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AIMS: Heart transplantation is a well-established treatment for end-stage heart failure in paediatric patients, demonstrating excellent long-term outcomes. METHODS: This retrospective study analyses 35 years of data on 244 paediatric recipients (<18 years) at a single institution from 1986 to 2022. The analysis explores changes in diagnoses, survival, waiting times and mechanical circulatory support (MCS) over three decades (1991-2000, 2001-2010 and 2011-2020). RESULTS: Survival outcomes significantly improved over the study period, with 1-year survival rates increasing from 79.3% (1991-2000) to 92.3% (2011-2020, P = 0.041). The median overall survival was 18.0 years, and median conditional survival to 1 year post-transplant was 20.9 years. Survival differences were noted among age groups, with infants under 1 year of age experiencing higher early mortality, and adolescents (aged 11-17 years) facing increased long-term risks, possibly linked to adult donor characteristics. Waiting times for heart transplantation increased, especially for younger age groups (0-5 and 6-10 years), reflecting the growing demand for donor organs. The use of MCS, including ventricular assist devices (VAD), surged, with 67% of recipients in the most recent decade receiving pre-transplant VAD support. Importantly, despite prolonged waiting times and increased VAD use, overall survival continued to be favourable. CONCLUSIONS: Early and long-term results after paediatric heart transplantation have been continuously improving over the past decades. Despite an increased demand for donor organs and the growing reliance on VAD as bridge to transplantation, post-transplantation survival is not compromised.
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Recently, extracellular vesicles (EVs) have been developed as therapeutic targets for various diseases. Biodistribution is crucial for EVs intended for therapeutic purposes because it can determine the degree of on- and off-target effects. This study aimed to explore techniques to evaluate the biodistribution of unmodified EVs. We devised a novel quantitative polymerase chain reaction (qPCR)-based assay to detect unmodified EVs by targeting mitochondrial deoxyribonucleic acid (mtDNA), a constituent of EVs. We focused on specific mtDNA regions that exhibited homologous variations distinct from their rodent mtDNA counterparts to establish this analytical approach. Herein, we successfully designed primers and probes targeting human and rodent mtDNA sequences and developed a highly specific and sensitive qPCR method. Furthermore, the quantification range of EVs isolated from various cells differed based on the manufacturer and cell source. IRDye 800CW-labelled Expi293F EV mimetics were administered to the animals via the tail vein to compare the imaging test and mtDNA-qPCR results. The results obtained from imaging tests and mtDNA-qPCR to investigate EV biodistribution patterns revealed differences. The results revealed that our newly developed method effectively determined the biodistribution of unmodified EVs with high sensitivity and reproducibility.
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DNA Mitocondrial , Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Animais , DNA Mitocondrial/metabolismo , Humanos , Distribuição Tecidual , Camundongos , Ratos , Mitocôndrias/metabolismoRESUMO
OBJECTIVES: This study aimed to evaluate the short-/mid-term outcome of patients with complex dextro (d)-/levo (l)-transposition of the great arteries (TGA), ventricular septal defect and left ventricular outflow tract obstructions. METHODS: A single-centre, retrospective review of all complex dextro-TGA (n = 85) and levo-TGA (n = 22) patients undergoing different surgeries [Arterial switch operation + left ventricular outflow tract obstruction-resection (ASO-R), half-turned truncal switch/Mair (HTTS), Nikaidoh and Rastelli] between May 1990 and September 2022 was performed. Groups were analysed using Kruskal-Wallis test with post hoc pairwise comparison and Kaplan-Meier time-to-event models. RESULTS: A total of 107 patients [ASO-R (n = 20), HTTS (n = 23), Nikaidoh (n = 21), Rastelli (n = 43)] were included, with a median age of 1.0 year (0.5-2.5) and surgical repair median follow-up was 3.8 years (0.3-10.5). Groups did not differ in respect to early postoperative complications/early mortality. Five-year overall survival curves were comparable: ASO-R 78.9% (53.2-91.5), HTTS 75.3% (46.8-89.9), Nikaidoh 85% (60.4-94.9) and Rastelli 83.9% (67.5-92.5), P = 0.9. Highest rates of right ventricular outflow tract (RVOT) reinterventions [33.3% and 32.6% (P = 0.04)] and reoperations [28.6% and 32.6% (P = 0.02)] occurred after Nikaidoh and Rastelli procedures. However, overall freedom from RVOT reinterventions and RVOT reoperations at 5 years did not differ statistically significantly between the groups (ASO-R, HTTS, Nikaidoh and Rastelli): 94.4% (66.6-99.2), 69.1% (25.4-90.5), 67.8% (34-86.9), 64.4% (44.6-78.7), P = 0.2, and 90.0% (65.6-97.4), 91% (50.8-98.7), 65.3% (32.0-85.3) and 67.0% (47.4-80.6), P = 0.3. CONCLUSIONS: Surgical repair of complex dextro-/levo-TGA can be performed with satisfying early/mid-term survival. RVOT reinterventions/reoperations were frequent, with highest rates after Nikaidoh and Rastelli procedures. Left ventricular outflow tract obstruction reoperations were rare with zero events after Nikaidoh and HTTS procedures.
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Transposição das Grandes Artérias , Transposição dos Grandes Vasos , Obstrução da Via de Saída Ventricular Esquerda , Obstrução do Fluxo Ventricular Externo , Humanos , Lactente , Transposição dos Grandes Vasos/cirurgia , Obstrução do Fluxo Ventricular Externo/cirurgia , Transposição das Grandes Artérias/efeitos adversos , Transposição das Grandes Artérias/métodos , Artérias , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.
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Neoplasias , Proteínas Proto-Oncogênicas c-akt , Proteína com Valosina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Paraptose , Adenosina Trifosfatases/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismoRESUMO
Rock bream iridovirus (RBIV), belonging to Megalocytivirus, causes severe mortality in rock bream. Almost all deaths associated with RBIV are accompanied by splenic enlargement and anemia. Although red blood cells (RBCs) are involved in the immune response against viral infections, their involvement in rock bream has not yet been studied in terms of the immune response against RBIV. In this study, the viral replication patterns, blood characteristics and anemia-related factors were evaluated in rock bream post RBIV infection. The virus-infected RBCs of rock bream demonstrated similarities in the expression levels of hemoglobins (HGB) (α and ß), cytokine-dependent hematopoietic cell linker (CLNK) and hematopoietic transcription factor GATA (GATA), with significantly decreasing levels from 4 days post infection (dpi) to 17 (dpi), when the viral replication was at its peak. This suggests that the expression of blood-related genes is inadequate for HGB synthesis and RBC production, thereby causing anemia leading to death. Moreover, the levels of complete blood cell count (CBC) indicators, such as RBCs, HGB and hematocrit (HCT), significantly decreased from 10 to 17 dpi. This phenomenon suggests that blood-related gene expression and/or RBC-, HGB- and HCT-related levels are critical factors in RBIV-induced anemia and disease progression. These results highlight the significance of blood-mediated immune responses against RBIV infection in rock bream. Understanding blood-related gene levels to identify blood-related immune response interactions in rock bream will be useful for development of future strategies in controlling RBIV diseases in rock bream.
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Anemia , Infecções por Vírus de DNA , Doenças dos Peixes , Iridoviridae , Iridovirus , Animais , Iridovirus/genética , Infecções por Vírus de DNA/veterinária , Iridoviridae/fisiologia , Eritrócitos/metabolismo , FilogeniaRESUMO
The impact of bacteria on cancer progression and treatment is becoming increasingly recognized. Cancer-associated bacteria are linked to metastases, reduced efficacy, and survival challenges. In this study, we present a sensitive hypoxia-activated prodrug, NR-NO2, which comprises an antibiotic combined with a chemotherapeutic. This prodrug demonstrates rapid and robust fluorescence enhancement and exhibits potent antibacterial activity against both Gram-positive and Gram-negative bacteria as well as tumor cells. Upon activation, NR-NO2 produces a distinct "fluorescence-on" signal, enabling real-time drug release monitoring. By leveraging elevated nitroreductase in cancer cells, NR-NO2 gives rise to heightened bacterial cytotoxicity while sparing normal cells. In A549 solid tumor-bearing mice, NR-NO2 selectively accumulated at tumor sites, displaying fluorescence signals under hypoxia superior to those of a corresponding prodrug-like control. These findings highlight the potential of NR-NO2 as a promising cancer therapy prodrug that benefits from targeted release, antibacterial impact, and imaging-based guidance.
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Infecções Bacterianas , Neoplasias , Pró-Fármacos , Camundongos , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Medicina de Precisão , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Dióxido de Nitrogênio/uso terapêutico , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Hipóxia/diagnóstico por imagem , Hipóxia/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Linhagem Celular TumoralRESUMO
Mechanical support options for children and small adolescents with acute left ventricular failure are often limited to extracorporeal life support (ECLS) and subsequent left ventricular assist device implantation. We report a case of a 3-year-old child weighing 12 kg with acute humoral rejection after cardiac transplantation not adequately responding to medical therapy who presented in persistent low cardiac output syndrome. We successfully stabilized the patient by implanting a Impella 2.5 device via a 6-mm Hemashield prosthesis on the right axillary artery. The patient was bridged to recovery.
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Insuficiência Cardíaca , Coração Auxiliar , Adolescente , Humanos , Pré-Escolar , Choque Cardiogênico/terapia , Resultado do Tratamento , Implantação de Prótese , Estudos RetrospectivosRESUMO
Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as a repurposed drug. We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although the covalent inhibition of thioredoxin reductase (TrxR), an enzyme that critically controls intracellular redox homeostasis, is considered the primary mechanism of AF's anticancer activity, knockdown of TrxR1 did not induce paraptosis. Instead, both TrxR1 knockdown plus the proteasome inhibitor (PI), bortezomib (Bz), and 2 µM AF plus Bz induced paraptosis, thereby mimicking the effect of 5 µM AF. These results suggest that the paraptosis induced by 5 µM AF requires the inhibition of both TrxR1 and proteasome. We found that TrxR1 knockdown/Bz or subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells, whereas 4~5 µM AF killed both cancer and MCF10A cells. GSH depletion was found to be more critical than ROS generation for the paraptosis induced by dual TrxR1/proteasome inhibition. In this process, the ATF4/CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1) axis leads to GSH degradation, contributing to proteotoxic stress possibly due to the accumulation of misfolded thiol-containing proteins. These results suggest that the paraptosis-inducing strategy of AF plus a PI may provide an effective therapeutic strategy against pro-apoptotic therapy-resistant cancers and reduce the potential side effects associated with high-dose AF.
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Auranofina , Neoplasias da Mama , Humanos , Feminino , Auranofina/farmacologia , Complexo de Endopeptidases do Proteassoma , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Tiorredoxina Redutase 1 , Bortezomib/farmacologia , ApoptoseRESUMO
OBJECTIVE: The aim was to report mid-term performance of decellularized equine pericardium used for repair of various congenital heart defects in the pediatric population. METHODS: A retrospective review of all patients undergoing patch implantation between 2016 - 2020 was performed. Patch quality, surgical handling, hemostasis and early patch-related complications were studied on all patients. Mid-term performance was observed in patients with ≥12 months follow-up and intact patch at discharge (without reoperation/stent implantation). RESULTS: A total of 201 patients with median age of 2.5 years [interquartile range (IQR): 0.6-6.5] underwent 207 procedures at 314 implant locations. The patch was used in following numbers/locations: 171 for pulmonary artery (PA) augmentation, 36 for aortic repair, 35 for septal defect closure, 22 for valvular repair and 50 at other locations. Early/30-day mortality was 6.5%. Early patch-related reoperations/stent implantations occurred in 28 locations (8.9%). No patch-related complications were noted except for bleeding from implant site in three locations (1%). Follow-up ≥ 12 months was available for 132 patients/200 locations. During a median follow-up of 29.7 months [IQR: 20.7-38.3], 53 patch-related reoperations/catheter reinterventions occurred (26.5%) with the majority in PA position (88.7%, 47/53). Overall 12- and 24-months freedom from patch-related reoperation/catheter reintervention per location was 91.5% (95% CI: 86.7%-94.6%) and 85.2% (95% CI: 78.9%-89.6%) respectively. CONCLUSION: Decellularized equine pericardium used for repair of various congenital heart defects showed acceptable mid-term performance. Reoperation/reintervention rates were in a range as observed with other xenogeneic materials previously reported articles, occurring most frequently after PA augmentation.
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Miamiensis avidus is a parasitic pathogen that causes the disease scuticociliatosis in teleost fish species. It is a ciliate and a free-living marine protozoan belonging to the order Philasterida, subclass Scuticociliatida, class Oligohymenophorea, and phylum Ciliophora. The complete mt-genome of M. avidus was linear and 38,695 bp in length with 47 genes, including 40 protein-coding genes, two ribosomal RNA (rRNA) genes, and five transfer RNA (tRNA) genes. Of these, 20 genes typically belong to the clusters of orthologous groups, playing roles in energy production and conversion, translation, ribosomal structure and biogenesis, and defense mechanisms. This is the first report of sequencing and characterization of the mt-genome of M. avidus, which was observed to be linear and possessing the typical ciliate mitochondrial genome organization and phylogenetic relationships. Remarkable differences were observed between M. avidus and other ciliates in the mitochondrially encoded rRNAs, extensive gene loss in ribosomal genes and tRNAs, terminal repeat sequences, and stop codon usage. A comparative and phylogenetic analysis of M. avidus and Uronema marinum of the order Hymenostomatida, which is most closely related to the order Philasterida, signified the promise of the mitogenome data of M. avidus as a valuable genetic marker in species detection and taxonomic research. The present study has potential applications in epidemiological studies and host-parasite interaction investigations facilitating disease control.
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Infecções por Cilióforos , Doenças dos Peixes , Genoma Mitocondrial , Oligoimenóforos , Animais , Infecções por Cilióforos/genética , Infecções por Cilióforos/parasitologia , Filogenia , Doenças dos Peixes/genética , Doenças dos Peixes/parasitologia , Oligoimenóforos/genéticaRESUMO
The heterotypic CIC structures formed of cancer and immune cells have been observed in tumor tissues. We aimed to assess the feasibility of using heterotypic CICs as a functional biomarker to predict NK susceptibility and drug resistance. The heterotypic CIC-forming cancer cells showed a lower response to NK cytotoxicity and higher proliferative ability than non-CIC cancer cells. After treatment with anticancer drugs, cancer cells that formed heterotypic CICs showed a higher resistance to anticancer drugs than non-CIC cancer cells. We also observed the formation of more CIC structures in cancer cells treated with anticancer drugs than in the non-treated group. Our results confirm the association between heterotypic CIC structures and anticancer drug resistance in CICs formed from NK and cancer cells. These results suggest a mechanism underlying immune evasion in heterotypic CIC cancer cells and provide insights into the anticancer drug resistance of cancer cells.
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Background: Uneven hepatic venous blood flow distribution (HFD) to the pulmonary arteries is hypothesized to be responsible for the development of intrapulmonary arteriovenous malformations (PAVM) in patients with univentricular physiology. Thus, achieving uniform distribution of hepatic blood flow is considered favorable. However, no established method for the prediction of the post-interventional hemodynamics currently exists. Computational fluid dynamics (CFD) offers the possibility to quantify HFD in patient-specific anatomies before and after virtual treatment. In this study, we evaluated the potential benefit of CFD-assisted treatment planning. Materials and methods: Three patients with total cavopulmonary connection (TCPC) and PAVM underwent cardiovascular magnetic resonance imaging (CMR) and computed tomography imaging (CT). Based on this imaging data, the patient-specific anatomy was reconstructed. These patients were considered for surgery or catheter-based intervention aiming at hepatic blood flow re-routing. CFD simulations were then performed for the untreated state as well as for different surgical and interventional treatment options. These treatment options were applied as suggested by treating cardiologists and congenital heart surgeons with longstanding experience in interventional and surgical treatment of patients with univentricular physiology. HFD was quantified for all simulations to identify the most viable treatment decision regarding redistribution of hepatic blood flow. Results: For all three patients, the complex TCPC anatomy could be reconstructed. However, due to the presence of metallic stent implants, hybrid models generated from CT as well as CMR data were required. Numerical simulation of pre-interventional HFD agreed well with angiographic assessment and physiologic considerations. One treatment option resulting in improvement of HFD was identified for each patient. In one patient follow-up data after treatment was available. Here, the virtual treatment simulation and the CMR flow measurements differed by 15%. Conclusion: The combination of modern computational methods as well as imaging methods for assessment of patient-specific anatomy and flow might allow to optimize patient-specific therapy planning in patients with pronounced hepatic flow mismatch and PAVM. In this study, we demonstrate that these methods can also be applied in patients with complex univentricular physiology and extensive prior interventions. However, in those cases, hybrid approaches utilizing information of different image modalities may be required.
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Hypoxia is a feature of most solid tumors and a key determinant of cancer growth and propagation. Sensing hypoxia effectively could lead to more favorable clinical outcomes. Here, we report a molecular antenna-based bimodal probe designed to exploit the complementary advantages of magnetic resonance (MR)- and optical-based imaging. Specifically, we describe the synthesis and evaluation of a dual-action probe (NO2-Eu) that permits hypoxia-activated chemical exchange saturation transfer (CEST) MR and optical imaging. In CT26 cells, this NO2-Eu probe not only provides an enhanced CEST MRI signal but also turns "on" the optical signal under hypoxic conditions. Time-dependent in vivo CEST imaging in a hypoxic CT26 tumor xenograft mouse model revealed probe-dependent tumor detection by CEST MRI contrast in the tumor area. We thus suggest that dual-action hypoxia probes, like that reported here, could have a role to play in solid tumor diagnosis and monitoring.
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Neoplasias , Dióxido de Nitrogênio , Animais , Meios de Contraste/química , Humanos , Hipóxia/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Camundongos , Neoplasias/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: There has been growing concern regarding the impact of air pollution, especially fine dust, on human health. However, it is difficult to estimate the toxicity of fine dust on the human body because of its diverse effects depending on the composition and environmental factors. RESULTS: In this study, we focused on the difference in the biodistribution of fine dust according to the size distribution of particulate matter after inhalation into the body to predict its impact on human health. We synthesized Cy7-doped silica particulate matters (CSPMs) having different particle sizes and employed them as model fine dust, and studied their whole-body in vivo biodistribution in BALB/c nude mice. Image-tracking and quantitative and qualitative analyses were performed on the ex vivo organs and tissues. Additionally, flow cytometric analysis of single cells isolated from the lungs was performed. Smaller particles with a diameter of less than 100 nm (CSPM0.1) were observed to be removed relatively rapidly from the lungs upon initial inhalation. However, they were confirmed to accumulate continuously over 4 weeks of observation. In particular, smaller particles were found to spread rapidly to other organs during the early stages of inhalation. CONCLUSIONS: The results show in vivo behavioral differences that arisen from particle size through mouse experimental model. Although these are far from the human inhalation studies, it provides information that can help predict the effect of fine dust on human health. This study might provide with insights on association between CSPM0.1 accumulation in several organs including the lungs and adverse effect to underlying diseases in the organs.
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Poluentes Atmosféricos , Poeira , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Animais , Poeira/análise , Camundongos , Camundongos Nus , Tamanho da Partícula , Material Particulado/toxicidade , Distribuição TecidualRESUMO
BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) and bone morphogenetic protein-2 (BMP-2) have been studied for bone repair because they have regenerative potential to differentiate into osteoblasts. The development of injectable and in situ three-dimensional (3D) scaffolds to proliferate and differentiate BMSCs and deliver BMP-2 is a crucial technology in BMSC-based tissue engineering. METHODS: The proliferation of mouse BMSCs (mBMSCs) in collagen/poly-γ-glutamic acid (Col/γ-PGA) hydrogel was evaluated using LIVE/DEAD and acridine orange and propidium iodide assays. In vitro osteogenic differentiation and the gene expression level of Col/γ-PGA(mBMSC/BMP-2) were assessed by alizarin red S staining and quantitative reverse-transcription polymerase chain reaction. The bone regeneration effect of Col/γ-PGA(mBMSC/BMP-2) was evaluated in a mouse calvarial bone defect model. The cranial bones of the mice were monitored by micro-computed tomography and histological analysis. RESULTS: The developed Col/γ-PGA hydrogel showed low viscosity below ambient temperature, while it provided a high elastic modulus and viscous modulus at body temperature. After gelation, the Col/γ-PGA hydrogel showed a 3D and interconnected porous structure, which helped the effective proliferation of BMSCs with BMP-2. The Col/γ-PGA (mBMSC/BMP-2) expressed more osteogenic genes and showed effective orthotopic bone formation in a mouse model with a critical-sized bone defect in only 3-4 weeks. CONCLUSION: The Col/γ-PGA(mBMSC/BMP-2) hydrogel was suggested to be a promising platform by combining collagen as a major component of the extracellular matrix and γ-PGA as a viscosity reducer for easy handling at room temperature in BMSC-based bone tissue engineering scaffolds.
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Hidrogéis , Células-Tronco Mesenquimais , Laranja de Acridina/metabolismo , Laranja de Acridina/farmacologia , Animais , Regeneração Óssea , Colágeno/metabolismo , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese , Ácido Poliglutâmico/análogos & derivados , Propídio/metabolismo , Propídio/farmacologia , Microtomografia por Raio-XRESUMO
Several criteria to identify suitable candidates for anatomic repair in congenitally corrected transposition (cc-TGA) have been proposed. The purpose of this study was to critically re-evaluate adequacy of these recommendations in our patient cohort. All cc-TGA patients undergoing anatomic repair between 2010 and 2019 were reviewed. Evaluated eligibility criteria for repair included age ≤ 15 years, LV mass index ≥ 45-50 g/m2, LV mass/volume ratio > 0.9-1.5 and systolic LV to right ventricle pressure ratio > 70-90% among others. Repair failure was defined as postoperative early mortality or LV dysfunction requiring mechanical circulatory support. Twenty-five patients were included (median [interquartile range] age at surgery 1.8 years [0.7;6.6]; median postoperative follow-up 3.2 years [0.7;6.3]). Median preoperative LV ejection fraction was 60% [56;64], indexed LV mass 48.5 g/m2 [43.7;58.1] and LV mass/volume ratio 1.5 [1.1;1.6], respectively. A total of 12 patients (48%) did not meet at least one of the previously recommended criteria, however, all but two patients (92%) experienced favorable early outcome. Of 7 patients (28%) with indexed LV mass < 45 g/m2, 6 were successfully operated. There were two early repair failures (8%) with LV dysfunction: one patient died and one required mechanical circulatory support but recovered well. Surgery was performed successfully in patients with LV mass and volume Z-scores as low as - 2 and - 2.5, respectively. Anatomic correction for cc-TGA can be performed with excellent early outcome and is feasible even in patients with LV mass below previously recommended cut-offs. The use of LV mass and volume Z-scores might help to refine eligibility criteria.
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Transposição dos Grandes Vasos , Adolescente , Transposição das Grandes Artérias Corrigida Congenitamente , Humanos , Lactente , Volume Sistólico , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
Double-chambered right ventricle (DCRV) is a progressive division of the right ventricular outflow tract (RVOT) often associated with a subaortic ventricular defect (VSD). The septation is caused by a mixture of hypertrophied muscle bundles and fibrous tissue, whereof the latter is of unclear pathogenesis. Our group has previously reported that flow disturbances lead to formation of fibroelastic tissue through a process called endothelial-to-mesenchymal transition (EndMT) but it is unclear whether the same mechanism exists in the RV. Tissue from patients undergoing repair of DCRV was examined to identify the histomorphological substrate of this tissue. Demographic and pre-/post-operative echocardiographic data were collected from nine patients undergoing surgery for DCRV. RVOTO tissue samples were histologically analyzed for myocardial hypertrophy, fibrosis, elastin content, and active EndMT (immunohistochemical double-staining for endothelial and mesenchymal markers and transcription factors Slug/Snail) and compared to four healthy controls. Indication for surgery were symptoms and progressive RVOT gradients. A highly turbulent flow jet through the RVOTO and VSD was observed in all patients with a preoperative median RVOT peak gradient of 77 mmHg (IQR 55.0-91.5), improved to 6 mmHg (IQR 4.5-17) postoperatively. Histological analysis revealed muscle and thick infiltratively growing fibroelastic tissue. EndMT was confirmed as underlying patho-mechanism of this fibroelastic tissue but the degree of myocardial hypertrophy was not different compared to controls (P = 0.08). This study shows for the first time that an invasive fibroelastic remodeling processes of the endocardium into the underlying myocardium through activation of EndMT contributes to the septation of the RVOT.
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Comunicação Interventricular , Ventrículos do Coração , Cardiomegalia , Ecocardiografia , Endocárdio/patologia , Comunicação Interventricular/cirurgia , Ventrículos do Coração/cirurgia , Humanos , Miocárdio/patologiaRESUMO
OBJECTIVES: Very low birthweight (<1500 g, VLBW) infants with severe congenital heart defect (CHD) are at increased risk for perinatal and operative mortality. This study aims to describe morbidity, long-term mortality and neuro-developmental outcome in early childhood in VLBW infants who received cardiac surgery for severe CHD within 1 year after birth. METHODS: Monocentric observational study on VLBW infants with severe CHD born between 2008 and 2017. Neurodevelopmental impairment at 2 years corrected age was defined as cognitive deficit, cerebral palsy or major neurosensory deficit. RESULTS: A total of 24 patients were included. Twenty-one (87.5%) infants underwent cardiac surgery with hypothermia during cardiopulmonary bypass (median temperature 30.3°C, interquartile range 27.0-32.0°C) at a median age of 96 (40-188) days. Seven (29.2%, 95% confidence interval 14.9-49.2%) patients died within the first year after cardiac surgery. Survival rates decreased with increasing STAT mortality category of the surgical procedure. Neurodevelopmental impairment at 2 years of corrected age was found in 9 out of 17 (52.9%) surviving infants, with 8 infants (47.1%) presenting with a cognitive deficit or delay and 4 infants (23.5%) being diagnosed with cerebral palsy. Survival without neuro-developmental impairment was 29.2% (n = 7, 95% confidence interval 14.9-49.2%) in the entire study cohort. Eighty percent of the newborns with dextro-transposition of the great arteries, but no patient with univentricular anatomy, survived without neuro-developmental impairment. CONCLUSIONS: Individual VLBW infants with severe CHD may develop well despite the high combined risk for adverse outcomes. The type of cardiac malformation may affect early- and long-term outcomes.
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Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Recém-Nascido de muito Baixo Peso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Recém-Nascido , Gravidade do Paciente , Resultado do TratamentoRESUMO
Prematurity is a risk factor for adverse outcomes after arterial switch operation in newborns with D-TGA (D-TGA). In this study, we sought to investigate the impact of prematurity on postnatal and perioperative clinical management, morbidity, and mortality during hospitalization in neonates with simple and complex D-TGA who received arterial switch operation (ASO). Monocentric retrospective analysis of 100 newborns with D-TGA. Thirteen infants (13.0%) were born premature. Preterm infants required significantly more frequent mechanical ventilation in the delivery room (69.2% vs. 34.5%, p = 0.030) and during the preoperative course (76.9% vs. 37.9%, p = 0.014). Need for inotropic support (30.8% vs. 8.0%, p = 0.035) and red blood cell transfusions (46.2% vs. 10.3%, p = 0.004) was likewise increased. Preoperative mortality (23.1% vs 0.0%, p = 0.002) was significantly increased in preterm infants, with necrotizing enterocolitis as cause of death in two of three infants. In contrast, mortality during and after surgery did not differ significantly between the two groups. Cardiopulmonary bypass times were similar in both groups (median 275 vs. 263 min, p = 0.322). After ASO, arterial lactate (34.5 vs. 21.5 mg/dL, p = 0.007), duration of mechanical ventilation (median 175 vs. 106 h, p = 0.038), and venous thrombosis (40.0% vs. 4.7%, p = 0.004) were increased in preterm, as compared to term infants. Gestational age (adjusted unit odds ratio 0.383, 95% confidence interval 0.179-0.821, p = 0.014) was independently associated with mortality. Prematurity is associated with increased perioperative morbidity and increased preoperative mortality in D-TGA patients.
Assuntos
Transposição das Grandes Artérias , Transposição dos Grandes Vasos , Transposição das Grandes Artérias/efeitos adversos , Artérias , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Morbidade , Estudos Retrospectivos , Transposição dos Grandes Vasos/cirurgia , Resultado do TratamentoRESUMO
Natural killer (NK) cells are immune effector cells with outstanding features for adoptive immunotherapy. Immune effector cells with chimeric antigen receptors (CARs) are promising targeted therapeutic agents for various diseases. Because tumor cells exhibit heterogeneous antigen expression and lose cell surface antigen expression during malignant progression, many CARs fixed against only one antigen have limited efficacy and are associated with tumor relapse. To expand the utility of CAR-NK cells, we designed a split and universal cotinine-CAR (Cot-CAR) system, comprising a Cot-conjugator and NK92 cells (α-Cot-NK92 cells) engineered with a CAR containing an anti-Cot-specific single-chain variable fragment and intracellular signaling domain. The efficacy of the Cot-CAR system was assessed in vitro using a cytolysis assay against various tumor cells, and its single- or multiple- utility potential was demonstrated using an in vivo lung metastasis model by injecting A549-Red-Fluc cells. The α-Cot-NK92 cells could switch targets, logically respond to multiple antigens, and tune cytolytic activation through the alteration of conjugators without re-engineering. Therefore the universal Cot-CAR system is useful for enhancing specificity and diversity of antigens, combating relapse, and controlling cytolytic activity. In conclusion, this universal Cot-CAR system reveals that multiple availability and controllability can be generated with a single, integrated system.