Brain-Derived Neurotrophic Factor Levels in Cord Blood from Growth Restricted Fetuses with Doppler Alteration Compared to Adequate for Gestational Age Fetuses.

Background and Objectives: Fetal growth restriction (FGR) is a severe obstetric disease characterized by a low fetal size entailing a set of undesired consequences. For instance, previous studies have noticed a worrisome association between FGR with an abnormal neurodevelopment. However, the precise link between FGR and neurodevelopmental alterations are not yet fully understood yet. Brain-derived neurotrophic factor (BDNF) is a critical neurotrophin strongly implicated in neurodevelopmental and other neurological processes. In addition, serum levels of BDNF appears to be an interesting indicator of pathological pregnancies, being correlated with the neonatal brain levels. Therefore, the aim of this study is to analyze the blood levels of BDNF in the cord blood from fetuses with FGR in comparison to those with weight appropriate for gestational age (AGA). Materials and Methods: In this study, 130 subjects were recruited: 91 in group A (AGA fetuses); 39 in group B (16 FGR fetuses with exclusively middle cerebral artery (MCA) pulsatility index (PI) < 5th percentile and 23 with umbilical artery (UA) PI > 95th percentile). Serum levels of BDNF were determined through ELISA reactions in these groups. Results: Our results show a significant decrease in cord blood levels of BDNF in FGR and more prominently in those with UA PI >95th percentile in comparison to AGA. FGR fetuses with exclusively decreased MCA PI below the 5th percentile also show reduced levels of BDNF than AGA, although this difference was not statistically significant. Conclusions: Overall, our study reports a potential pathophysiological link between reduced levels of BDNF and neurodevelopmental alterations in fetuses with FGR. However, further studies should be conducted in those FGR subjects with MCA PI < 5th percentile in order to understand the possible implications of BDNF in this group.

Easily available ECG and echocardiographic parameters for prediction of left atrial remodeling and atrial fibrillation recurrence after pulmonary vein isolation: A multicenter study.

BACKGROUND: The assessment of noninvasive markers of left atrial (LA) low-voltage substrate (LVS) enables the identification of atrial fibrillation (AF) patients at risk for arrhythmia recurrence after pulmonary vein isolation (PVI). METHODS: In this prospective multicenter study, 292 consecutive AF patients (72% male, 62 ± 11 years, 65% persistent AF) underwent high-density LA voltage mapping in sinus rhythm. LA-LVS (<0.5 mV) was considered as significant at 2 cm2  or above. Preprocedural clinical electrocardiogram and echocardiographic data were assessed to identify predictors of LA-LVS. The role of the identified LA-LVS markers in predicting 1-year arrhythmia freedom after PVI was assessed in 245 patients. RESULTS: Significant LA-LVS was identified in 123 (42%) patients. The amplified sinus P-wave duration (APWD) best predicted LA-LVS, with a 148-ms value providing the best-balanced sensitivity (0.81) and specificity (0.88). An APWD over 160 ms was associated with LA-LVS in 96% of patients, whereas an APWD under 145 ms in 15%. Remaining gray zones improved their accuracy by introduction of systolic pulmonary artery pressure (sPAP) of 35 mmHg or above, age, and sex. According to COX regression, the risk of arrhythmia recurrence 12 months following PVI was twofold and threefold higher in patients with APWD 145-160 and over 160 ms, compared to APWD under 145 ms. Integration of pulmonary hypertension further improved the outcome prediction in the intermediate APWD group: Patients with APWD 145-160 ms and normal sPAP had similar outcome than patients with APWD under 145 ms (hazard ratio [HR] 1.62, p = .14), whereas high sPAP implied worse outcome (HR 2.56, p < .001). CONCLUSIONS: The APWD identifies LA-LVS and risk for arrhythmia recurrence after PVI. Our prediction model becomes optimized by means of integration of the pulmonary artery pressure.

Clinical characteristics of patients with sustained ventricular arrhythmias after sacubitril/valsartan initiation.

Our aim was to describe the clinical profile of patients presenting sustained ventricular arrhythmias after sacubitril/valsartan (SV) initiation. All cases of sustained ventricular arrhythmias in patients receiving SV were consecutively recorded in two centers. Nineteen patients had sustained ventricular arrhythmias after SV. All were men and were previously receiving angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers before SV initiation. Fifteen patients (78.9%) had electrical stability in the previous 6 months. Nine patients (47.4%) initiated SV at the lowest available dose (24/26 mg). Globally, in all but five patients alive at discharge, SV was discontinued after the event. Six patients presented new arrhythmic events after discontinuation of SV. Two deaths and three heart transplants occurred (one due to heart failure and the other two due to persistent ventricular arrhythmias). All patients had a high arrhythmic risk, and 17 (89.5%) had an implanted cardioverter defibrillator. No specific triggers for the arrhythmic event were found. Male sex and previous episodes of ventricular arrhythmias could be associated with an increased risk of sustained ventricular tachycardia after SV initiation. Discontinuation of the drug might be an additional approach to enable a better control of ventricular arrhythmias in some patients.

Diagnosis-to-ablation time in atrial fibrillation: A modifiable factor relevant to clinical outcome.

INTRODUCTION: Recurrences after atrial fibrillation (AF) ablation are still common. Among the reported clinical and imaging predictors of recurrences, diagnosis-to-ablation time (DAT) has been defined as a predictor of ablation outcome in single-center studies. We aimed to validate DAT in a multicenter real-life cohort. METHODS: This was a multicenter study including consecutive patients undergoing first paroxysmal and persistent AF ablation with radiofrequency or cryoballoon catheters during 2013. Cox proportional hazard regression models were performed to identify predictors of recurrence. RESULTS: In total, 309 patients were included across nine centers (71% men, 57 ± 10 years old, 46% with hypertension, and 66% with CHA2 DS2 -VASc ≤ 1). Most patients had paroxysmal AF (67%) and underwent radiofrequency ablation (68%) with a median DAT of 51 (43) months. Patients with DAT ≤ 1 year (16.6%) were less likely to have repeat procedures (4% vs 18%; P = .017). The adjusted proportional hazards Cox model identified hypertension (P = .005), heart failure (P = .011), nonparoxysmal AF (P = .038), DAT > 1 year (P = .007), and LA diameter (P = .026) as independent predictors for AF recurrence. DAT > 1 year was the only modifiable factor independently associated with recurrence (HR 4.2 [95% CI, 1.5-11.9]) CONCLUSION: Diagnosis-to-ablation time is a modifiable factor independently associated with recurrent arrhythmia and repeat ablation after first AF ablation. An early intervention strategy during the first year from AF diagnosis might improve outcomes.

MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo-HSCT response and prognostic factor of MLL 3' region mRNA expression.

OBJECTIVE: MLL gene is involved in more than 80 known genetic fusions in acute leukemia. To study the relevance of MLL partner gene and selected gene's expression, in this work, we have studied a cohort of 20 MLL-rearranged acute myeloid leukemia (AML). METHODS: Twenty MLL-rearranged AML patients along with a control cohort of 138 AML patients are included in this work. By RT-PCR and sequencing, MLL genetic fusion was characterized, and relative gene expression quantification was carried out for EVI1, MEIS1, MLL-3', RUNX1, SETBP1, HOXA5, and FLT3 genes. Risk stratification and association of MLL genetic partner and gene expression to overall survival, in the context of received therapy, were performed. RESULTS: MLLr cohort showed to have an OS more similar to intermediate-risk AML. Type of MLL genetic partner showed to be relevant in allo-HSCT response; having MLLT1 and MLLT3, a better benefit from it. Expression of MLL-3' region, EVI1 and FLT3, showed association with OS in patients undergoing allo-HSCT. CONCLUSION: We show that the MLL genetic partner could have implications in allo-HSCT response, and we propose three genes whose expression could be useful for the prognosis of this leukemia in patients undergoing allo-HSCT: 3' region of MLL, EVI1, and FLT3.

Comparison between endocardial and epicardial cardiac resynchronization in an experimental model of non-ischaemic cardiomyopathy.

Aims: Pacing from the left ventricular (LV) endocardium might increase the likelihood of response to cardiac resynchronization therapy. However, experimental and clinical data supporting this assumption are limited and controversial. The aim of this study was to compare the acute response of biventricular pacing from the LV epicardium and endocardium in a swine non-ischaemic cardiomyopathy (NICM) model of dyssynchrony. Methods and results: A NICM was induced in six swine by 3 weeks of rapid ventricular pacing. Biventricular stimulation was performed from 16 paired locations in the LV (8 epicardial and 8 endocardial) with two different atrioventricular (80 and 110 ms) intervals and three interventricular (0, +30, -30 ms) delays. The acute response of the aortic blood flow, LV and right ventricular (RV) pressures, LVdP/dtmax and LVdP/dtmin and QRS complex width and QT duration induced by biventricular stimulation were analysed. The haemodynamic and electrical beneficial responses to either LV endocardial or epicardial biventricular pacing were similar (ΔLVdP/dtmax: +7.8 ± 2.2% ENDO vs. +7.3 ± 1.5% EPI, and ΔQRS width: -16.8 ± 1.3% ENDO vs. -17.1 ± 1.9% EPI; P = ns). Pacing from LV basal regions either from the epicardium or endocardium produced better haemodynamic responses as compared with mid or apical LV regions (P < 0.05). The LV regions producing the maximum QRS complex shortening did not correspond to those inducing the best haemodynamic responses (EPI: r2 = 0.013, P = ns; ENDO: r2 = 0.002, P = ns). Conclusion: Endocardial LV pacing induced similar haemodynamic changes than pacing from the epicardium. The response to endocardial LV pacing is region dependent as observed in epicardial pacing.

Isoquinoline Alkaloids from Fumaria officinalis L. and Their Biological Activities Related to Alzheimer's Disease.

Two new isoquinoline alkaloids, named fumaranine (2) and fumarostrejdine (10), along with 18 known alkaloids were isolated from aerial parts of Fumaria officinalis. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses and by comparison with literature data. The absolute configuration of the new compound 2 was determined by comparing its circular dichroism spectra with those of known analogs. Compounds isolated in sufficient amounts were evaluated for their acetylcholinesterase, butyrylcholinesterase, prolyl oligopeptidase (POP), and glycogen synthase kinase-3ß inhibitory activities. Parfumidine (8) and sinactine (15) exhibited potent POP inhibition activities (IC50 99±5 and 53±2 µM, resp.).

Hematological Neoplasms with Eosinophilia.

Eosinophils in peripheral blood account for 0.3-5% of leukocytes, which is equivalent to 0.05-0.5 × 109/L. A count above 0.5 × 109/L is considered to indicate eosinophilia, while a count equal to or above 1.5 × 109/L is defined as hypereosinophilia. In bone marrow aspirate, eosinophilia is considered when eosinophils make up more than 6% of the total nuclear cells. In daily clinical practice, the most common causes of reactive eosinophilia are non-hematologic, whether they are non-neoplastic (allergic diseases, drugs, infections, or immunological diseases) or neoplastic (solid tumors). Eosinophilia that is associated with a hematological malignancy may be reactive or secondary to the production of eosinophilopoietic cytokines, and this is mainly seen in lymphoid neoplasms (Hodgkin lymphoma, mature T-cell neoplasms, lymphocytic variant of hypereosinophilic syndrome, and B-acute lymphoblastic leukemia/lymphoma). Eosinophilia that is associated with a hematological malignancy may also be neoplastic or primary, derived from the malignant clone, usually in myeloid neoplasms or with its origin in stem cells (myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, acute myeloid leukemia with core binding factor translocations, mastocytosis, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, and myelodysplastic neoplasms). There are no concrete data in standardized cytological and cytometric procedures that could predict whether eosinophilia is reactive or clonal. The verification is usually indirect, based on the categorization of the accompanying hematologic malignancy. This review focuses on the broad differential diagnosis of hematological malignancies with eosinophilia.