Abstract
Funding Acknowledgements
Type of funding sources: None.
INTRODUCTION
Exercise stress echocardiography (ESE) is still underused in paediatric patients, and very little data is available for ...congenital heart diseases (CHDs).
PURPOSE
To describe the current application of ESE in our Paediatric Cardiology Departments.
METHODS
Data from patients who underwent ESE in our Centres, including baseline and under stress symptoms, vital parameters, ECG, and echocardiograms were retrospectively analyzed and compared, as well as clinical management plans formulated based on ESEs results.
RESULTS
Forty-five patients from Centre 1 (median age 16 years), including 87% of patients with CHDs, and 20 patients from Centre 2 (median age 11 years), mainly tested to rule out myocardial ischemia, were included. Among patients from Centre 1, 28 had previously been treated surgically, 6 percutaneously and 11 were under follow-up. Indications for ESE/patients’ native diagnosis are illustrated in the picture.
Centre 1: Exercise was maximal in 17 patients, with 2 of them having symptoms at the peak of exercise. It was stopped beforehand in 28 patients because of dyspnea (3) and muscle fatigue (25). No arrhythmia was detected. ESE was considered as positive in 14 patients; after that, 3 patients underwent percutaneous interventions, 2 underwent cardiac surgery, 3 received indication for cardiac catheterization, 4 for advanced cardiac imaging and 2 for exercise restriction and medical therapy.
Centre 2: Fifteen patients (75%) completed the exercise, and none of them developed symptoms. In the remaining 25%, exercise was stopped because of muscle exhaustion. No arrhythmia was detected, and all the ESEs were negative.
Comparing the cohorts, no significant differences in terms of ejection fraction were noticed at rest and under stress. Patients in cohort 1 were older (p = 0,002), they achieved lower average maximal heart rate (p = 0,0001), performed less lasting exercise (p = 0,05) and ESE was maximal less frequently (p = 0,005). Lastly, they had significant changes in clinical decisions (p = 0,004).
CONCLUSIONS
ESE is a feasible and promising technique in paediatric cardiology, particularly in children with congenital heart diseases, and could influence significantly clinical management plans. Abstract Figure.
γ-Retroviral vectors (γ-RV) are powerful tools for gene therapy applications. Current clinical vectors are produced from stable producer cell lines which require minimal further downstream ...processing, while purification schemes for γ-RV produced by transient transfection have not been thoroughly investigated. We aimed to develop a method to purify transiently produced γ-RV for early clinical studies. Here, we report a simple one-step purification method by high-speed centrifugation for γ-RV produced by transient transfection for clinical application. High-speed centrifugation enabled the concentration of viral titers in the range of 107–108 TU/mL with >80% overall recovery. Analysis of research-grade concentrated vector revealed sufficient reduction in product- and process-related impurities. Furthermore, product characterization of clinical-grade γ-RV by BioReliance demonstrated two-logs lower impurities per transducing unit compared with regulatory authority-approved stable producer cell line vector for clinical application. In terms of CAR T cell manufacturing, clinical-grade γ-RV produced by transient transfection and purified by high-speed centrifugation was similar to γ-RV produced from a clinical-grade stable producer cell line. This method will be of value for studies using γ-RV to bridge vector supply between early- and late-stage clinical trials.
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High-speed centrifugation purified γ-RV was produced by transient transfection at a scale sufficient for a phase I CAR T cell study. This one-step inexpensive downstream process combines high recovery, concentrated viral titers and good impurity clearances, and can be bridged to a stable producer cell line for subsequent larger confirmatory clinical studies.
Development of fibrosis and subsequent stricture formation in Crohn's disease (CD) increases morbidity and rates of surgery and reduces patients' quality of life. There are currently no biomarkers of ...intestinal fibrosis that might allow earlier identification and better management of patients at increased risk of stricture formation.
MicroRNA profiling of serum from CD patients was used to identify microRNAs associated with stricture formation. Differential expression of miR-19a-3p and miR-19b-3p was validated by quantitative PCR in independent CD cohort of stricturing and nonstricturing patients (n = 46 and n = 62, respectively). Levels of miR-19a-3p and miR-19b-3p were also quantified in baseline serum samples, and expression compared between CD patients who subsequently developed stricture and those who did not (n = 11 and n = 44, respectively).
Serum levels of miR-19a-3p and miR-19b-3p in the array were lower in CD patients with a stricturing phenotype than in control CD patients (P = 0.007 and 0.008, respectively). The reduction in miR-19a-3p and 19b-3p was verified in a second cohort (P = 0.002). The association of miR-19-3p with stricturing CD was independent of potential confounding clinical variables, including disease duration, disease activity, site, gender, and age. Serum analyses in patients with 4 years of follow-up support the hypothesis that reduced miR-19a-3p and miR-19b-3p predate stricture development with a trend toward significance (P = 0.077 and P = 0.060, respectively).
These data identify miR-19-3p as a potential circulating marker of stricturing CD. Our data show that microRNAs have utility as noninvasive biomarkers of stricturing CD. Further longitudinal studies are required to determine the prognostic value of miR-19-3p at diagnosis.
In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X ...chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.
Abstract
We describe the case of a 78–year old male who acceded to high intensity medicine ward for acute heart failure after some days management in the emergency room, with acuity stabilization. In ...his history all atherosclerosis‘ risk factors were present (diabetes mellitus type 2, arterial hypertension, dyslipidemia and kidney chronic disease) together with no active IgGk multiple myeloma, diagnosed the month before. A previous echocardiogram demonstrated aortic valve calcifications, preserved ejection fraction and mild mitral valve failure. the emergency echocardiography service was activated and the patient received echocardiography on first day. Echocardiography revealed severe aortic insufficiency secondary to erosive endocarditis of 15 mm in diameter, increased left ventricular filling pressures, and increased estimated right ventricular pressures. empirical antibiotic therapy was immediately undertaken and were carried out blood cultures.from the emergency echocardiography service the cardiology service was activated for a trans–esophageal echocardio execution which confirmed the findings Streptococcus gallolyticus was isolated. only after performing the echocardiogram did the patient remember having had fever for a few days, more than a month before the first symptoms of heart failure. In the next days, colon adenocarcinoma‘s diagnosis was made. Notably Streptococcus gallolyticus‘s infections are frequent in immunocompromised patients and its most common clinical manifestation is infective endocarditis.This kind of infection is usually connected with colon rectum cancer, mostly in patients that have already started chemotherapy. When endocarditis regards people who don‘t make use of intravenous drugs or that haven‘t congenital or acquired valves defects, the most involved one is the aortic valve. This is especially true in elderly patients.That could be explained by aortic valve damage caused by shear stress and atherosclerotic process, that always involves aortic valve‘s endothelium. This damage manifests itselves as calcium endothelium overload and aortic valve stenosis. All of these factors transform the aortic valve into the perfect target for bacteremia.The patient underwent aortic replacement surgery, because of acute massive aortic valve failure, that impaired patient‘s hemodynamic, and proper antibiotics therapy was started, with benefit. Finally, the colon cancer was treated with surgery, no chemotherapy was needed.
Abstract
Aim of the Study
To evaluate the mechanical changes of the right ventricle in patients undergoing balloon pulmonary valvuloplasty using transthstandard transthoracic echocardiography (TTE) ...and speckle–tracking echocardiography (STE) and to investigate the correlation between haemodynamic and echocardiographic parameters before and after treatment.
Materials and Methods
43 pediatric patients (19 males), mean age 3,2±4,9 years with severe pulmonary valve stenosis and indication for percutaneous balloon valvuloplasty were recruited. All patients underwent TTE and STE with analysis of right ventricle global longitudinal strain (RVGLS) one day before and after the procedure. For each patient were collected invasive parameters during balloon valvulopasty.
Results
After the procedure, there was an immediate reduction of both peak–to–peak transpulmonary gradient (Dp post) and ratio between the systolic pressure of right and left ventricle (RV/LV ratio) with a drop of 29,3±14,67mmHg and 0,43±0,03, respectively. Post–procedural echocardiography showed peak and mean transvalvar pressure gradient drop (50±32,23 and 31±17,97, respectively). The degree of pulmonary valve regurgitation was mild in 8% of patients before the procedure, following the intervention it reached 29% with a statistically significant increase (p = 0,007). However, moderate and severe regurgitation remained stable after the procedure. There was a significant improvement of Fractional Area Change (FAC) after the procedure (40,11% vs 44,42%, p = 0,01). TAPSE (p = 0,60) and longitudinal strain (p = 0,31), did not improve significantly after intervention. Finally, pre–procedural invasive RV/LV ratio showed good correlation to echocardiographic transvalvular peak and mean pressure gradient (R = 0,375, p = 0,019 and R = 0,40, p = 0,012, respectively), as well as with FAC (R = 0,31 p = 0,05), TAPSE (R = 0,62 p < 0,001)and RVGLS (R = 0,46 p = 0,01)
Conclusions
Percutaneous balloon pulmonary valvuloplasty represents an efficient and safe procedure. Right ventricular global systolic function improved following afterload reduction, while longitudinal systolic function did not show improvement immediately after intervention. Finally, invasive preprocedural RV/LV ratio demonstrated better correlation with echocardiographic evaluation of stenosis degree and right ventricular function compared to invasive peak–to–peak pressure gradient. Therefore, RV/LV ratio should be preferred for the assessment of pulmonary valve stenosis.
An altered balance between effector and regulatory factors is supposed to sustain the tissue-damaging immune response in inflammatory bowel disease (IBD). We have recently shown that in IBD, there is ...a defective synthesis of the counter-regulatory cytokine, interleukin (IL)-25. In this study we investigated factors that control IL-25 production in the gut. IBD patients produced less IL-25 when compared with normal controls. Stimulation of normal intestinal explants with tumor necrosis factor-α (TNF-α), but not interferon-γ (IFN-γ) or IL-21, reduced IL-25 synthesis. Consistently, IL-25 production was enhanced by anti-TNF-α both in vitro and in vivo. Upregulation of IL-25 was also seen in normal colonic explants stimulated with transforming growth factor-β1 (TGF-β1). As in IBD, TGF-β1 activity is abrogated by Smad7, we next assessed whether inhibition of Smad7 with an antisense oligonucleotide enhanced IL-25 expression. Knockdown of Smad7 was accompanied by an increase in IL-25 production. Data show that IL-25 production is differently regulated by TNF-α and TGF-β1 in the human gut.
Abstract
Funding Acknowledgements
EACVI Training Grant
Introduction
Kawasaki disease (KD) is an acute vasculitis of unknown etiology. It is associated with high morbidity and mortality due to the ...development of coronary artery aneurysms and myocardial dysfunction.
Purpose
The aim of this study was to evaluate sensitivity and specificity of left ventricular (LV) pressure–strain loop (PSL) area, which reflects regional myocardial work and metabolic demand, in predicting subtle myocardial abnormalities in KD patients with coronaries aneurisms.
Methods
A total of 88 patients (59 male, age 8.95 ± 4.95 years) were included in our study. Among the children admitted in our institution with a diagnosis of KD during the study time frame, 42 patients (KDg) (29 male) with coronary artery dilatation (Z-score >2.5) were selected. These cases were compared with 46 (30 male) age-matched controls (CTRg). Classical echocardiographic parameters of LV systolic function were normal in both groups, while global longitudinal strain (GLS) was decreased in 6 KD patients. Global work index (GWI) was calculated as the area of the LV PSL. From GWI, it was estimated also Global Constructive Work (GCW), Global Wasted Work (GWW) and Global Work Efficiency (GWE). We also made a subgroup analysis between KD patients with normal GLS (> -19 %) and control patients.
Results
Despite normal LV systolic function by routine echocardiography, compared to controls, KD patients had lower GWI (1448 ± 382 mmHg% in KDg vs 1751 ± 263 mmHg% in CTRg, p = 0.00003), GCW (1904 ± 390 mmHg% in KDg vs 2174 ± 292 mmHg% in CTRg, p= 0.0004) and GWE (94 ± 5 % in KDg vs 96 ± 2 % in CTRg, p= 0.01). There was not significant difference in GWW between the KDg and CTRg. When KD patients with normal GLS were analysed separately, they preserved a significant difference in GWI, GCW and GWE in comparison with controls (GWI: 1490 ± 347 mmHg% in KDg vs 1751 ± 263 mmHg% in CTRg, p = 0.0002; GCW: 1972 ± 321 mmHg% in KDg vs 2174 ± 292 mmHg% in CTRg, p = 0.004; GWE: 95 ± 3 in KDg vs 96 ± 2 % in CTRg, p= 0.04). No association was found between GWI, GCW, GWW, GWE and number or dimension of the involved aneurysmatic coronaries.
Conclusions
The estimation of myocardial work by PSL is a novel tool for the evaluation of patients with KD. GWI, GCW and GWE were significantly reduced in KD patients with dilated coronaries. In KD patients with normal GLS, estimation of GWI, GCW and GWE may be a sensitive indicator of myocardial dysfunction and an adjuvant criterion to avoid delayed diagnosis of KD.
Abstract P316 Figure. Myocardial work in KD and CTR.
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