leukemia, the NPM1 expression has not been widely studied so far. In acute myeloid leukemia (AML), the mutational status of the gene seems to play a pivotal role in carcinogenesis. Therefore, the aim of the study was to quantify alternative NPM1 transcripts in two types of acute leukemia, AML and ALL (acute lymphoblastic leukemia). Methods Using droplet digital PCR, we analyzed the levels of three protein-coding NPM1 transcripts in 66 samples collected from AML and ALL patients and 16 control samples. Using RNA-seq, we detected 8 additional NPM1 transcripts, including non-coding splice variants with retained introns. For data analysis, Welch two sample t-test, Pearson’s correlation and Kaplan–Meier analysis were applied. Results The levels of the particular NPM1 transcripts were significantly different but highly correlated with each other in both leukemia and control samples. Transcript NPM1.1, encoding the longest protein (294 aa), had the highest level of accumulation and was one of the most abundant transcripts in the cell. Comparing to NPM1.1, the levels of the NPM1.2 and NPM1.3 transcripts, encoding a 265-aa and 259-aa proteins, were 30 and 3 times lower, respectively. All three NPM1 transcripts were proportionally upregulated in both types of leukemia compared to control samples. In AML, the levels of NPM1 transcripts decreased in complete remission and increased again with relapse of the disease. Low levels of NPM1.1 and NPM1.3 were associated with better prognosis. The contribution of non-coding transcripts to the total level of NPM1 gene seemed to be marginal, except for one short 5-end transcript accumulated at high levels in AML and control cells. Aberrant proportions of particular NPM1 splice variants could be linked to abnormal expression of genes encoding alternative splicing factors. Conclusions The levels of the studied NPM1 transcripts were different but highly correlated with each other. Their upregulation in AML and ALL, decrease after therapy and association with patient outcome suggests the involvement of elevated NPM1 expression in the acute leukemia pathogenesis