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With rising cases for the first time in years, malaria remains a significant public health burden. The sexual stage of the malaria parasite infects mosquitoes to transmit malaria from host to host. Hence, an infected mosquito plays an essential role in malaria transmission. Plasmodium falciparum is the most dominant and dangerous malaria pathogen. Previous studies identified a sexual stage-specific protein 16 (Pfs16) localized to the parasitophorous vacuole membrane. Here, we elucidate the function of Pfs16 during malaria transmission. Our structural analysis identified Pfs16 as an alpha-helical integral membrane protein with one transmembrane domain connecting to two regions across parasitophorous vacuole membrane. ELISA assays showed that insect cell-expressed recombinant Pfs16 (rPfs16) interacted with Anopheles gambiae midguts, and microscopy found that rPfs16 was bound to midgut epithelial cells. Transmission-blocking assays demonstrated that polyclonal antibodies against Pfs16 significantly reduced the number of oocysts in mosquito midguts. However, on the contrary, feeding rPfs16 increased the number of oocysts. Further analysis revealed that Pfs16 reduced the activity of mosquito midgut caspase 3/7, a key enzyme in the mosquito Jun-N-terminal kinase immune pathway. We conclude that Pfs16 facilitates parasites to invade mosquito midguts by actively silencing the mosquito's innate immunity through its interaction with the midgut epithelial cells. Therefore, Pfs16 is a potential target to control malaria transmission.
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Anopheles , Malária Falciparum , Plasmodium falciparum , Proteínas de Protozoários , Animais , Humanos , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Proteínas de Membrana/metabolismo , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Vacúolos/metabolismo , Proteínas de Protozoários/metabolismoRESUMO
INTRODUCTION: Optimal occlusion of pulmonary vein (PV) is essential for atrial fibrillation (AF) cryoballoon ablation (CBA). The aim of the study was to investigate the performance of two different tools for the assessment of PV occlusion with a novel navigation system in CBA procedure. METHODS: In consecutive patients with paroxysmal AF who underwent CBA procedure with the guidance of the novel 3-dimentional mapping system, the baseline tool, injection tool and pulmonary venography were all employed to assess the degree of PV occlusion, and the corresponding cryoablation parameters were recorded. RESULTS: In 23 patients (mean age 60.0 ± 13.9 years, 56.5% male), a total of 149 attempts of occlusion and 122 cryoablations in 92 PVs were performed. Using pulmonary venography as the gold standard, the overall sensitivity, specificity of the baseline tool was 96.7% (95% confidence interval [CI] 90.0%-99.1%), and 40.5% (95% CI 26.0%-56.7%), respectively, while the corresponding value of the injection tool was 69.6% (95% CI 59.7%-78.1%), and 100.0% (95% CI 90.6%-100.0%), respectively. Cryoablation with optimal occlusion showed lower nadir temperature (baseline tool: -44.3 ± 8.4°C vs. -35.1 ± 6.5°C, p < .001; injection tool: -46.7 ± 6.4°C vs. -38.3 ± 9.2°C, p < .001) and longer total thaw time (baseline tool: 53.3 ± 17.0 s vs. 38.2 ± 14.9 s, p = .003; injection tool: 58.5 ± 15.5 s vs. 41.7 ± 15.2 s, p < .001) compared with those without. CONCLUSIONS: Both tools were able to accurately assess the degree of PV occlusion and predict the acute cryoablation effect, with the baseline tool being more sensitive and the injection tool more specific.
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Fibrilação Atrial , Ablação por Cateter , Criocirurgia , Veias Pulmonares , Pneumopatia Veno-Oclusiva , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Resultado do Tratamento , Criocirurgia/efeitos adversos , Criocirurgia/métodos , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodosRESUMO
INTRODUCTION: To investigate the optimal range of quantitative ablation index (AI) value during superior vena cava (SVC) electrical isolation by radiofrequency catheter ablation (RFCA). METHODS: First, in a development cohort of patients with atrial fibrillation (AF), the RFCA with 40 W was performed to complete SVC isolation guided by the conduction breakthrough point from the right atrium to SVC. Then, the range of AI value was calculated by offline analysis on different segments of SVC. Lastly, for the validation of AF patients, the safety and effectiveness of SVC isolation with the optimized target range of AI value were evaluated with an additional adenosine test. RESULTS: A total of 101 patients with AF were included in the study (44 patients in the development cohort/57 in the validation cohort). The segmental ablation strategy was applied in 70% of the patients. According to the offline analysis of the AI values in the development cohort, the target AI value range was set as 350-400. The success rate of SVC isolation in the validation cohort was significantly higher than that in the exploration cohort (100% vs. 90.9%, p = .02), and no complications occurred in the exploration cohort. During the adenosine test, the recovery rate of electrical conduction in SVC was significantly lower than that in the pulmonary vein (3.5% vs. 17.5%). CONCLUSION: The target AI value with a range from 350 to 400 is safe and effective for high-power RFCA to complete SVC isolation.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Veia Cava Superior/cirurgia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Átrios do Coração , Frequência Cardíaca , Ablação por Cateter/efeitos adversos , Adenosina , Veias Pulmonares/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The present study aimed to investigate the prevalence, predictors, and management of left atrial appendage (LAA) thrombogenic milieu (TM) identified with transesophageal echocardiography (TEE) in non-valvular atrial fibrillation (NVAF) patients with low to moderate thromboembolic (TE) risk. METHODS: We retrospectively analyzed the baseline clinical data and TEE findings in 391 NVAF patients (54.7 ± 8.9 years, 69.1% male) with low to moderate TE risk according to the CHA2DS2-VASc score. LAA TM was defined as LAA thrombus (LAAT), sludge or spontaneous echo contrast (SEC). Management of LAA TM was at the discretion of the treating physician. RESULTS: A total of 43 patients (11.0%) were detected with LAA TM, including 5 with LAAT (11.6%), 4 with LAAT + Sect. (9.3%), 3 with sludge (7.0%), and 31 with Sect. (72.1%). In multivariate model, non-paroxysmal AF (OR 3.121; 95% CI 1.205-8.083, p = 0.019), and a larger left atrial diameter (LAD) (OR 1.134; 95% CI 1.060-1.213, p < 0.001) were significantly associated with the presence of LAA TM. All LAATs or sludges effectively resolved after mean duration of 117.5 ± 20.0 days for oral anticoagulant (OAC) medication. TE events occurred in 3 patients (18.8%) among those discontinuing OAC over a mean follow-up of 26.2 ± 8.8 months, while no TE events occurred in patients with continuous OAC. CONCLUSIONS: LAA TM could be identified in 11.0% in NVAF patients with low to moderate TE risk, especially in those with non-paroxysmal AF and enlarged LAD. Short-term OAC medication could effectively resolve the LAAT or sludge.
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Vector control is considered an effective approach to controlling diseases spread by mosquito bites. Entomopathogenic fungi are widely used in agriculture to control insect pests, and fungal metabolites can potentially be developed as effective mosquitocides. In this study, a high-throughput screening method was used to search for potential mosquitocides in the Global Fungal Extract Library (GFEL). We tested the larvicidal activity of 264 fungal ethyl acetate crude extracts against Culex pipiens quinquefasciatus. Nine fungal extracts caused moderate to high mortality rates (>50%), with two fungal extracts (58A7 and 101H12) causing a 100% mortality rate. The lethal concentrations for 50% of the population (LC50) were 44.27 mg/L and 31.90 mg/L, respectively. Fraction 14 had a high mortality rate, with an LC50 value of 12.13 mg/L, and was isolated from 58A7 (Fractions 1-11) and 101H12 (Fractions 12-15). Further analyses showed that Fraction 14 was made up of vermistatin and dihydrovermistatin. In a Cx. p. quinquefasciatus larvicidal bioassay, vermistatin (LC50 = 28.13 mg/L) was more toxic than dihydrovermistatin (LC50 = 83.87 mg/L). Our findings suggested that the active fungal extract 101H12 from Talaromyces sp. and its compound vermistatin could be developed as mosquitocides.
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BACKGROUND: The effects of epicardial connections (ECs) involving pulmonary veins (PVs) in atrial fibrillation (AF) ablation have been revealed recently. However, no systematic approaches to identify and ablate the ECs were established. METHODS: Patients with AF undergoing radiofrequency (RF) catheter ablation were retrospectively analyzed. ECs were identified when (1) PV isolation (PVI) cannot be achieved after first-pass isolation; (2) PVI was still absent although the conduction gap was detected and ablated; (3) the earliest activation area (EAA) was revealed located within the PV antrum distant from the initial ablation line using high-density mapping (HDM) technique; (4) focal ablation at the EAA was effective to achieve PVI. Relevant pacing maneuvers were performed to elucidate ECs' bidirectional conduction. RESULTS: Overall, 36 ECs were identified and ablated in 35/597 (5.86%) patients. Among the 35 patients with ECs, at least one PV insertion of ECs was located at the carina region. The most common pattern was a single breakthrough in 31 (88.6%) patients, followed by multiple breakthroughs in 3 and wide breakthroughs in 1. The median distance from EAA to the initial ablation line was 10.0 mm. The average number of RF energy delivery was 1.75 ± 1.00, and single RF delivery was adequate in 16/36 (44.4%) patients. Continuous potentials were present at the EAA in 9/34 (26.5%) patients. CONCLUSION: ECs were confirmed and ablated successfully in 5.86% (35/597) AF patients using HDM. PV insertions of ECs were mainly located at the carina region. Continuous potentials might assist in the prediction of ECs.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Humanos , Incidência , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIMS: The study aims to describe the long-term outcome of radiofrequency catheter ablation for ventricular tachycardia (VT) in a large cohort arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. METHODS AND RESULTS: Radiofrequency catheter ablation was performed in 284 ARVC patients due to VT between July 2000 and January 2019. An endocardial approach was used initially, with epicardial ablation procedures reserved for those patients who failed an endocardial ablation. Activation, entrainment, pace and substrate mapping strategies were used with regional ablation applied. A total of 393 ablation procedures were performed including endocardial approach only (n = 377) and endo and epicardial combined (n = 16). Right ventricular basal free wall was accounted as the primary substrate of VT in 258 (65.6%) patients. There were 81 patients underwent redo ablation procedure (second time = 81; ≥3 times = 28). New targets were observed in 68.8% of redo procedures. There were 171 VT recurrences and 19 deaths occurred during the follow-up. Ventricular tachycardia-free survival rate of the first, second, and last ablation procedure was 56.7%, 73.2%, and 78.1%, respectively. Multivariate analysis showed ≥3 induced VTs in the procedure was correlated with rehospitalized VT recurrence [hazard ratio (HR) 1.467, 95% confidence interval (CI) 1.052-2.046; P = 0.024]. For all-cause mortality, rehospitalized VT and ≥3 induced VTs were the independent risk factors (HR 2.954, 95% CI 1.8068.038; P = 0.034; HR 3.189, 95% CI 1.073-9.482; P = 0.037). CONCLUSION: Endocardial ablation is effective to ARVC VT though it may require repeated procedures. Induced multiple VTs was correlated with worse outcomes.
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Displasia Arritmogênica Ventricular Direita , Ablação por Cateter , Taquicardia Ventricular , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/cirurgia , Endocárdio/cirurgia , Humanos , Recidiva , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/cirurgia , Resultado do TratamentoRESUMO
Mosquito-transmitted Plasmodium parasites cause millions of people worldwide to suffer malaria every year. Drug-resistant Plasmodium parasites and insecticide-resistant mosquitoes make malaria hard to control. Thus, the next generation of antimalarial drugs that inhibit malaria infection and transmission are needed. We screened our Global Fungal Extract Library (GFEL) and obtained a candidate that completely inhibited Plasmodium falciparum transmission to Anopheles gambiae. The candidate fungal strain was determined as Aspergillus aculeatus. The bioactive compound was purified and identified as asperaculane B. The concentration of 50% inhibition on P. falciparum transmission (IC50) is 7.89 µM. Notably, asperaculane B also inhibited the development of asexual P. falciparum with IC50 of 3 µM, and it is nontoxic to human cells. Therefore, asperaculane B is a new dual-functional antimalarial lead that has the potential to treat malaria and block malaria transmission.
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Antimaláricos/farmacologia , Aspergillus/crescimento & desenvolvimento , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Aspergillus/metabolismo , Proliferação de Células , Feminino , Células HEK293 , Humanos , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Malária Falciparum/transmissão , Plasmodium falciparum/isolamento & purificaçãoRESUMO
FREP1 in mosquito midguts facilitates Plasmodium falciparum parasite transmission. The fibrinogen-like (FBG) domain of FREP1 is highly conserved (>90% identical) among Anopheles species from different continents, suggesting that anti-FBG antibodies may block malaria transmission to all anopheline mosquitoes. Using standard membrane-feeding assays, anti-FREP1 polyclonal antibodies significantly blocked transmission of Plasmodium berghei and Plasmodium vivax to Anopheles gambiae and Anopheles dirus, respectively. Furthermore, in vivo studies of mice immunized with FBG achieved >75% blocking efficacy of P. berghei to A. gambiae without triggering immunopathology. Anti-FBG serum also reduced >81% of P. falciparum infection to A. gambiae Finally, we showed that FBG interacts with Plasmodium gametocytes and ookinetes, revealing the molecular mechanism of its antibody transmission-blocking activity. Collectively, our data support that FREP1-mediated Plasmodium transmission to mosquitoes is a conserved pathway and that targeting the FBG domain of FREP1 will limit the transmission of multiple Plasmodium species to multiple Anopheles species.
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Anopheles/metabolismo , Proteínas de Insetos/uso terapêutico , Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Sequência de Aminoácidos , Animais , Anopheles/imunologia , Anopheles/parasitologia , Anticorpos Bloqueadores/análise , Sequência Conservada , Feminino , Células Germinativas/imunologia , Células Germinativas/metabolismo , Humanos , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Vacinas Antimaláricas/química , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/metabolismo , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Malária Vivax/sangue , Malária Vivax/imunologia , Malária Vivax/parasitologia , Masculino , Camundongos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/imunologia , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium vivax/crescimento & desenvolvimento , Plasmodium vivax/imunologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Vacinas Sintéticas/química , Vacinas Sintéticas/metabolismo , Vacinas Sintéticas/uso terapêuticoRESUMO
INTRODUCTION: Radiofrequency catheter ablation is an effective therapy for focal idiopathic outflow tract ventricular arrhythmia (OTVA). However, visual inspection of the unipolar electrogram (EGM) QS morphology is subjective with a poor specificity for predicting successful ablation sites. This study aims to evaluate the predictive value of unipolar and bipolar EGMs in OTVA mapping and ablation. METHODS AND RESULTS: Twenty-two patients scheduled for idiopathic OTVA ablation were prospectively enrolled. During the procedure, unipolar and bipolar EGMs were recorded simultaneously and visually inspected by the operator to identify their values for predicting arrhythmogenic sites. Quantitative features of the unipolar EGM including the ratio of amplitude of the first positive peak versus the nadir (R-ratio), the maximum descending slope (MaxSlope), and the time interval between the initial deflection point to the MaxSlope (D-Max) were calculated for each target site in offline analysis. EGMs from 100 sites were collected in 20 patients and analyzed. The bipolar reverse polarity characteristic was not as practical for identifying successful ablation site as the unipolar QS characteristic. Successful ablation sites demonstrated smaller R-ratio and shorter D-Max than unsuccessful sites, but no significant difference in MaxSlope. A unipolar EGM-derived quantitative criterion provided significantly better specificity (0.70) than visual inspection (0.37) without compromising on the sensitivity (0.83 vs. 0.89). CONCLUSION: The bipolar reverse polarity characteristic was not a practical method for identifying target in idiopathic OTVA ablation. The unipolar EGM-derived quantitative criteria have better predictive performance than visual inspection of the QS characteristic and are likely to reduce unnecessary ablation sites.
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Potenciais de Ação , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/cirurgia , Ablação por Cateter , Técnicas Eletrofisiológicas Cardíacas , Ventrículos do Coração/cirurgia , Adulto , Arritmias Cardíacas/fisiopatologia , Ablação por Cateter/efeitos adversos , Estudos de Viabilidade , Feminino , Frequência Cardíaca , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Malaria transmission depends on sexual stage Plasmodium parasites successfully invading Anopheline mosquito midguts following a blood meal. However, the molecular mechanisms of Plasmodium invasion of mosquito midguts have not been fully elucidated. Previously, we showed that genetic polymorphisms in the fibrinogen-related protein 1 (FREP1) gene are significantly associated with Plasmodium falciparum infection in Anopheles gambiae, and FREP1 is important for Plasmodium berghei infection of mosquitoes. Here we identify that the FREP1 protein is secreted from the mosquito midgut epithelium and integrated as tetramers into the peritrophic matrix, a chitinous matrix formed inside the midgut lumen after a blood meal feeding. Moreover, we show that the FREP1 can directly bind Plasmodia sexual stage gametocytes and ookinetes. Notably, ablating FREP1 expression or targeting FREP1 with antibodies significantly decreases P. falciparum infection in mosquito midguts. Our data support that the mosquito-expressed FREP1 mediates mosquito midgut invasion by multiple species of Plasmodium parasites via anchoring ookinetes to the peritrophic matrix and enabling parasites to penetrate the peritrophic matrix and the epithelium. Thus, targeting FREP1 can limit malaria transmission.
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Anopheles/metabolismo , Anopheles/parasitologia , Fibrinogênio/metabolismo , Proteínas de Insetos/metabolismo , Insetos Vetores/metabolismo , Insetos Vetores/parasitologia , Plasmodium falciparum/fisiologia , Animais , Anopheles/genética , Anopheles/crescimento & desenvolvimento , Sistema Digestório/metabolismo , Sistema Digestório/parasitologia , Feminino , Fibrinogênio/genética , Interações Hospedeiro-Parasita , Proteínas de Insetos/genética , Insetos Vetores/genética , Insetos Vetores/crescimento & desenvolvimento , MasculinoRESUMO
AIMS: This study was aimed to report the characteristics and treatment of ventricular tachycardia (VT) following surgical treatment of pulmonary stenosis with intact ventricular septum. METHODS AND RESULTS: Five patients underwent radiofrequency catheter ablation for sustained monomorphic left bundle branch block (LBBB) type VT who previously underwent surgical treatment of pulmonary stenosis. Except stimulation, voltage and activation mapping was performed using three-dimensional (3D) electro-anatomic mapping and ablation was applied accordingly. Four VTs were induced during EP study. Two VTs were focal and the earliest activity was targeted in the right ventricular apex (RVA). The other two VTs were reentrant and the critical isthmus located in the mid-lateral wall and anterior wall of right ventricle, respectively. Ablation abolished all inducible VTs in four patients. In the patient whose VT was non-inducible, radiofrequency (RF) energy was delivered to the RVA where pacing mapping matched the clinical VT. One focal VT recurred 60 months after the initial RF ablation. Repeat mapping and ablation was performed and no VT recurred over a 24-month period. CONCLUSIONS: The mechanism of VT following surgical treatment of pulmonary stenosis can be either focal or reentrant. Ablation of this subgroup of VT is feasible.
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Estimulação Cardíaca Artificial/métodos , Ablação por Cateter/métodos , Complicações Pós-Operatórias/terapia , Estenose da Valva Pulmonar/cirurgia , Taquicardia Ventricular/terapia , Procedimentos Cirúrgicos Torácicos/efeitos adversos , Adulto , Antiarrítmicos/uso terapêutico , Bloqueio de Ramo/fisiopatologia , Eletrocardiografia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia Ventricular/etiologiaRESUMO
BACKGROUND: Ventricular conduction blocks (VCBs) are associated with poor outcomes in patients with known cardiac diseases. However, the prognostic implications of VCB patterns in dilated cardiomyopathy (DCM) patients need to be evaluated. The purpose of this study was to determine all-cause mortality in patients with DCM and VCB. METHODS: This cohort study included 1119 DCM patients with a median follow-up of 34.3 (19.5-60.8) months, patients were then divided into left bundle branch block (LBBB), right bundle branch block (RBBB), intraventricular conduction delays (IVCD) and narrow QRS groups. The all-cause mortality was assessed using Kaplan-Meier survival curves and Cox regression. RESULTS: Of those 1119 patients, the all-cause mortality rates were highest in patients with IVCD (47.8, n = 32), intermediate in those with RBBB (32.9, n = 27) and LBBB (27.1 %, n = 60), and lowest in those with narrow QRS (19.9 %, n = 149). The all-cause mortality risk was significantly different between the VCB and narrow QRS group (log-rank χ2 = 51.564, P < 0.001). The presence of RBBB, IVCD, PASP ≥ 40 mmHg, left atrium diameter and NYHA functional class were independent predictors of all-cause mortality in DCM patients. CONCLUSIONS: Our findings indicate that RBBB and IVCD at admission,but not LBBB, were independent predictors of all-cause mortality in patients with DCM.
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Cardiomiopatia Dilatada/mortalidade , Bloqueio Cardíaco/mortalidade , Sistema de Condução Cardíaco/fisiopatologia , Hospitalização , Potenciais de Ação , Adulto , Idoso , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/fisiopatologia , Causas de Morte , Distribuição de Qui-Quadrado , China , Ecocardiografia Doppler em Cores , Ecocardiografia Doppler de Pulso , Eletrocardiografia , Feminino , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/fisiopatologia , Frequência Cardíaca , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Dual-phase cardiac computed tomography (CCT) has been applied to detect left atrial appendage (LAA) thrombosis, which is characterized as the presence of left atrial appendage filling defects (LAADF) in both early- and delayed-phase scanning. However, the clinical implication of LAAFD in exclusive early-phase scanning (LAAFD-EEpS) of CCT in patients with atrial fibrillation (AF) is unclear. METHODS: The baseline clinical data and dual-phase CCT findings in 1183 AF patients (62.1 ± 11.6 years, 59.9% male) was collected and analyzed. A further analysis of CCT and transesophageal echocardiography (TEE) data (within 5 days) in a subgroup of 687 patients was performed. LAAFD-EEpS was defined as LAAFD present in early-phase and absent in delayed-phase scanning of dual-phase CCT. RESULTS: A total of 133 (11.2%) patients were detected with LAAFD-EEpS. Patients with LAAFD-EEpS had a higher prevalence of ischemic stroke or transient ischemic attack (TIA) (p < 0.001) and a higher predefined thromboembolic risk (p < 0.001). In multivariate analysis, a history of ischemic stroke or TIA was independently associated with LAAFD-EEpS (odds ratio [OR] 11.412, 95% confidence interval [CI] 6.561-19.851, p < 0.001). When spontaneous echo contrast in TEE was used as the reference standard, the sensitivity, specificity, positive predictive value, and negative predictive value of LAAFD-EEpS was 77.0% (95% CI 66.5-87.6%), 89.0% (95% CI 86.5-91.4%), 40.5% (95% CI 31.6-49.5%), 97.5% (96.3-98.8%), respectively. CONCLUSIONS: In AF patients, LAAFD-EEpS is not an uncommon finding in dual-phase CCT scanning, and is associated with elevated thromboembolic risk.
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Apêndice Atrial , Fibrilação Atrial , Ataque Isquêmico Transitório , AVC Isquêmico , Humanos , Masculino , Feminino , Apêndice Atrial/diagnóstico por imagem , Estudos Retrospectivos , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Tomografia Computadorizada Multidetectores/métodos , Ecocardiografia Transesofagiana , AVC Isquêmico/complicaçõesRESUMO
Plasmodium ookinetes use an invasive apparatus to invade mosquito midguts, and tubulins are the major structural proteins of this apical complex. We examined the role of tubulins in malaria transmission to mosquitoes. Our results demonstrate that the rabbit polyclonal antibodies (pAb) against human α-tubulin significantly reduced the number of P. falciparum oocysts in Anopheles gambiae midguts, while rabbit pAb against human ß-tubulin did not. Further studies showed that pAb, specifically against P. falciparum α-tubulin-1, also significantly limited P. falciparum transmission to mosquitoes. We also generated mouse monoclonal antibodies (mAb) using recombinant P. falciparum α-tubulin-1. Out of 16 mAb, two mAb, A3 and A16, blocked P. falciparum transmission with EC50 of 12 µg/ml and 2.8 µg/ml. The epitopes of A3 and A16 were determined to be a conformational and linear sequence of EAREDLAALEKDYEE, respectively. To understand the mechanism of the antibody-blocking activity, we studied the accessibility of live ookinete α-tubulin-1 to antibodies and its interaction with mosquito midgut proteins. Immunofluorescent assays showed that pAb could bind to the apical complex of live ookinetes. Moreover, both ELISA and pull-down assays demonstrated that insect cell-expressed mosquito midgut protein, fibrinogen-related protein 1 (FREP1), interacts with P. falciparum α-tubulin-1. Since ookinete invasion is directional, we conclude that the interaction between Anopheles FREP1 protein and Plasmodium α-tubulin-1 anchors and orients the ookinete invasive apparatus towards the midgut PM and promotes the efficient parasite infection in the mosquito.
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Anopheles , Malária Falciparum , Malária , Plasmodium , Animais , Camundongos , Coelhos , Humanos , Tubulina (Proteína)/metabolismo , Plasmodium falciparum , Mosquitos Vetores , Malária Falciparum/parasitologia , Anopheles/parasitologiaRESUMO
Malaria, caused by Plasmodium protozoal parasites, remains a leading cause of morbidity and mortality. The Plasmodium parasite has a complex life cycle, with asexual and sexual forms in humans and Anopheles mosquitoes. Most antimalarials target only the symptomatic asexual blood stage. However, to ensure malaria eradication, new drugs with efficacy at multiple stages of the life cycle are necessary. We previously demonstrated that arsinothricin (AST), a newly discovered organoarsenical natural product, is a potent broad-spectrum antibiotic that inhibits the growth of various prokaryotic pathogens. Here, we report that AST is an effective multi-stage antimalarial. AST is a nonproteinogenic amino acid analog of glutamate that inhibits prokaryotic glutamine synthetase (GS). Phylogenetic analysis shows that Plasmodium GS, which is expressed throughout all stages of the parasite life cycle, is more closely related to prokaryotic GS than eukaryotic GS. AST potently inhibits Plasmodium GS, while it is less effective on human GS. Notably, AST effectively inhibits both Plasmodium erythrocytic proliferation and parasite transmission to mosquitoes. In contrast, AST is relatively nontoxic to a number of human cell lines, suggesting that AST is selective against malaria pathogens, with little negative effect on the human host. We propose that AST is a promising lead compound for developing a new class of multi-stage antimalarials.
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AIMS: Patients undergo ablation for focal atrial fibrillation (AF) as a result of failure of anti-arrhythmic drugs. Our basic studies have implicated cholinergic and adrenergic neurotransmitter release as the underlying mechanism for focal AF. Therefore, we tested the efficacy of a combination of sodium channel-blocking agents with additional vagolytic properties and a ß-blocker to terminate and prevent focal AF. METHODS AND RESULTS: In 18 Na-pentobarbital-anaesthetized dogs, after a right or left thoracotomy, acetylcholine (Ach, 0.5 cc, 100 mM) was injected into a fat pad containing ganglionated plexi (GP) or applied on an atrial appendage (AA) to induce focal firing at the pulmonary veins (PVs) or AA, respectively. Disopyramide (2-4 mg/kg, n= 6) or quinidine (3-6 mg/kg, n= 12) combined with esmolol or propranolol (1 mg/kg, n= 13 and 5, respectively) were slowly injected to terminate (Group I, n= 12) or prevent (Group II, n= 6) Ach-induced sustained focal AF. In another four dogs, only the sodium channel-blocking agents with additional vagolytic properties or only the ß-blocker was injected prior to or after the initiation of focal AF. At baseline, the mean duration of AF induced by Ach was 26 ± 4 min. Group I: After drugs, Ach-induced AF duration was 3 ± 1 min (P< 0.001). Group II: Prior to drugs, Ach-induced AF lasted for 19 ± 3 min. With the drug combination the duration of Ach-induced AF, decreased to 6 ± 1/min, P< 0.001. Either quinidine or propranolol alone did not change the duration of Ach-induced AF, mean 25 ± 10 min compared with Ach alone, 28 ± 16 min, P= 0.2. CONCLUSIONS: Type IA (cholinergic antagonist) plus Type II (ß-adrenergic antagonist) provides significant prevention and suppression of focal AF arising at PV and non-PV sites.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Acetilcolina/administração & dosagem , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Apêndice Atrial/efeitos dos fármacos , Disopiramida/uso terapêutico , Cães , Quimioterapia Combinada , Veias Pulmonares/efeitos dos fármacos , Quinidina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
The navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), is the most destructive lepidopteran pest of almonds [Prunus dulcis (Mill.) D.A.Webb] and pistachios (Pistacia vera L.) in California and is a serious problem in figs (Ficus carica L.) and walnuts (Juglans spp.). In addition to direct damage, larval feeding leaves nuts vulnerable to infection by Aspergillus spp., fungi that produce toxic aflatoxins. A potentially safe and sustainable approach for managing navel orangeworm in orchards may be to use natural essential oil synergists to interfere with this insect's ability to detoxify insecticides and phytochemicals. We tested the effects of a naturally occurring plant-derived chemical, myristicin, and a synthetic inhibitor of cytochrome P450 monooxygenases (P450s), piperonyl butoxide, on the toxicity of three insecticides (alpha-cypermethrin, tau-fluvalinate, and methoxyfenozide [Intrepid]) and a phytochemical (xanthotoxin) to A. transitella. Piperonyl butoxide significantly synergized alpha-cypermethrin and tau-fluvalinate, whereas myristicin synergized only alpha-cypermethrin. Piperonyl butoxide synergized the toxicity of xanthotoxin as early as 72 h after exposure, whereas myristicin synergized xanthotoxin after 120 h. In view of these findings and the limited availability of environmentally safe synthetic insecticides for sustainable management, particularly in organic orchards, myristicin is a potential field treatment in combination with insecticides to reduce both navel orangeworm survival and aflatoxin contamination of nuts. In addition, this study demonstrates that in A. transitella the insect growth regulator methoxyfenozide is not detoxified by P450s.
Assuntos
Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Metoxaleno/farmacologia , Mariposas/efeitos dos fármacos , Sinergistas de Praguicidas/metabolismo , Derivados de Alilbenzenos , Animais , Compostos de Benzil/metabolismo , California , Dioxolanos/metabolismo , Hidrazinas/farmacologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/metabolismo , Dose Letal Mediana , Mariposas/crescimento & desenvolvimento , Mariposas/metabolismo , Nitrilas/farmacologia , Butóxido de Piperonila/metabolismo , Piretrinas/farmacologia , Pirogalol/análogos & derivados , Pirogalol/metabolismoRESUMO
A new polymorph of the mycotoxin alternariol is reported and characterized by single crystal X-ray diffraction. Structural data, Hirshfeld surface analysis, and 2D fingerprint plots are used to compare differences in the intermolecular interactions of the orthorhombic Pca21 Form I (previously reported) and the monoclinic P21/c Form II (herein reported). The polymorphs have small differences in planarity-7.55° and 2.19° between the terminal rings for Form I and Form II, respectively-that brings about significant differences in the crystal packing and O-H H interactions.
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Introduction: Different opinions exist about the role of subchondral bone in osteoarthritis (OA), probably because subchondral bone has different effects on cartilage degeneration in OA induced by different pathologies. Animal studies to illustrate the role of subchondral bone in cartilage degeneration were mostly based on post-traumatic OA (PT-OA). Postmenopausal women experience a much higher occurrence of OA than similar-aged men. The physiological changes and pathogenesis of the osteochondral unit in ovariectomy-induced OA (OVX-OA) might be distinct from other types of OA. Methods: The osteochondral alterations of post-traumatic OA (PT-OA) and OVX-OA at week 9 after surgery were compared. Then the alterations of osteochondral units in OVX-OA rats were tracked over time for the designed groups: Sham, OVX and OVX rats treated with estrogen (OVX+E). DXA, micro-CT, and histochemical staining were performed to observe alterations in osteochondral units. Results: Rapid cartilage degeneration and increased bone formation were observed in PT-OA, while only mild cartilage erosion and significant bone loss were observed in OVX-OA at week 9 after surgery. Subchondral bone degradation preceded cartilage degeneration by 6 weeks in OVX-OA. TGF-ß expression was downregulated in the osteochondral unit of OVX rats. Estrogen supplementation inhibited subchondral bone loss, cartilage degradation and TGF-ß expression decrease. Discussion: This research demonstrated the distinct behaviors of the osteochondral unit and the critical role of subchondral bone in early OVX-OA compared with PT-OA. Inhibiting subchondral bone catabolism at the early stage of OVX-OA could be an effective treatment for post-menopausal OA. Based on the results, estrogen supplementation and TGF-ß modulation at the early stage are both potential therapies for post-menopausal OA.