Monocrotaline presence in the Crotalaria (Fabaceae) plant genus and its influence on arthropods in agroecosystems

Abstract Crotalaria (Fabaceae) occurs abundantly in tropical and subtropical regions and has about 600 known species. These plants are widely used in agriculture, mainly as cover plants and green manures, in addition to their use in the management of phytonematodes. A striking feature of these species is the production of pyrrolizidine alkaloids (PAs), secondary allelochemicals involved in plant defense against herbivores. In Crotalaria species, monocrotaline is the predominant PA, which has many biological activities reported, including cytotoxicity, tumorigenicity, hepatotoxicity and neurotoxicity, with a wide range of ecological interactions. Thus, studies have sought to elucidate the effects of this compound to promote an increase in flora and fauna (mainly insects and nematodes) associated with agroecosystems, favoring the natural biological control. This review summarizes information about the monocrotaline, showing such effects in these environments, both above and below ground, and their potential use in pest management programs.

Resumo Crotalaria (Linnaeus, 1753) (Fabaceae) ocorre abundantemente em regiões tropicais e subtropicais e tem cerca de 600 espécies conhecidas. Estas plantas são amplamente utilizadas na agricultura, principalmente como cobertura e adubos verdes, além da sua utilização no manejo de fitonematoides. Uma característica marcante destas espécies é a produção de alcalóides pirrolizidinicos (APs), aleloquímicos secundários envolvidos na defesa das plantas contra os herbívoros. Nas espécies de Crotalaria, a monocrotalina é a AP predominante, que tem muitas atividades biológicas relatadas, incluindo citotoxicidade, tumorigenicidade, hepatotoxicidade e neurotoxicidade, além de uma vasta gama de interações ecológicas. Assim, estudos têm procurado elucidar os efeitos desse composto para promover um incremento na flora e fauna (principalmente insetos e nematoides) associados aos agroecossistemas, favorecendo o controle biológico natural. Esta revisão compila informações sobre a monocrotalina, mostrando tais efeitos nesses ambientes, tanto acima como abaixo do solo e a sua potencial utilização em programas de manejo de pragas.

Monocrotaline presence in the Crotalaria (Fabaceae) plant genus and its influence on arthropods in agroecosystems / Presença de monocrotalina em plantas do gênero Crotalaria (Fabaceae) e a sua influência sobre artrópodes nos agroecossistemas

Abstract Crotalaria (Fabaceae) occurs abundantly in tropical and subtropical regions and has about 600 known species. These plants are widely used in agriculture, mainly as cover plants and green manures, in addition to their use in the management of phytonematodes. A striking feature of these species is the production of pyrrolizidine alkaloids (PAs), secondary allelochemicals involved in plant defense against herbivores. In Crotalaria species, monocrotaline is the predominant PA, which has many biological activities reported, including cytotoxicity, tumorigenicity, hepatotoxicity and neurotoxicity, with a wide range of ecological interactions. Thus, studies have sought to elucidate the effects of this compound to promote an increase in flora and fauna (mainly insects and nematodes) associated with agroecosystems, favoring the natural biological control. This review summarizes information about the monocrotaline, showing such effects in these environments, both above and below ground, and their potential use in pest management programs.

Resumo Crotalaria (Linnaeus, 1753) (Fabaceae) ocorre abundantemente em regiões tropicais e subtropicais e tem cerca de 600 espécies conhecidas. Estas plantas são amplamente utilizadas na agricultura, principalmente como cobertura e adubos verdes, além da sua utilização no manejo de fitonematoides. Uma característica marcante destas espécies é a produção de alcalóides pirrolizidinicos (APs), aleloquímicos secundários envolvidos na defesa das plantas contra os herbívoros. Nas espécies de Crotalaria, a monocrotalina é a AP predominante, que tem muitas atividades biológicas relatadas, incluindo citotoxicidade, tumorigenicidade, hepatotoxicidade e neurotoxicidade, além de uma vasta gama de interações ecológicas. Assim, estudos têm procurado elucidar os efeitos desse composto para promover um incremento na flora e fauna (principalmente insetos e nematoides) associados aos agroecossistemas, favorecendo o controle biológico natural. Esta revisão compila informações sobre a monocrotalina, mostrando tais efeitos nesses ambientes, tanto acima como abaixo do solo e a sua potencial utilização em programas de manejo de pragas.

Monocrotaline presence in the Crotalaria (Fabaceae) plant genus and its influence on arthropods in agroecosystems.

Crotalaria (Fabaceae) occurs abundantly in tropical and subtropical regions and has about 600 known species. These plants are widely used in agriculture, mainly as cover plants and green manures, in addition to their use in the management of phytonematodes. A striking feature of these species is the production of pyrrolizidine alkaloids (PAs), secondary allelochemicals involved in plant defense against herbivores. In Crotalaria species, monocrotaline is the predominant PA, which has many biological activities reported, including cytotoxicity, tumorigenicity, hepatotoxicity and neurotoxicity, with a wide range of ecological interactions. Thus, studies have sought to elucidate the effects of this compound to promote an increase in flora and fauna (mainly insects and nematodes) associated with agroecosystems, favoring the natural biological control. This review summarizes information about the monocrotaline, showing such effects in these environments, both above and below ground, and their potential use in pest management programs.

Pre-procedural proton pump inhibition is associated with fewer peri-oesophageal lesions after cryoballoon pulmonary vein isolation.

Pulmonary vein isolation (PVI) using cryoenergy is safe and efficient for treatment of atrial fibrillation (AF). Pre-existing upper gastrointestinal (GI) pathologies have been shown to increase the risk for AF. Therefore, this study aimed at assessing incidental pathologies of the upper GI tract in patients scheduled for PVI and to analyse the impact of patients' characteristics on PVI safety outcome. In 71 AF patients, who participated in the MADE-PVI trial, oesophagogastroduodenoscopy and endosonography were prospectively performed directly before and the day after PVI to assess pre-existing upper GI pathologies and post-interventional occurrence of PVI-associated lesions. Subgroup analysis of the MADE-PVI trial identified clinically relevant incidental findings in 53 patients (74.6%) with age > 50 years being a significant risk factor. Pre-existing reflux oesophagitis increased risk for PVI-associated mediastinal oedema, while patients already treated with proton pump inhibitors (PPI) had significantly fewer mediastinal oedema. Our results suggest that AF patients with pre-existing reflux oesophagitis are at higher risk for PVI-associated mediastinal lesions, which is decreased in patients with constant PPI-treatment prior to PVI. Since PVI-associated mediastinal lesions are regarded as surrogate parameter for an increased risk of the fatal complication of an oesophago-atrial fistula, our findings hint at a beneficial effect of pre-interventional prophylactic PPI-treatment to reduce risk for PVI-associated complications.German Clinical Trials Register (DRKS00016006; date of registration: 17/12/2018).

Triggered activity in atrial myocytes is influenced by Na+/Ca2+ exchanger activity in genetically altered mice.

AIMS: In atrial fibrillation, increased function of the Na+/Ca2+-exchanger (NCX) is one among several electrical remodeling mechanisms. METHODS/RESULTS: Using the patch-clamp- and Ca2+ imaging-methods, we investigated atrial myocytes from NCX-homozygous-overexpressor (OE)- and heterozygous-knockout (KO)-mice and their corresponding wildtypes (WTOE; WTKO). NCX mediated Ca2+ extrusion capacity was reduced in KO and increased in OE. There was no evidence for structural or molecular remodeling. During a proarrhythmic pacing-protocol, the number of low amplitude delayed afterdepolarizations (DADs) was unaltered in OE vs. WTOE and KO vs. WTKO. However, DADs triggered full spontaneous action potentials (sAP) significantly more often in OE vs. WTOE (ratio sAP/DAD: OE:0.18±0.05; WTOE:0.02±0.02; p<0.001). Using the same protocol, a DAD triggered an sAP by tendency less often in KO vs. WTKO (p=0.06) and significantly less often under a more aggressive proarrhythmic protocol (ratio sAP/DAD: KO:0.01±0.003; WT KO: 0.12±0.05; p=0.007). The DAD amplitude was increased in OE vs. WTOE and decreased in KO vs. WTKO. There were no differences in SR-Ca2+-load, the number of spontaneous Ca2+-release-events or IKACh/IK1. CONCLUSIONS: Atrial myocytes with increased NCX expression exhibited increased vulnerability towards sAPs while atriomyocytes with reduced NCX expression were protected. The underlying mechanism consists of a modification of the DAD-amplitude by the level of NCX-activity. Thus, although the number of spontaneous Ca2+-releases and therefore DADs is unaltered, the higher DAD-amplitude in OE made a transgression of the voltage-threshold of an sAP more likely. These findings indicate that the level of NCX activity could influence triggered activity in atrial myocytes independent of possible remodeling processes.

ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia.

The European Society for Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (i) the elderly patient, (ii) prognostic factors suitable for clinical use and (iii) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address four clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were then presented to the entire panel and a consensus was reached. This manuscript presents recommendations dedicated to the second area of interest, i.e. prognostic factors suitable for clinical use. The four topics [i.e. interim positron emission tomography (PET), TP53 mutations, cell of origin (COO) and minimal residual disease (MRD)] were primarily chosen because of the bulk of available data together with the lack of clear guidance regarding their use in clinical practice and within clinical trials. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. The panel acknowledged that detection of TP53 inactivation by deletion or mutation in CLL should be implemented in clinical practice (level of evidence I, strength of recommendation A). Due to their potentially high prognostic value, at least in some lymphoma entities, implementation of interim PET, COO and MRD was highly recommended in the context of clinical trials. All expert panel members approved this final article.

Safety profile of multielectrode-phased radiofrequency pulmonary vein ablation catheter and irrigated radiofrequency catheter.

BACKGROUND: Silent cerebral lesions with the multielectrode-phased radiofrequency (RF) pulmonary vein ablation catheter (PVAC(®)) have recently been investigated. However, comparative data on safety in relation to irrigated RF ablation are missing. METHODS AND RESULTS: One hundred and fifty consecutive patients (58 ± 12 years, 56 female) underwent first pulmonary vein isolation (PVI) for atrial fibrillation (61% paroxysmal) using PVAC(®) (PVAC). Procedure data as well as in-hospital complications were compared with 300 matched patients who underwent PVI using irrigated RF (iRF). Procedure duration (148 ± 63 vs. 208 ± 70 min; P < 0.001), RF duration (24 ± 10 vs. 49 ± 25 min; P < 0.001), and fluoroscopy time (21 ± 10 vs. 35 ± 13 min; P < 0.001) were significantly shorter using PVAC. Major complication rates [major bleeding, transitoric ischaemic attack (TIA), and pericardial tamponade] were not significantly different between groups (PVAC, n = 3; 2% vs. iRF n = 17; 6%). Overall complication rate, including minor events, was similar in both groups [n = 21 (14%) vs. n = 48 (16%)]. Most of these were bleeding complications due to vascular access [n = 8 (5.3%) vs. n = 22 (7.3%)], which required surgical intervention in five patients [n = 1 (0.7%) vs. n = 4 (1.3%)]. Pericardial effusion [n = 4 (2.7%) vs. n = 19 (6.3%); pericardial tamponade requiring drainage n = 0 vs. n = 6] occurred more frequently using iRF. Two patients in each group developed a TIA (1.3% vs. 0.6%). Of note, four of five thromboembolic events in the PVAC group (two TIAs and three transient ST elevations during ablation) occurred when all 10 electrodes were used for ablation. CONCLUSION: Pulmonary vein isolation using PVAC as a 'one-shot-system' has a comparable complication rate but a different risk profile. Pericardial effusion and tamponade occurred more frequently using iRF, whereas thromboembolic events were more prevalent using PVAC. Occurrence of clinically relevant thromboembolic events might be reduced by avoidance of electrode 1 and 10 interaction and uninterrupted anticoagulation, whereas contact force sensing for iRF might minimize pericardial effusion.

Genomic and epigenomic co-evolution in follicular lymphomas.

Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma, we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstructed phylogenetic trees of the evolution by taking advantage of the activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter-selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array-based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co-evolution in FL.

Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders.

In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

Advantages and limitations of transgenic mice: the role of the Na+/Ca2+ exchanger in cardiac electrophysiology and arrhythmia.

In the search for novel antiarrhythmic strategies, the cardiac Na(+)/Ca(2+) exchanger (NCX) seems to be a promising target. Recent insights into the role of NCX in proarrhythmia stem from transgenic murine models with knockout or overexpression of NCX. There are significant differences regarding cellular electrophysiology, excitation-contraction coupling and Ca(2+) handling when comparing mice to higher mammal and most importantly human physiology. We here review findings derived from transgenic mouse models regarding the role of NCX in the generation of arrhythmia and discuss principle aspects to consider when translating physiological and pathophysiological mechanisms from mouse models into human physiology and the clinical context.

Idiopathic ventricular outflow tract arrhythmias from the great cardiac vein: challenges and risks of catheter ablation.

INTRODUCTION: Catheter ablation for idiopathic ventricular arrhythmia is well established but epicardial origin, proximity to coronary arteries, and limited accessibility may complicate ablation from the venous system in particular from the great cardiac vein (GCV). METHODS: Between April 2009 and October 2010 14 patients (56 ± 15 years; 9 male) out of a total group of 117 patients with idiopathic outflow tract tachycardias were included undergoing ablation for idiopathic VT or premature ventricular contractions (PVC) originating from GCV. All patients in whom the PVC arose from the GCV were subject to the study. In these patients angiography of the left coronary system was performed with the ablation catheter at the site of earliest activation. RESULTS: Successful ablation was performed in 6/14 (43%) and long-term success was achieved in 5/14 (36%) patients. In 4/14 patients (28.6%) ablation was not performed. In another 4 patients (26.7%), ablation did not abolish the PVC/VT. In the majority, the anatomical proximity to the left coronary system prohibited effective RF application. In 3 patients RF application resulted in a coronary spasm with complete regression as revealed in repeat coronary angiography. CONCLUSION: A relevant proportion idiopathic VT/PVC can safely be ablated from the GCV without significant permanent coronary artery stenosis after RF application. Our data furthermore demonstrate that damage to the coronary artery system is likely to be transient.

Long-term clinical and molecular remissions in patients with follicular lymphoma following high-dose therapy and autologous stem cell transplantation.

BACKGROUND: Long-term clinical and molecular remissions in patients with follicular lymphoma (FL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Results are especially limited for second-line HDT with BEAM (BCNU, etoposide, cytarabine and melphalan). PATIENTS AND METHODS: Sixty patients with FL received ASCT in our institution (18 first-line with total body irradiation and cyclophosphamide, 34 second-line with BEAM and 8 ≥ third-line with BEAM). In the case of long-term remission (>6 years; N = 17), peripheral blood was tested for minimal residual disease by t(14;18)- and IGH-PCR. RESULTS: Ten-year overall survival, progression-free survival and freedom from progression (FFP) after first-line ASCT were 79%, 57% and 64% after second-line ASCT 41%, 35% and 42%, respectively. Prognostic factors for FFP were treatment line and FLIPI (Follicular Lymphoma International Prognostic Index). Ten-year FFP for second-line ASCT and low-risk FLIPI was 57%, intermediate risk 37% and high risk 33%. No relapses occurred after 6 years following ASCT. Sixteen patients developed sustained long-term clinical and molecular remissions of up to 17.5 years. CONCLUSION: Sustained long-term clinical and molecular remissions can be achieved following ASCT, including HDT with BEAM in second line.

[Catecholaminergic polymorphic ventricular tachycardia]. / Katecholaminerge polymorphe ventrikuläre Tachykardien.

Catecholaminergic polymorphic ventricular tachycardia (PCVT) is a rare, congenital ventricular tachyarrhythmia which occurs in the setting of adrenergic activation. It potentially leads to syncope and/or sudden cardiac death (SCD). PCVT represents one of the most dangerous congenital ion channel diseases. Mutations of the ryanodine receptor gene (RYR2), the calsequestrin gene (CASQ2), and the triadin gene (TRDN) have been identified as an underlying correlate. ß-Blockers are employed as therapy and are sometimes combined with class IC antiarrhythmic drugs, or calcium antagonists of the verapamil type. ICD implantation is recommended in case of persisting syncope in the presence of ß-blocker therapy or survived SCD. Left thoracic sympathectomy represents a subsidiary interventional therapy for individual cases. In addition, modifications of the patient's lifestyle including avoidance of physical stress and heart rates> 120/min are recommended.

Current treatment of mantle cell lymphoma: results of a national survey and consensus meeting.

In most patients, mantle cell lymphoma (MCL) shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. In the current study generation of the European MCL Network, the addition of high-dose Ara-C to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival in younger patients. In elderly patients, rituximab maintenance led to a marked prolongation of remission duration. Emerging strategies include mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, immune modulatory drugs, Bruton's tyrosine kinase inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. In the current survey, the application of the molecular targeted compounds were collected and evaluated by a representative national network of 14 haematological institutions. Optimised strategies are recommended for clinical routine. Future studies will apply individualised approaches according to the molecular risk profile of the patient.

Blockade of I(Ca) suppresses early afterdepolarizations and reduces transmural dispersion of repolarization in a whole heart model of chronic heart failure.

BACKGROUND AND PURPOSE Chronic heart failure (CHF) is associated with action potential prolongation and Ca(2+) overload, increasing risk of ventricular tachyarrhythmias (VT). We therefore investigated whether I(Ca) blockade was anti-arrhythmic in an intact perfused heart model of CHF. EXPERIMENTAL APPROACH CHF was induced in rabbits after 4 weeks of rapid ventricular pacing. Hearts from CHF and sham-operated rabbits were isolated and perfused (Langendorff preparation), with ablation of the AV node. VT was induced by erythromycin and low [K(+) ] (1.5mM). Electrophysiology of cardiac myocytes, with block of cation currents, was simulated by a mathematical model. KEY RESULTS Repolarization was prolonged in CHF hearts compared with sham-operated hearts. Action potential duration (APD) and overall dispersion of repolarization were further increased by erythromycin (300 µM) to block I(Kr) in CHF hearts. After lowering [K(+) ] to 1.5mM, CHF and sham hearts showed spontaneous episodes of polymorphic non-sustained VT. Additional infusion of verapamil (0.75 µM) suppressed early afterdepolarizations (EAD) and VT in 75% of sham and CHF hearts. Verapamil shortened APD and dispersion of repolarization, mainly by reducing transmural dispersion of repolarization via shortening of endocardial action potentials. Mathematical simulations showed that EADs were more effectively reduced by verapamil assuming a state-dependent block than a simple block of I(Ca) . CONCLUSIONS AND IMPLICATIONS Blockade of I(Ca) was highly effective in suppressing VT via reduction of transmural dispersion of repolarization and suppression of EAD. Such blockade might represent a novel therapeutic option to reduce risk of VT in structurally normal hearts and also in heart failure. LINKED ARTICLE This article is commented on by Stams et al., pp. 554-556 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01818.x.

[Class I antiarrhythmic drugs: mechanisms, contraindications, and current indications]. / Klasse-I-Antiarrhythmika: Wirkmechanismen, Kontraindikationen und aktuelle Indikationen.

Class I antiarrhythmic drugs are sodium channel inhibitors that act by slowing myocardial conduction and, thus, interrupting or preventing reentrant arrhythmia. Due to proarrhythmic effects and the risk of ventricular tachyarrhythmia, class I antiarrhythmics should not be administered in patients with structural heart disease. Nevertheless, there remains a broad spectrum of arrhythmias--among the most common being atrial fibrillation--that can successfully be treated with class I antiarrhythmic drugs. This review gives an overview on the classification, antiarrhythmic mechanisms, indications, side effects, and application modes of class I antiarrhythmic drugs.

[The ICD as primary prevention. Rare indications]. / ICD-Therapie zur Primärprävention. Seltene Indikationen.

The most frequent cause of sudden cardiac death (SCD) is underlying coronary artery disease. Healthy appearing young individuals are affected in a minority of cases. These individuals are usually diagnosed with electrical or genetically determined structural heart disease. Arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, long and short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and early repolarization syndrome are generally considered rare underlying causes of SCD in these young patients. Affected patients typically present with syncope or cardiac arrest. Occasionally, disease is diagnosed during family screening. Risk stratification is difficult in this patient population. Risk of sudden death has to be weighed individually against risks associated with an implantable cardioverter defibrillator (ICD) in these young patients.