Multiresistant Kawasaki Disease in a Young Infant with Giant Aneurysms Growing Fast.

BACKGROUND: Kawasaki disease (KD) is a type of vasculitis in which giant coronary artery aneurysms (CAAs) can occur. There are no specific guidelines for managing giant CAAs that develop quickly and are at risk of rupture. Regarding cardiovascular drugs, only beta-blockers are formally recommended in the acute phase of KD. CASE PRESENTATION: A 6-month-old male patient with multiresistant Kawasaki disease and giant CAAs that continued to enlarge after controlling systemic inflammation was examined. The patient required three doses of intravenous immunoglobulin, methylprednisolone pulses, and anakinra and infliximab to normalize systemic inflammation. Due to the rapid increment of aneurysms' dimensions and the risk of rupture, we introduced anticoagulant therapy and propranolol plus captopril, and titration doses were introduced according to a tolerated decrease in heart rate and arterial pressure. CAAs increment stabilized and slowly reduced their dimensions. CONCLUSIONS: The authors describe an atypical case of multiresistant KD with giant rapidly increasing CAAs even after controlling systemic inflammation. The introduction of a beta-blocker and an angiotensin-converting enzyme (ACE) inhibitor was demonstrated to be useful for stabilizing giant CAAs growth and reducing the potential risk of rupture.

Assessing the Genotoxicity of Cellulose Nanomaterials in a Co-Culture of Human Lung Epithelial Cells and Monocyte-Derived Macrophages.

Cellulose micro/nanomaterials (CMNMs) are innovative materials with a wide spectrum of industrial and biomedical applications. Although cellulose has been recognized as a safe material, the unique properties of its nanosized forms have raised concerns about their safety for human health. Genotoxicity is an endpoint that must be assessed to ensure that no carcinogenic risks are associated with exposure to nanomaterials. In this study, we evaluated the genotoxicity of two types of cellulose micro/nanofibrils (CMF and CNF) and one sample of cellulose nanocrystals (CNC), obtained from industrial bleached Eucalyptus globulus kraft pulp. For that, we exposed co-cultures of human alveolar epithelial A549 cells and THP-1 monocyte-derived macrophages to a concentration range of each CMNM and used the micronucleus (MN) and comet assays. Our results showed that only the lowest concentrations of the CMF sample were able to induce DNA strand breaks (FPG-comet assay). However, none of the three CMNMs produced significant chromosomal alterations (MN assay). These findings, together with results from previous in vitro studies using monocultures of A549 cells, indicate that the tested CNF and CNC are not genotoxic under the conditions tested, while the CMF display a low genotoxic potential.

The TANGO2 disease and the therapeutic challenge of acute arrhythmia management: a case report.

Background: TANGO2-related metabolic encephalopathy and arrhythmia are a rare, newly recognized, and likely under-diagnosed condition. First described in 2016, it is characterized by developmental delay and recurrent metabolic crisis. During these episodes, patients may present QTc prolongation and ventricular arrhythmias. Case summary: A 13-year-old female, with developmental delay, presented with severe rhabdomyolysis and an initially normal electrocardiogram (ECG). Due to the worsening of rhabdomyolysis, QTc prolongation was identified (QTc 570 ms) and oral ß-blocker therapy started. A non-sustained ventricular tachycardia developed, initially managed with magnesium and lidocaine. After a short period, an arrhythmic storm of polymorphic ventricular extrasystoles induced Torsade de Pointes (TdP) was triggered. A temporary percutaneous pacing lead was placed and esmolol infusion started. The electrical instability ran in parallel with the increasing severity of rhabdomyolysis and systolic ventricular function decline. Genetic testing identified a pathogenic variant in homozygosity in the TANGO2 gene. A stable sinus rhythm was achieved with metabolic and serum electrolytes optimization. ECG showed normalization of the QTc interval. Discussion: The full TANGO2-related phenotype emerges over time and the prognosis is linked to the appearance of ECG abnormalities. QT interval prolongation can lead to life-threatening ventricular tachycardias. The arrhythmia mechanism seems to be secondary to metabolite build-up in cardiomyocytes, which can explain the cardiac phenotype during the crisis which subsides after their resolution. In these patients, avoiding bradycardia is fundamental, since long QT-related TdP seems to be triggered by bradycardia and short-long-short ventricular premature beats (VPB). During an acute metabolic crisis, the management of arrhythmias relies on metabolic control.

Infective endocarditis in a cohort of adult CHD patients.

BACKGROUND: CHD increases the risk of infective endocarditis due to the substrate of prosthetic materials and residual lesions. However, lesion-specific and mortality risks data are lacking. We sought to analyse clinical course and mortality of infective endocarditis in a cohort of adult CHD. METHODS: Retrospective analysis of all cases of proven and probable infective endocarditis (Duke's criteria) followed in our adult CHD clinic between 1970 and August, 2021. Epidemiological, clinical and imaging data were analysed. Predictors of surgical treatment and mortality were assessed using regression analysis. RESULTS: During a mean follow-up of 15.8 ± 10.9 years, 96 patients had 105 infective endocarditis episodes, half with previous cardiac surgery (corrective or palliative). The most frequent diagnoses were: ventricular septal defect, bicuspid aortic valve, Tetralogy of Fallot and pulmonary atresia. The site of infection was identified by echocardiography in 82 episodes (91%), most frequently in aortic (n = 27), tricuspid (n = 15), and mitral (n = 13) valves. Blood cultures were positive in 79% of cases, being streptococci (n = 29) and staphylococci (n = 23) the predominant pathogens. Surgery was necessary in 40% and the in-hospital mortality was 10.5%, associated with heart failure (p < 0.001; OR 13.5) and a non-surgical approach (p = 0.003; OR 5.06). CONCLUSIONS: In an adult CHD cohort, infective endocarditis was more frequent in patients with ventricular septal defect and bicuspid aortic valves, which contradicts the current guidelines that excludes them from prophylaxis. Surgical treatment is often required and mortality remains substantial. Prevention of this serious complication should be one of the major tasks in the care of adults with CHD.

Non-VKA Oral Anticoagulants in Adult Congenital Heart Disease: a Single-Center Study.

PURPOSE: Non-VKA oral anticoagulants (NOACs) prescription is increasing in adults with congenital heart disease (ACHD). However, data on efficacy and safety in ACHD is unclear, particularly in severe CHD. The study aimed to review the safety and efficacy of NOACs in ACHD. METHODS: Retrospective evaluation of ACHD patients started on NOACs from 2014 to 2020, with the primary endpoints of bleeding or thromboembolic events (TE). CHA2DS2-VASc and HAS-BLED scores were calculated, mortality was assessed, and risk factors for bleeding were identified. RESULTS: A total of 93 patients were included, the mean age was 52 ± 15 years, 58% were female, 55.9% had moderate CHD, and 23.7% had severe CHD (3.2% Fontan). Most (66%) had a CHA2DS2-VASc score ≥ 2 and 82% HAS-BLED ≤ 2. In a median follow-up of 41 (IQR 21) months (400.4 patient-years), there were TE in two patients. The annual risk for TE was 0.49%/patient/year. The cardiovascular mortality was 2% and all-cause mortality 5%; there were no fatal TE or bleeding events. Minor (n = 6, 6.5%) and major (n = 3, 3.2%) bleeding events were observed, a median of 12 (IQR 15) months after starting NOAC therapy. The annual risk for bleeding was 2.2%/patient/year. Renal disease (HR 14.6 [95% CI 1.23-73.6], p = 0.033) and the HAS-BLED score were predictors of major (adjusted HR 6.97 [95% CI 1.69-28.78], p = 0.007) and minor (adjusted HR 3.80 [95% CI 1.48-9.78], p = 0.006) bleeding complications. CONCLUSION: In this real-life cohort of selected ACHD, the use of NOACs was safe and effective, with a low incidence of bleeding events.

Adverse Outcome Pathways Associated with the Ingestion of Titanium Dioxide Nanoparticles-A Systematic Review.

Titanium dioxide nanoparticles (TiO2-NPs) are widely used, and humans are exposed through food (E171), cosmetics (e.g., toothpaste), and pharmaceuticals. The oral and gastrointestinal (GIT) tract are the first contact sites, but it may be systemically distributed. However, a robust adverse outcome pathway (AOP) has not been developed upon GIT exposure to TiO2-NPs. The aim of this review was to provide an integrative analysis of the published data on cellular and molecular mechanisms triggered after the ingestion of TiO2-NPs, proposing plausible AOPs that may drive policy decisions. A systematic review according to Prisma Methodology was performed in three databases of peer-reviewed literature: Pubmed, Scopus, and Web of Science. A total of 787 records were identified, screened in title/abstract, being 185 used for data extraction. The main endpoints identified were oxidative stress, cytotoxicity/apoptosis/cell death, inflammation, cellular and systemic uptake, genotoxicity, and carcinogenicity. From the results, AOPs were proposed where colorectal cancer, liver injury, reproductive toxicity, cardiac and kidney damage, as well as hematological effects stand out as possible adverse outcomes. The recent transgenerational studies also point to concerns with regard to population effects. Overall, the findings further support a limitation of the use of TiO2-NPs in food, announced by the European Food Safety Authority (EFSA).

Mechanical circulatory support in children: Strategies, challenges and future directions.

INTRODUCTION: The use of mechanical circulatory support (MCS) in the pediatric population has evolved significantly in the past 20 years, but its management still poses several challenges. We aim to describe patient characteristics, outcomes, and morbidity associated with different modalities of MCS, in a tertiary center. METHODS: Retrospective analysis of data from all the children who underwent MCS between 2002 and 2018 at a pediatric cardiology unit. RESULTS: Between 2002 and 2018, 22 devices were implanted in 20 patients. Patients were divided into three groups: Group A (n=11) extracorporeal membrane oxygenator (ECMO); Group B (n=8) pulsatile paracorporeal ventricular assist device (VAD) and group C (n=3) paracorporeal continuous flow VAD. The median age was similar in groups A and B (18 and 23 months, respectively), and higher in group C (13 years). ECMO patients were cannulated mainly as a bridge to recovery (post cardiotomy- 8) while group B and C patients were bridged to transplantation. The most frequent complications were bleeding (group A - 36%, group C - 66.6%) and thromboembolic events (group B - 50%, group C - 33.3%). As for outcomes, in group A the majority of patients (54.5%) were weaned and 27.3% died. Half of group B and all of group C patients underwent transplantation. CONCLUSION: Bleeding and thromboembolic events were the main complications observed. Group B showed the highest mortality, probably related to the low weight of the patients. Overall, outcomes and complications are related to the type of device and patient status and characteristics.

Genotoxicity of Three Micro/Nanocelluloses with Different Physicochemical Characteristics in MG-63 and V79 Cells.

(1) Background: Nanocellulose is an innovative engineered nanomaterial with an enormous potential for use in a wide array of industrial and biomedical applications and with fast growing economic value. The expanding production of nanocellulose is leading to an increased human exposure, raising concerns about their potential health effects. This study was aimed at assessing the potential toxic and genotoxic effects of different nanocelluloses in two mammalian cell lines; (2) Methods: Two micro/nanocelluloses, produced with a TEMPO oxidation pre-treatment (CNFs) and an enzymatic pre-treatment (CMFs), and cellulose nanocrystals (CNCs) were tested in osteoblastic-like human cells (MG-63) and Chinese hamster lung fibroblasts (V79) using the MTT and clonogenic assays to analyse cytotoxicity, and the micronucleus assay to test genotoxicity; (3) Results: cytotoxicity was observed by the clonogenic assay in V79 cells, particularly for CNCs, but not by the MTT assay; CNF induced micronuclei in both cell lines and nucleoplasmic bridges in MG-63 cells; CMF and CNC induced micronuclei and nucleoplasmic bridges in MG-63 cells, but not in V79 cells; (4) Conclusions: All nanocelluloses revealed cytotoxicity and genotoxicity, although at different concentrations, that may be related to their physicochemical differences and availability for cell uptake, and to differences in the DNA damage response of the cell model.

Analysis of the In Vitro Toxicity of Nanocelluloses in Human Lung Cells as Compared to Multi-Walled Carbon Nanotubes.

Cellulose micro/nanomaterials (CMNM), comprising cellulose microfibrils (CMF), nanofibrils (CNF), and nanocrystals (CNC), are being recognized as promising bio-nanomaterials due to their natural and renewable source, attractive properties, and potential for applications with industrial and economical value. Thus, it is crucial to investigate their potential toxicity before starting their production at a larger scale. The present study aimed at evaluating the cell internalization and in vitro cytotoxicity and genotoxicity of CMNM as compared to two multi-walled carbon nanotubes (MWCNT), NM-401 and NM-402, in A549 cells. The exposure to all studied NM, with the exception of CNC, resulted in evident cellular uptake, as analyzed by transmission electron microscopy. However, none of the CMNM induced cytotoxic effects, in contrast to the cytotoxicity observed for the MWCNT. Furthermore, no genotoxicity was observed for CNF, CNC, and NM-402 (cytokinesis-block micronucleus assay), while CMF and NM-401 were able to significantly raise micronucleus frequency. Only NM-402 was able to induce ROS formation, although it did not induce micronuclei. Thus, it is unlikely that the observed CMF and NM-401 genotoxicity is mediated by oxidative DNA damage. More studies targeting other genotoxicity endpoints and cellular and molecular events are underway to allow for a more comprehensive safety assessment of these nanocelluloses.

LipNanoCar Technology - A Versatile and Scalable Technology for the Production of Lipid Nanoparticles.

The extensive knowledge in the miniemulsion technique used in biocatalysis applications by the authors allowed the development of drug delivery systems that constitutes the LipNanoCar technology core for the production of lipid nanoemulsions and solid lipid nanoparticles. The LipNanoCar technology, together with adequate formulations of different oils, fatty acids, surfactants, and temperature, allows the entrapment of several bioactive and therapeutic compounds in lipid nanoparticles for cosmetic, nutrition, and pharmaceutical applications.The LIpNanoCar technology allowed lipid nanoparticles production with average sizes ranging from 100 to 300 nm and Zeta Potentials between -55 and -20 mV. Concomitantly, high entrapment or encapsulation efficiencies (%EE) were achieved, as illustrated in this work for ß-carotene and vitamins derivatives (>85%) for cosmetic application, and for antibiotics currently used in chemotherapy, like rifampicin (69-85%) and pyrazinamide (14-29%) against Mycobacterium tuberculosis (TB), and ciprofloxacin (>65%) and tobramycin (~100%) in Cystic Fibrosis (CF) respiratory infections therapy. Ciprofloxacin presented, for example, a quick-release from the lipid nanoparticles using a dialysis tubing (96% in the first 7 h), but slower than the free antibiotic (95% in the first 3 h). This result suggests that ciprofloxacin is loaded near the external surface of the lipid nanoparticles.The toxicity and validation of entrapment of antibiotics in lipid nanoparticles for Cystic Fibrosis therapy were assessed using Caenorhabditis elegans as an animal model of bacterial infection. Fluorescence microscopy of an entrapped fluorescent dye (DiOC) confirmed the uptake of the lipid nanoparticles by ingestion, and their efficacy was successfully tested in C. elegans. Burkholderia contaminans IST408 and Burkholderia cenocepacia K56-2 infections were tested as model bacterial pathogens difficult to eradicate in Cystic Fibrosis respiratory diseases.

Dermal Delivery of Lipid Nanoparticles: Effects on Skin and Assessment of Absorption and Safety.

During the recent decades, dermal delivery has achieved visible popularity mainly due to the increase of chronic skin diseases and the demand for targeted delivery and patient compliance. Dermal delivery provides an attractive alternative to oral drug delivery, promoting the drug application directly at the site of action, resulting in higher localized drug concentration with reduced systemic drug exposure. Among several types of drug delivery systems used in dermal delivery are the lipid nanoparticles, which include solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers have attracted great interest and have been intensively studied for their use in dermal applications. Lipid nanoparticles increase the transport of active compounds through the skin by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Moreover, these nanocarriers are composed of biologically active and biodegradable lipids that show less toxicity and offer many favorable attributes such as adhesiveness, occlusion, skin hydration, lubrication, smoothness, skin penetration enhancement, modified release, improvement of formulation appearance providing a whitening effect, and offering protection of actives against degradation.This chapter focuses on the effects of lipid nanoparticles in dermal delivery, on the types of active compounds that are used in their formulation and application, some aspects related to their possible toxicity, and a description of the most commonly used techniques for the evaluation of drug absorption on the skin.

A Rare but Real Necessity: Case Report of Coronary Artery Stenting in an Infant.

Percutaneous coronary intervention (PCI) is an extremely common and well-established procedure in adults which is rarely performed in children. We present a case of a successful left main coronary artery stenting in a small infant with a congenital coronary artery anomaly. We highlight the technical challenges of performing a PCI in a small patient, the risks of antithrombotic prophylaxis in this age group, and the importance of the combined work of the adult and pediatric interventional cardiologist.

Paediatric giant cell myocarditis: a case report.

A previously healthy 15-year-old teenage boy was admitted for fever and heart failure. Myocarditis was suspected, and endomyocardial biopsy revealed giant cell myocarditis. Immunosuppressive treatment was initiated, with excellent response. A plausible link to previous leptospirosis was identified. At 18-month follow-up, left ventricular function is normal. Only one other reported case of paediatric giant cell myocarditis had such a favourable outcome.

Campylobacter coli Myocarditis: a case report.

We report the case of a 14-year-old male presented with raised myocardial injury biomarkers, on the workout, Campylobacter coli was identified on stool culture, treated with antibiotics with total resolution. Cardiac magnetic resonance showed interventricular septum and lateral wall hypokinesia and subepicardial delayed enhancement, with preserved ventricular systolic function. To our knowledge, this is the first report linking Campylobacter coli to myopericarditis in children.

Acquired anomalies of the coronary arteries after arterial switch operation. Usefulness of coronary computed tomography angiography and impact on follow-up.

INTRODUCTION: Mortality and morbidity in patients with transposition of the great arteries after an arterial switch operation depends mainly on the status of coronary perfusion. Coronary computed tomography angiography (CCTA) provides accurate information on coronary morphology, however its use in these patients is not yet routine procedure. OBJECTIVE: We sought to assess its accuracy to identify acquired coronary anomalies in this population, compared to conventional angiography in a subset of patients, and assess its impact on postoperative management. METHODS: Retrospective analysis of clinical data on transposition of the great arteries in patients who underwent CCTA between January 2013 and September 2017. RESULTS: Between January 2013 and September 2017, 18 patients underwent CCTA. Seven patients (39%) disclosed iatrogenic coronary lesions (stenosis 1; kinking 2, occlusion 1; filiform coronary 3). The exam was performed in 78% of patients due to suggestion of myocardial ischemia (symptoms or altered exams). Only 16% needed to undergo additional exams, and in four patients the CCTA result modified therapeutic management. Conventional coronary angiography was also performed in 10 patients (55%), and in three cases, the results were discordant with underestimation or non-identification of coronary lesions on conventional angiography. The medium radiation dose used was 2.4 mSv and no complications after CT were reported. CONCLUSION: CCTA accurately identified iatrogenic postoperative coronary lesions and it has proven to be superior to conventional angiography in this population. It should be performed routinely in this group of patients, even in the absence of symptoms.

Acquired anomalies of the coronary arteries after arterial switch operation. Usefulness of coronary computed tomography angiography and impact on follow-up.

INTRODUCTION: Mortality and morbidity in patients with transposition of the great arteries after an arterial switch operation depends mainly on the status of coronary perfusion. Coronary computed tomography angiography (CCTA) provides accurate information on coronary morphology, however its use in these patients is not yet routine procedure. OBJECTIVE: We sought to assess its accuracy to identify acquired coronary anomalies in this population, compared to conventional angiography in a subset of patients, and assess its impact on postoperative management. METHODS: Retrospective analysis of clinical data on transposition of the great arteries in patients who underwent CCTA between January 2013 and September 2017. RESULTS: Between January 2013 and September 2017, 18 patients underwent CCTA. Seven patients (39%) disclosed iatrogenic coronary lesions (stenosis 1; kinking 2, occlusion 1; filiform coronary 3). The exam was performed in 78% of patients due to suggestion of myocardial ischemia (symptoms or altered exams). Only 16% needed to undergo additional exams, and in four patients the CCTA result modified therapeutic management. Conventional coronary angiography was also performed in 10 patients (55%), and in three cases, the results were discordant with underestimation or non-identification of coronary lesions on conventional angiography. The medium radiation dose used was 2.4 mSv and no complications after CT were reported. CONCLUSION: CCTA accurately identified iatrogenic postoperative coronary lesions and it has proven to be superior to conventional angiography in this population. It should be performed routinely in this group of patients, even in the absence of symptoms.

Long-term follow-up after recanalisation of aortic arch atresia.

AIMS: Aortic arch atresia (AAA) is one of the rarest obstructive defects. The presence of this anomaly in adult age is uncommon. The typical anatomic feature consists of a complete occlusion of the membranous obstruction resulting in an acquired atresia without flow continuity between the proximal and distal segments. This feature is important in determining the feasibility of percutaneous intervention. The aim of the present study was to share long-term follow-up data of adult patients with AAA requiring percutaneous interventions for the management of this rare anomaly involving five different centres. METHODS AND RESULTS: Retrospective data of 19 patients (12 males, 63.2%, mean age 32.2±18.9 years) diagnosed with AAA treated in five different centres between 1999 and 2017 were collected. All patients underwent percutaneous recanalisation by (1) radiofrequency (RF) system (five patients, 26.3%), (2) extra-stiff guidewire (12 patients, 63.2%), and (3) transseptal needle (two patients, 10.5%). All procedures were subsequently followed by covered stent implantation. Two patients developed complications during the procedure and one of them died. Over a median follow-up of 4.94 years, four (21%) patients were able to be weaned from medications for hypertension. All the patients underwent reassessment for recurrence or restenosis during the follow-up. Seven (36.8%) patients underwent successful stent dilatation with a balloon. After the intervention, one patient experienced a late complication; however, one patient died due to an unknown cause believed to be unrelated to the previous recanalisation procedure. CONCLUSIONS: Percutaneous treatment of AAA is feasible with good long-term survival. This study reports the largest case series so far available in the literature.