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We previously showed cell-cell contacts of human dermal fibroblasts to induce expression of the hepatocyte growth factor/scatter factor (HGF) in a process designated as nemosis. Now we report on nemosis initiation in bone marrow mesenchymal stem cells (BMSCs). Because BMSCs are being used increasingly in cell transplantation therapy we aimed to demonstrate a functional effect and benefit of BMSC nemosis for wound healing. Nemotic and monolayer cells were used to stimulate HaCaT keratinocyte migration in a scratch-wound healing assay. Both indicators of nemosis, HGF production and cyclooxygenase-2 expression, were induced in BMSC spheroids. When compared with a similar amount of cells as monolayer, nemotic cells induced keratinocyte in vitro scratch-wound healing in a concentration-dependent manner. The HGF receptor, c-Met, was rapidly phosphorylated in the nemosis-stimulated keratinocytes. Nemosis-induced in vitro scratch-wound healing was inhibited by an HGF-neutralizing antibody as well as the small molecule c-Met inhibitor, SU11274. HGF-induced in vitro scratch-wound healing was inhibited by PI3K inhibitors, wortmannin and LY294002, while LY303511, an inactive structural analogue of LY294002, had no effect. Inhibitors of the mitogen-activated protein kinases MEK/ERK1/2 (PD98059 and U0126), and p38 (SB203580) attenuated HGF-induced keratinocyte in vitro scratch-wound healing. We conclude that nemosis of BMSCs can induce keratinocyte in vitro scratch-wound healing, and that in this effect signaling via HGF/c-Met is involved. [ABSTRACT FROM AUTHOR]

Objective:  The aim of this cross-sectional study was to investigate the relationship between periodontitis, potential periodontitis oral fluid biomarkers, and prediabetes., Materials and Methods:  This study included 150 Greek adults aged 25 to 78 years who were tested with an Hemoglobin A1C (HBA1c) diagnostic system, an active-matrix metalloproteinase-8 (aMMP-8) point-of-care (PoC) test, and several salivary biomarkers enzyme-linked immunosorbent assay tests and gelatin zymography. A full-mouth clinical examination was performed to assess their periodontal and oral health status., Statistical Analysis:  The Kruskal-Wallis test was used to determine the statistically significant difference in the levels of periodontal oral fluid biomarkers between the different periodontitis stages, periodontitis grades, and the stages and grades of periodontitis combined. Spearman's rank correlation was performed to assess the strength and direction of the association between aMMP-8 and HbA1c levels (<5.7 and ≥5.7%) and with the other oral fluid biomarkers among patients with severe periodontitis. A two-sided p -value below 0.05 was considered statistically significant in this study., Results:  aMMP-8, but not total MMP-8 or other biomarkers, associated significantly with the stage and grade of periodontitis combined ( p  < 0.001, Kruskal-Wallis test). Among stage III grade C periodontitis patients, aMMP-8 levels were significantly positively correlated with prediabetes (Spearman's rho = 0.646, p  = 0.044), total MMP-8 (rho = 0.636, p  = 0.048), PMN Elastase (rho = 0.729, p  = 0.017), total MMP-9 (rho = 0.721, p  = 0.019), and total MMP-8/TIMP-1 molar ratio (rho = 0.879, p  < 0.001)., Conclusion:  Prediabetic disease development can upregulate MMP-8 expression (total MMP-8) in rapidly progressing, severe periodontitis, where MMP-8 latent species are further activated into their active forms (aMMP-8). Simultaneously, several proinflammatory biomarker levels are elevated in this tissue-destructive biomarker cascade. This development is easily detectable online/in real-time within 5 minutes by aMMP-8 PoC testing at the dentist's office., Competing Interests: T.S. is the inventor of U.S. patents 1,274,416, 5,652,223, 5,736,341, 5,864,632, 6,143,476 and US 2017/0023571A1 (issued June 6, 2019), WO 2018/060553 A1 (issued May 31, 2018), 10,488,415 B2, and US 2017/0023671A1, Japanese Patent 2016-554676 and South Korean Patent No. 10-2016-7025378. T.P. is the Chairman of the board and owns stocks in Koite Health LTD. The company has filed patents P21233F100 and P22769F100 and owns trademarks related to antibacterial dual-light. Koite Health LTD develops, sells, and markets dual-light antibacterial products for the prevention and treatment of dental and periodontal infections. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Bone marrow mononuclear cells (BMMCs) have been evaluated for their ability to improve cardiac repair and benefit patients with severe ischemic heart disease and heart failure. In our single-center trial in 2006-2011 we demonstrated the safety and efficacy of BMMCs injected intramyocardially in conjunction with coronary artery bypass surgery. The effect persisted in the follow-up study 5 years later. In this study, we investigated the efficacy of BMMC therapy beyond 10 years. A total of 18 patients (46%) died during over 10-years follow-up and 21 were contacted for participation. Late gadolinium enhancement cardiac magnetic resonance imaging (CMRI) and clinical evaluation were performed on 14 patients, seven from each group. CMRIs from the study baseline, 1-year and 5-years follow-ups were re-analyzed to enable comparison. The CMRI demonstrated a 2.1-fold larger reduction in the mass of late gadolinium enhancement values between the preoperative and the over 10-years follow-up, suggesting less scar or fibrosis after BMMC treatment (- 15.1%; 95% CI - 23 to - 6.7% vs. - 7.3%; 95% CI - 16 to 4.5%, p = 0.039), compared to placebo. No differences in mortality or morbidity were observed. Intramyocardially injected BMMCs may exert long-term benefits in patients with ischemic heart failure. This deserves further evaluation in patients who have received BMMCs in international clinical studies over two decades., (© 2024. The Author(s).)

Background . It has been unclear whether simple atrial septal defect (ASD) is an independent risk factor for infective endocarditis (IE). This study aimed to untangle the risk of endocarditis in a large nationwide cohort. Methods . We acquired data from the Finnish hospital discharge register on all individuals with ASD diagnosis from 1969 to 2019. Patients with complex congenital cardiac abnormalities were ruled out. Five individualized controls from the general population were matched to the ASD patient's birth year, sex, and residence at the index date. All the patients with ICD-8, -9, or -10 diagnosis codes for IE were gathered from the hospital discharge registry. Results . Altogether, 8322 patients with ASD and 39,237 individualized controls were enrolled in the study. Median follow-up was 21.6 years (IQR 11.8-36.9) from the first hospital contact. In total, 24 (16 male) cases of infective endocarditis among ASD patients and 10 (8 male) cases among controls were diagnosed during the follow-up. The incidence of endocarditis was 0.11 per 1000 person-years in the patients with ASD and 0.011 per 1000 person-years in the controls. The adjusted risk ratio for endocarditis was 13.51 (95% CI: 6.20-29.46) in patients with ASD compared to the control cohort. Patients with ASD and endocarditis had higher long-term mortality than individualized control patients (MRR 2.25, 95% CI: 1.23-4.11). Conclusions . The incidence of IE in patients with ASD was higher than in the general population. Mortality associated with IE was higher in patients with ASD compared to controls.

Active matrix metalloproteinase-8 (aMMP-8) is a promising biomarker candidate for the modern periodontal and peri-implant disease diagnostics utilizing the chairside/point-of-care oral fluid technologies. These rapid biomarker analysis technologies utilize gingival crevicular fluid (GCF), peri-implant sulcular fluid (PISF), or mouth rinse as the oral fluid matrices that can be collected patient-friendly and non-invasively without causing bacteremia. aMMP-8, but not total or latent proMMP-8, has been shown to be a relevant biomarker to be implemented to the latest 2017 classification system of periodontitis and peri-implantitis. Thus, aMMP-8 point-of-care-testing (POCT)-but not total or latent proMMP-8-can be conveniently used as an adjunctive and preventive diagnostic tool to identify and screen the developing and ongoing periodontal and peri-implant breakdown and disease as well as predict its episodic progression. Similarly, aMMP-8 POCT provides an important tool to monitor the treatment effect of these diseases, but also other diseases such as head and neck cancer, where it can identify and predict the rapid tissue destructive oral side-effects during and after the radiotherapy. Additionally, recent studies support aMMP-8 POCT benefitting the identification of periodontitis and diabetes as the escalating risk diseases for COVID-19 infection. Overall, aMMP-8 POCT has launched a new clinical field in oral medicine and dentistry, i.e., oral clinical chemistry.

Objectives: Several studies have reported mortality risk factors associated with hypoplastic left heart syndrome (HLHS). However, these data are ambiguous and mainly focused on the independent effects of these factors. We examined both the independent and the cumulative effects of preoperative risk factors for poor outcome in patients undergoing the Norwood procedure. Moreover, we studied the risk factors associated with prolonged initial hospital stays in these patients., Methods: We performed a retrospective national 18-year observational study of preoperative risk factors for 1 year, as well as total follow-up mortality or need for transplant in patients with HLHS (N = 99) born in Finland between 1 January 2004 and 31 December 2021., Results: Overall, one-year survival was 85.6%. In a multivariable analysis, having a major extracardiac anomaly and being small for gestational age were significant predictors of one-year mortality or the need for a transplant. Aortic atresia was a predictor of total follow-up mortality. An analysis of the cumulative effect indicated that the presence of 2 risk factors was associated with higher mortality., Conclusions: HLHS remains the defect with the highest procedural risks for mortality in paediatric cardiac surgery. From a prognostic point of view, recognition of independent preoperative risk factors as well as the cumulative effect of risk factors for mortality is essential.The results of this study were presented orally at the 55th Annual Meeting of the Association for European Paediatric and Congenital Cardiology, Geneva, Switzerland, 28 May 2022., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Introduction: When collected in a standardized fashion, oral fluid analysis can refine the diagnosis of periodontal and peri-implant disease. In practice, dental professionals can perform active matrix metalloproteinase (aMMP-8) analysis chairside., Areas Covered: Periodontal tissues are mainly made up of type I collagen, and collagen breakdown is one of the main events in periodontal and peri-implantitis destructive lesions. In addition to traditional measurements, their diagnosis can be refined with tests utilizing oral fluids. The active matrix metalloproteinase-8 (aMMP-8) is possible to be determined from the gingival crevicular fluid (GCF), peri-implant sulcus fluid (PISF), and other oral fluids such as mouth rinse and saliva. We also investigated the applicability of aMMP-8 chair-side test kits in the evaluation of oral health benefits of different adjunctive host-modulating periodontal therapies including fermented lingonberry mouthwash (FLJ) and antibacterial photodynamic therapy (aPDT)., Expert Opinion: The aMMP-8 levels can more reliably detect early activation of periodontal and peri-implant disease as compared to traditional diagnostic methods that assess the experienced health status or past disease, rather than the present or future pathology. Novel therapies like, fermented lingonberry juice as a mouthrinse or aPDT, are potential host-modulating adjunctive treatments to reduce the signs of oral inflammation and infection.

Background: Previous studies have revealed the potential diagnostic utility of aMMP-8, an active form of MMP-8, in periodontal and peri-implant diseases. While non-invasive point-of-care (PoC) chairside aMMP-8 tests have shown promise in this regard, there is a dearth of literature on the evaluation of treatment response using these tests. The present study aimed to investigate treatment-related changes in aMMP-8 levels in individuals with Stage III/IV-Grade C periodontitis compared to a healthy control group, using a quantitative chairside PoC aMMP-8 test, and to determine its correlation with clinical parameters., Methods: The study included 27 adult patients (13 smoker, 14 non-smoker) with stage III/IV-grade C periodontitis and 25 healthy adult subjects. Clinical periodontal measurements, real-time PoC aMMP-8, IFMA aMMP-8, and Western immunoblot analyses were performed before and 1 month after anti-infective scaling and root planing periodontal treatment. Time 0 measurements were taken from the healthy control group to test the consistency of the diagnostic test., Results: Both PoC aMMP-8 and IFMA aMMP-8 tests showed a statistically significant decrease in aMMP-8 levels and improvement in periodontal clinical parameters following treatment ( p < 0.05). The PoC aMMP-8 test had high diagnostic sensitivity (85.2%) and specificity (100.0%) for periodontitis and was not affected by smoking ( p > 0.05). Treatment also reduced MMP-8 immunoreactivity and activation as demonstrated by Western immunoblot analysis., Conclusion: The PoC aMMP-8 test shows promise as a useful tool for the real-time diagnosis and monitoring of periodontal therapy.

Objectives. Several approaches devised for clinical utilization of cell-based therapies for heart failure often suffer from complex and lengthy preparation stages. Epicardial delivery of autologous atrial appendage micrografts (AAMs) with a clinically used extracellular matrix (ECM) patch provides a straightforward therapy alternative. We evaluated the operative feasibility and the effect of micrografts on the patch-induced epicardial foreign body inflammatory response in a porcine model of myocardial infarction. Design. Right atrial appendages were harvested and mechanically processed into AAMs. The left anterior descending coronary artery was ligated to generate acute infarction. Patches of ECM matrix with or without AAMs were transplanted epicardially onto the infarcted area. Four pigs received the ECM and four received the AAMs patch. Cardiac function was studied by echocardiography both preoperatively and at 3-week follow-up. The primary outcome measures were safety and feasibility of the therapy administration, and the secondary outcome was the inflammatory response to ECM. Results. Neither AAMs nor ECM patch-related complications were detected during the follow-up time. AAMs patch preparation was feasible according to time and safety. Inflammation was greatly reduced in AAMs when compared with ECM patches as measured by the amount of infiltrated inflammatory cells and area of inflammation. Immunohistochemistry demonstrated an increased CD3+ cell density in the AAMs patch infiltrate. Conclusions. Epicardial AAMs transplantation demonstrated safety and clinical feasibility. The use of micrografts significantly inhibited ECM-induced foreign body inflammatory reactivity. Transplantation of AAMs shows good clinical applicability as adjuvant therapy to cardiac surgery and can suppress acute inflammatory reactivity.

A single-site, randomized clinical trial was designed to determine the efficacy of regular home use of Lumoral ® dual-light antibacterial aPDT in periodontitis patients. For the study, 200 patients were randomized to receive non-surgical periodontal treatment (NSPT), including standardized hygiene instructions and electric toothbrush, scaling and root planing, or NSPT with adjunctive Lumoral ® treatment. A complete clinical intraoral examination was conducted in the beginning, at three months, and at six months. This report presents the three-month results of the first 59 consecutive randomized subjects. At three months, bleeding on probing (BOP) was lower in the NSPT + Lumoral ® -group than in the NSPT group ( p = 0.045), and more patients in the NSPT + Lumoral ® -group had their BOP below 10% (54% vs. 22%, respectively, p = 0.008). In addition, patients in the NSPT + Lumoral ® -group improved their oral hygiene by visible-plaque-index ( p = 0.0003), while the NSPT group showed no statistical improvement compared to the baseline. Both groups significantly reduced the number of deep periodontal pockets, but more patients with a reduction in their deep pocket number were found in the NSPT + Lumoral ® group (92% vs. 63%, p = 0.02). Patients whose number of deep pockets was reduced by 50% or more were also more frequent in the NSPT + Lumoral ® -group (71% vs. 33%, p = 0.01). Patients with initially less than ten deep pockets had fewer deep pockets at the three-month follow-up in the Lumoral ® group ( p = 0.01). In conclusion, adjunctive use of Lumoral ® in NSPT results in improved treatment outcomes at three months post-therapy.

Background: Improvements in mortality after congenital heart surgery have necessitated a shift in focus to postoperative morbidity as an outcome measure. We examined late morbidity after congenital heart surgery based on prescription medication use., Methods: Between 1953 and 2009, 10,635 patients underwent congenital heart surgery at <15 years of age in Finland. We obtained 4 age-, sex-, birth-time, and hospital district-matched controls per patient. The Social Insurance Institution of Finland provided data on all prescription medications obtained between 1999 and 2012 by patients and controls. Patients were assigned one diagnosis based on a hierarchical list of cardiac defects and dichotomised into simple and severe groups. Medications were divided into short- and long-term based on indication. Follow-up started at the first operation and ended at death, emigration, or 31 December, 2012., Results: Totally, 8623 patients met inclusion criteria. Follow-up was 99.9%. In total, 8126 (94%) patients required prescription medications. Systemic anti-bacterials were the most common short-term prescriptions among patients (93%) and controls (88%). Patients required betablockers (simple hazard ratio 1.9, 95% confidence interval 1.7-2.1; severe hazard ratio 6.5, 95% confidence interval 5.3-8.1) and diuretics (simple hazard ratio 3.2, 95% CI 2.8-3.7; severe hazard ratio 38.8, 95% CI 27.5-54.7) more often than the general population. Both simple and severe defects required medication for cardiovascular, gastrointestinal, psychiatric, neurologic, metabolic, autoimmune, and infectious diseases more often than the general population., Conclusions: The significant risk for postoperative cardiovascular and non-cardiovascular disease warrants close long-term follow-up after congenital heart surgery for all defects.

Until now, in clinical dentistry, antibacterial photodynamic therapy (aPDT) has been restricted to in-office treatments, which hampers repeated applications. This pilot study tested the benefit of a commercially available Lumoral ® device designed for regular periodontal dual-light aPDT treatment at home. Seven patients with peri-implant disease applied dual-light aPDT daily in addition to their normal dental hygiene for four weeks. A single Lumoral ® treatment includes an indocyanine green mouth rinse followed by 40 J/cm 2 radiant exposure to a combination of 810 nm and 405 nm light. A point-of-care analysis of active-matrix metalloproteinase (aMMP-8), visible plaque index (VPI), bleeding on probing (BOP), and peri-implant pocket depth (PPD) measurements was performed on day 0, day 15, and day 30. Reductions in aMMP-8 ( p = 0.047), VPI ( p = 0.03), and BOP ( p = 0.03) were observed, and PPD was measured as being 1 mm lower in the implant ( p = ns). These results suggest a benefit of regular application of dual-light aPDT in peri-implantitis. Frequently repeated application can be a promising approach to diminishing the microbial burden and to lowering the tissue destructive proteolytic and inflammatory load around dental implants. Further studies in larger populations are warranted to show the long-term benefits.

New means to reduce excessive antibiotic use are urgently needed. This study tested dual-light aPDT against Staphylococcus aureus biofilm with different relative ratios of light energy with indocyanine green. We applied single-light aPDT (810 nm aPDT, 405 aBL) or dual-light aPDT (simultaneous 810 nm aPDT and 405 nm aBL), in both cases, together with the ICG photosensitizer with constant energy of 100 or 200 J/cm 2 . Single-dose light exposures were given after one-day, three-day, or six-day biofilm incubations. A repeated daily dose of identical light energy was applied during biofilm incubations for the three- and six-day biofilms. Using 100 J/cm 2 light energy against the one-day biofilm, the dual-light aPDT consisting of more than half of aBL was the most effective. On a three-day maturated biofilm, single-dose exposure to aPDT or dual-light aPDT was more effective than aBL alone. With total light energy of 200 J/cm 2 , all dual-light treatments were effective. Dual-light aPDT improves the bactericidal effect on Staphylococcus aureus biofilm compared to aPDT or aBL and provides a sustained effect. An increase in the relative ratio of aBL strengthens the antibacterial effect, mainly when the treatment is repeatedly applied. Thus, the light components' energy ratio is essential with dual-light.

Background: Cardiopulmonary bypass (CPB) may lead to tissue hypoxia, inflammatory response, and risk for acute kidney injury (AKI). We evaluated the prevalence of AKI and inflammatory response in neonates undergoing heart surgery requiring CPB with or without antegrade cerebral perfusion (ACP)., Methods: Forty neonates were enrolled. The patients were divided into two groups depending on the use of ACP. AKI was classified based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Inflammatory response was measured using plasma concentrations of interleukins 6 (IL-6) and 10 (IL-10), white blood cell count (WBC), and C-reactive protein (CRP)., Results: Eight patients (20%) experienced AKI: five (29%) in the ACP group and three (13%) in the non-ACP group (P = 0.25). Postoperative peak plasma creatinine and urine neutrophil gelatinase-associated lipocalin were significantly higher in the ACP group than in the non-ACP group [46.0 (35.0-60.5) vs 37.5 (33.0-42.5), P = 0.044 and 118.0 (55.4-223.7) vs 29.8 (8.1-109.2), P = 0.02, respectively]. Four patients in the ACP group and one in the non-ACP group required peritoneal dialysis (P = 0.003). Postoperative plasma IL-6, IL-10, and CRP increased significantly in both groups. There were no significant differences between the ACP and non-ACP groups in any of the inflammatory parameters measured., Conclusions: No significant difference in the AKI occurrence or inflammatory response related to CPB modality could be found. In our study population, inflammation was not the key factor leading to AKI. Due to the limited number of patients, these findings should be interpreted with caution., Competing Interests: None

Background: Cardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) and are aimed at functionally repairing the myocardium that suffers from or is damaged by ischemia. This non-randomized open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery. Methods: Twelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs transplantation. Data from 30 elective CABG patients was collected for a center- and time-matched control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially onto the infarct scar site identified in preoperative late gadolinium enhancement cardiac magnetic resonance imaging (CMRI). The primary outcome measures at the 6-month follow-up were (i) patient safety in terms of hemodynamic and cardiac function over time and (ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide levels, NYHA class, number of days in hospital and changes in the quality of life. Results: Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment. Conclusions and Relevance: Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies. Trial Registration: ClinicalTrials.gov, identifier: NCT02672163., Competing Interests: AN and EK are stakeholders in EpiHeart Ltd. developing medical devices for the operating room. HS is the developer of the 15D. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nummi, Mulari, Stewart, Kivistö, Teittinen, Nieminen, Lampinen, Pätilä, Sintonen, Juvonen, Kupari, Suojaranta, Kankuri, Harjula, Vento and the AADC consortium.)

Introduction: Active matrix metalloproteinase (aMMP)-8 utilized in point-of-care testing (POCT) is regarded as a potential biomarker for periodontal and peri-implant diseases. Various host and microbial factors eventually influence the expression, degranulation, levels and activation of aMMP-8. The type of oral fluids (saliva, mouthrinse, gingival crevicular, and peri-implant sulcular fluids [GCF/PISF], respectively) affect the analysis., Areas Covered: With this background, we aimed to review here the recent studies on practical, inexpensive, noninvasive and quantitative mouthrinse and GCF/PISF chair-side POCT lateral flow aMMP-8 immunoassays (PerioSafe and ImplantSafe/ORALyzer) and how they help to detect, predict, monitor the course, treatment and prevention of periodontitis and peri-implantitis. The correlations of aMMP-8 POCT to other independent and catalytic activity assays of MMP-8 are also addressed., Expert Opinion: The mouthrinse aMMP-8 POCT can also detect prediabetes/diabetes and tissue destructive oral side-effects due to the head and neck cancers' radiotherapy. Chlorhexidine and doxycycline can inhibit collagenolytic human neutrophil and GCF aMMP-8. Furthermore, by a set of case-series we demonstrate the potential of mouthrinse aMMP-8 POCT to real-time/online detect periodontitis as a potential risk disease for coronavirus disease 2019 (COVID-19). The clinical interdisciplinary utilization of aMMP-8 POCT requires additional oral, medical, and interdisciplinary studies.

Aim: This study aimed to determine the feasibility and first efficacy of indocyanine green (ICG)-assisted antimicrobial photodynamictherapy (aPDT) as activated using LED light to the dental plaque., Methods: Fifteen healthy adults were assigned to this four-day randomized study. After rinsing with ICG, 100 J/cm 2 of 810 nm LED light was applied to the aPDT-treatment area. Plaque area and gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) were measured, and plaque bacteriomes before and after the study were analyzed using 16S rRNA sequencing., Results: aPDT administration was preformed successfully and plaque-specifically with the combination of ICG and the applicator. Total plaque area and endpoint MMP-8 levels were reduced on the aPDT-treatment side. aPDT reduced Streptococcus , Acinetobacteria , Capnocytophaga , and Rothia bacteria species in plaques., Conclusion: ICG-assisted aPDT reduces plaque forming bacteria and exerts anti-inflammatory and anti-proteolytic effects.

Purpose: During cancer treatment, oral mucositis due to radiotherapy or chemotherapy often leads to disruption of the oral mucosa, enabling microbes to invade bloodstream. Viridans streptococcal species are part of the healthy oral microbiota but can be frequently isolated from the blood of neutropenic patients.  We have previously shown the antibacterial efficacy of dual-light, the combination of antibacterial blue light (aBL) and indocyanine green photodynamic therapy (aPDT)., Methods: Here, we investigated the dual-light antibacterial action against four-day Streptococcus oralis biofilm. In addition, while keeping the total radiant exposure constant at 100J/cm2, we investigated the effect of changing the different relative light energies of aBL and aPDT to the antibacterial potential., Results: The dual-light had a significant antibacterial effect in all the tested combinations., Conclusion: Dual-light can be used as an effective disinfectant against S. oralis biofilm.

Introduction: Newborn infants with transposition of the great arteries (d-TGA) need immediate care for an optimal outcome. This study comprised a nationwide 11-year population-based cohort of d-TGA infants, and assessed whether the implementation of a nationwide systematic fetal screening program, or other perinatal, or perioperative factors, are associated with mortality or an increased need for hospital care., Material and Methods: The national cohort consisted of all live-born infants with simple d-TGA (TGA ± small ventricular septal defect, n = 127) born in Finland during 2004-2014. Data were collected from six national registries. Prenatal diagnosis and perinatal and perioperative factors associated with mortality and length of hospitalization were evaluated., Results: Preoperative mortality was 7.9%, and the total mortality was 8.7%. The prenatal detection rate increased after introducing systematic fetal anomaly screening from 5.0% to 37.7% during the study period (P < .0001), but the total mortality rate remained unchanged. All prenatally diagnosed infants (n = 27) survived. Lower gestational age (odds ratio 0.68, P = .012) and higher maternal age at birth (odds ratio 1.16, P = .036) were associated with increased mortality in multivariable analysis. Older infant age at time of operation (P = .002), longer aortic clamp time (P < .001), and higher maternal body mass index (P = .027) were associated with longer initial hospital stay. An extended need for hospital care during the first year of life was multi-factorial., Conclusions: In our cohort, none of the prenatally diagnosed d-TGA infants died. As a result of the limited prenatal detection rates, however, the sample size was insufficient to reach statistical significance. The d-TGA infants born with lower gestational age and to older mothers had increased mortality., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Background: Patients are surviving decades after congenital heart surgery (CHS), raising the importance of postoperative quality of life as an outcome measure. We determined the long-term social outcomes after CHS performed during childhood., Methods: Between 1953 and 2009, 10 635 patients underwent surgery for congenital heart defects at <15 years of age in Finland. We obtained 4 control subjects per patient, matched by age, sex, birth time, and hospital district, from Statistics Finland, which also provided data on the highest education level, employment status, marital status, and progeny for both patients and control subjects. We included patients who were alive and ≥18 years of age at the end of the follow-up on December 31, 2017., Results: A total of 7308 patients met inclusion criteria. Patients had on average similar high school or vocational education rates as the general population but lower undergraduate or higher education rates (female patients: risk ratio [RR] 0.8 [95% confidence interval (CI) 0.8-0.9]; male patients: RR 0.8 [95% CI 0.7-0.9]). Patients were less likely to be married or have progeny compared with the general population. The rate of employment was significantly lower (female patients: RR 0.8 [95% CI 0.8-0.9]; male patients: RR 0.8 [95% CI 0.8-0.9]) and the rate of retirement (female patients: RR 2.1 [95% CI 2.0-2.3]; male patients RR 3.1 [95% CI 2.9-3.5]) significantly higher among patients., Conclusions: Patients who undergo CHS at childhood age are, on average, more disadvantaged from both an educational and professional standpoint compared with the general population, regardless of the severity of the defect., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Antibacterial photodynamic therapy (aPDT) and antibacterial blue light (aBL) are emerging treatment methods auxiliary to mechanical debridement for periodontitis. APDT provided with near-infrared (NIR) light in conjunction with an indocyanine green (ICG) photosensitizer has shown efficacy in several dental in-office-treatment protocols. In this study, we tested Streptococcus mutans biofilm sensitivity to either aPDT, aBL or their combination dual-light aPDT (simultaneous aPDT and aBL) exposure. Biofilm was cultured by pipetting diluted Streptococcus mutans suspension with growth medium on the bottom of well plates. Either aPDT (810 nm) or aBL (405 nm) or a dual-light aPDT (simultaneous 810 nm aPDT and 405 nm aBL) was applied with an ICG photosensitizer in cases of aPDT or dual-light, while keeping the total given radiant exposure constant at 100 J/cm2. Single-dose light exposures were given after one-day or four-day biofilm incubations. Also, a model of daily treatment was provided by repeating the same light dose daily on four-day and fourteen-day biofilm incubations. Finally, the antibacterial action of the dual-light aPDT with different energy ratios of 810 nm and 405 nm of light were examined on the single-day and four-day biofilm protocols. At the end of each experiment the bacterial viability was assessed by colony-forming unit method. Separate samples were prepared for confocal 3D biofilm imaging. On a one-day biofilm, the dual-light aPDT was significantly more efficient than aBL or aPDT, although all modalities were bactericidal. On a four-day biofilm, a single exposure of aPDT or dual-light aPDT was more efficient than aBL, resulting in a four logarithmic scale reduction in bacterial counts. Surprisingly, when the same amount of aPDT was repeated daily on a four-day or a fourteen-day biofilm, bacterial viability improved significantly. A similar improvement in bacterial viability was observed after repetitive aBL application. This viability improvement was eliminated when dual-light aPDT was applied. By changing the 405 nm to 810 nm radiant exposure ratio in dual-light aPDT, the increase in aBL improved the antibacterial action when the biofilm was older. In conclusion, when aPDT is administered repeatedly to S. mutans biofilm, a single wavelength-based aBL or aPDT leads to a significant biofilm adaptation and increased S. mutans viability. The combined use of aBL light in synchrony with aPDT arrests the adaptation and provides significantly improved and sustained antibacterial efficacy., Competing Interests: We have a financial disclosure about the paper, including authors, Sakari Nikinmaa, Tommi Pätilä and Juha Rantala. These authors are shareholders in a company Koite Health Oy, where SN and TP are also members of the board. Koite Health has filed patents P21233F100 and P22769F100, which are related to antibacterial dual light. The company Koite Health is developing a dual light antibacterial product for prevention of dental infections. Martti Vaara is a shareholder and a board member in Northern Antibiotics INC, which is dedicated to developing novel Colistin antibiotics. This financial disclosure does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background Postoperative morbidity is an increasingly important outcome measure of patients who have undergone congenital heart surgery (CHS). We examined late postoperative morbidity after CHS on the basis of patients' government-issued medical special reimbursement rights. Methods and Results Between 1953 and 2009, 10 635 patients underwent CHS at <15 years of age in Finland. We excluded early deaths and mental disabilities. Noncyanotic and cyanotic defects were divided into simple and severe groups, respectively. We obtained 4 age-, sex-, birth time-, and hospital district-matched control subjects per patient. The Social Insurance Institution of Finland provided data on all medical special reimbursement rights granted between 1966 and 2012. Follow-up started at the first operation and ended at death, date of emigration, or December 31, 2012. A total of 8623 patients met inclusion criteria. Follow-up was 99.9%. A total of 3750 patients (43%) required special reimbursements rights for a chronic disease. Cardiovascular disease was the most common late morbidity among patients (28%), followed by obstructive pulmonary disease (9%), neurologic disease (3%), and psychiatric disease (2%). Heart failure (simple hazard ratio [HR], 56.3 [95% CI, 35.4-89.7]; severe HR, 918.0 [95% CI, 228.9-3681.7]) and arrhythmia (simple HR, 11.0 [95% CI, 7.1-17.0]; severe HR, 248.0 [95% CI, 61.3-1002.7]) were the most common cardiovascular morbidities. Hypertension was common among patients with coarctation of the aorta (13%; incidence risk ratio [RR], 8.9; 95% CI, 7.5-10.7). Psychiatric disease was more common among simple defects, particularly ventricular septal defects. Conclusions Chronic cardiac and noncardiac sequelae are common after CHS regardless of the severity of the defect, underscoring the importance of long-term follow-up of all patients after CHS.

BACKGROUND The appearance of human leukocyte antigen (HLA) antibodies after solid organ transplantation predisposes recipients to graft dysfunction. In theory, vascular homografts, which are widely used in children with congenital heart defects, may cause allosensitization. MATERIAL AND METHODS In this single-center retrospective study, the presence of pre-existing HLA antibodies in pediatric heart transplant (HTx) recipients with a vascular homograft was evaluated in a cohort of 12 patients. HLA antibodies were screened before and after HTx and positive screening results were confirmed and identified using the Luminex® single antigen bead method. Endomyocardial biopsies (EMB) and coronary angiography studies were re-evaluated to assess the prevalence of acute rejections and coronary artery change in these patients. RESULTS At the time of HTx, 8 patients (67%) had HLA antibodies detected by the Luminex assay, none of which were heart donor specific (DSA). All patients had negative leukocyte crossmatch. One patient developed DSAs against homograft donor prior to HTx. After the HTx, 5 patients (42%) developed DSAs against the heart donor and 4 patients (40%) against the homograft donor. In 2 patients (17%), the antibodies were against both heart and homograft donors. The rejection rate or prevalence of coronary artery vasculopathy did not differ significantly between the homograft cohort and our historical controls. CONCLUSIONS Our results suggest that the prevalence of DSAs against homograft donor prior to HTx is relatively rare. However, almost half of the patients developed DSAs against homograft post-HTx. The clinical importance of these antibodies warrants further studies.

Background: Operative mortality after complete atrioventricular septal defect (cAVSD) repair has improved vastly. Less improvement has been demonstrated regarding late mortality and reoperation rates, however. There is evident lack of comprehensive population-based studies analyzing the history and progress of the ever-changing operative results., Methods: This is a 5-million population-based retrospective study of consecutive 388 cAVSD patients operated in Finland between 1962 and 2014. Data were collected using Children's Cardiac Surgical Registry of Children's Hospital at the Helsinki University Hospital, Finland. Mortality data and reoperation rates were analyzed on a decade-by-decade basis., Results: During the early era, overall mortality was 17.4%, operative mortality constituting 10.9%. The operative results have improved significantly over the decades, and eventually, the last decade showed no mortality. A total of 23 late deaths occurred; of these, 20 were directly heart-related. Half of the late mortality occurred during the first postoperative year. The only significant risk factor for overall mortality was an earlier decade of operation (p < 0.001). Reoperation rates have not decreased but slightly increased over decades (p = 0.621), and reoperations have been performed mainly during the first year after the primary operation. Actuarial freedom from left side atrioventricular valve reoperation at 15 years was 90.9%., Conclusions: There has been an outstanding improvement in surgical results through the years even though the general operative approach has remained the same. Rates of reoperation have not been declining, but the reoperations are dated to early childhood years. The improvement in results has been ongoing., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate whether a nationwide prenatal anomaly screening programme improves detection rates of univentricular heart (UVH) and transposition of great arteries (TGA), and whether maternal risk factors for severe fetal heart disease affect prenatal detection., Design: Population-based cohort study., Setting: Nationwide data from Finnish registries 2004-14., Population: A total of 642 456 parturients and 3449 terminated pregnancies due to severe fetal anomaly., Methods: Prenatal detection rates were calculated in three time periods (prescreening, transition and screening phase). The effect of maternal risk factors (obesity, in vitro fertilisation, pregestational diabetes and smoking) was evaluated., Main Outcome Measures: Change in detection rates and impact of maternal risk factors on screening programme efficacy., Results: In total, 483 cases of UVH and 184 of TGA were detected. The prenatal detection rate of UVH increased from 50.4% to 82.8% and of TGA from 12.3% to 41.0% (P < 0.0001). Maternal risk factors did not affect prenatal detection rate, but detection rate differed substantially by region., Conclusions: A nationwide screening programme improved overall UVH and TGA detection rates, but regional differences were observed. Obesity or other maternal risk factors did not affect the screening programme efficacy. The establishment of structured guidelines and recommendations is essential when implementing the screening programme. In addition, a prospective screening register is highly recommended to ensure high quality of screening., Tweetable Abstract: Implementation of a nationwide prenatal anomaly screening improved detection rates of UVH and TGA., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Thymic commitment of human FOXP3 + regulatory T cells begins at the double-positive (DP) CD4 +  CD8 + stage. In the current study, we show that interleukin-2 promotes the development of FOXP3 + thymocytes and enhances their survival at the DP phase. IL-2 increases the frequency of FOXP3 + cells and promotes the Treg phenotype after TCR-mediated positive selection at the most mature DP stage. However, it has no effect on FOXP3 + cells at the earlier maturation steps before positive selection. DP FOXP3 + thymocytes are highly susceptible to cell death but IL-2 promotes their survival. The anti-apoptotic protein BCL-2 (B Cell Lymphoma 2) is also upregulated by IL-2 at the most mature DP stage. In addition to IL-2, we identify IL-15 to have a significant role in the upregulating FOXP3 and survival of Tregs at the DP phase. IL-7 also increases the expression of BCL-2 in the DP FOXP3 + thymocytes. Our results indicate that common gamma chain cytokines IL-2, IL-7 and IL-15 promote the development of regulatory T cells at the most mature DP stage after TCR-mediated positive selection through suppressing cell death., (© 2018 The Foundation for the Scandinavian Journal of Immunology.)

Background: The atrial appendages are a tissue reservoir for cardiac stem cells. During on-pump coronary artery bypass graft (CABG) surgery, part of the right atrial appendage can be excised upon insertion of the right atrial cannula of the heart-lung machine. In the operating room, the removed tissue can be easily cut into micrografts for transplantation. This trial aims to assess the safety and feasibility of epicardial transplantation of atrial appendage micrografts in patients undergoing CABG surgery., Methods/design: Autologous cardiac micrografts are made from leftover right atrial appendage during CABG of 6 patients. Atrial appendage is mechanically processed to micrografts consisting of atrial appendage-derived cells (AADCs) and their extracellular matrix (ECM). The micrografts are epicardially transplanted in a fibrin gel and covered with a tissue-engineered ECM sheet. Parameters including echocardiography-reflecting cardiac insufficiency-are studied pre- and post-operatively as well as at 3 and 6 months of the follow-up. Cardiac functional magnetic resonance imaging is performed preoperatively and at 6-month follow-up. The primary outcome measures are patient safety in terms of hemodynamic and cardiac function over time and feasibility of therapy administration in a clinical setting. Secondary outcome measures are left ventricular wall thickness, change in the amount of myocardial scar tissue, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, New York Heart Association class, days in hospital, and changes in the quality of life. Twenty patients undergoing routine CAGB surgery will be recruited to serve as a control group., Discussion: This study aims to address the surgical feasibility and patient safety of epicardially delivered atrial appendage micrografts during CABG surgery. Delivery of autologous micrografts and AADCs has potential applications for cell and cell-based gene therapies., Trial Registration: ClinicalTrials.gov Identifier: NCT02672163. Date of registration: 02.02.2016., Competing Interests: The AADC consortium has been focusing on the cell therapy as a treatment for heart failure for many years. Its knowledge is based on multidisciplinary cooperation between authorities and several previous studies in this field.The trial protocol has been evaluated and approved by the Surgical Ethics Committee of the Hospital District of Helsinki and Uusimaa (number 180/13/03/02/13). Informed and written consent to participate in the study will be obtained by the main researcher from all participants.Informed and written consent for publication will be obtained from all participants.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A diverse T cell receptor (TCR) repertoire is essential for adaptive immune responses and is generated by somatic recombination of TCRα and TCRβ gene segments in the thymus. Previous estimates of the total TCR diversity have studied the circulating mature repertoire, identifying 1 to 3×10(6) unique TCRβ and 0.5×10(6) TCRα sequences. Here we provide the first estimate of the total TCR diversity generated in the human thymus, an organ which in principle can be sampled in its entirety. High-throughput sequencing of samples from four pediatric donors detected up to 10.3×10(6) unique TCRβ sequences and 3.7×10(6) TCRα sequences, the highest directly observed diversity so far for either chain. To obtain an estimate of the total diversity we then used three different estimators, preseq and DivE, which measure the saturation of rarefaction curves, and Chao2, which measures the size of the overlap between samples. Our results provide an estimate of a thymic repertoire consisting of 40 to 70×10(6) unique TCRβ sequences and 60 to 100×10(6) TCRα sequences. The thymic repertoire is thus extremely diverse. Moreover, extrapolation of the data and comparison with earlier estimates of peripheral diversity also suggest that the thymic repertoire is transient, with different clones produced at different times., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Postoperative pain after median sternotomy is usually treated with i.v. opioids. We hypothesized that continuous wound infusion of ropivacaine decreases postoperative morphine consumption and improves analgesia in children who undergo cardiac surgery., Methods: This randomized, double-blind study comprised 49 children aged 1-9 years who underwent atrial septal defect (ASD) closure. Patients received continuous local anesthetic wound infiltration either with 0.2% ropivacaine, 0.3-0.4 mg·kg(-1) ·h(-1) (Group R) or with saline (Group C). Rescue morphine consumption, Objective Pain Scale (OPS), time to mobilization, time to enteral food intake, and time to discharge were recorded., Results: There were no statistically significant differences in morphine consumption at 24, 48, and 72 h postsurgery between R and C groups. There was a weak evidence for a difference in the time to the first morphine administration after tracheal extubation to be longer for Group R than Group C (186.2 vs 81.0 min; 95% CI (-236.5, 26.2), P = 0.114). The incidence of nausea and vomiting were comparable between the groups. No signs or symptoms of local anesthetic toxicity were registered., Conclusions: Contrary to our hypothesis, continuous ropivacaine wound infusion did not reduce morphine consumption, pain score values, or nausea and vomiting in children who underwent ASD closure with median sternotomy and mediastinal drain., (© 2016 John Wiley & Sons Ltd.)

Therapeutic effects of skeletal myoblast transplantation into the myocardium are mediated via paracrine factors. We investigated the ability of myoblast-derived soluble mediators to protect cardiomyocytes from oxidative stress. Fetal rat cardiac cells were treated with conditioned medium from cultures of myoblasts or cardiac fibroblasts, and oxidative stress was induced with H2O2. Myoblast-derived factors effectively prevented oxidative stress-induced cardiac cell death and loss of mitochondrial membrane potential. This protective effect was mediated via epidermal growth factor (EGF) receptor and c-Met signaling, and mimicked by neuregulin 1 but not EGF. Microarray analysis of cardiac cells treated with myoblast versus cardiac fibroblast-derived mediators revealed differential regulation of genes associated with antioxidative effects: cystathionine-γ-lyase (cst), xanthine oxidase, and thioredoxin-interacting protein as well as tribbles homolog 3 (trib3). Cardiac cell pretreatment with tunicamycin, an inducer of trib3, also protected them against H2O2-induced cell death. Epicardial transplantation of myoblast sheets in a rat model of acute myocardial infarction was used to evaluate the expression of CST and trib3 as markers of myoblasts' paracrine effect in vivo. Myoblast sheets induced expression of the CST as well as trib3 in infarcted myocardium. CST localized around blood vessels, suggesting smooth muscle cell localization. Our results provide a deeper molecular insight into the therapeutic mechanisms of myoblast-derived paracrine signaling in cardiac cells and suggest that myoblast transplantation therapy may prevent oxidative stress-induced cardiac deterioration and progression of heart failure.

Aims: Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are suggested to improve clinical decision-making in ischaemic cardiomyopathy. Here, we present a unique cohort of patients who underwent nuclear medicine studies and cardiac magnetic resonance imaging (MRI) both before and 1 year after coronary artery bypass (CABG) surgery to assess benefit from surgery., Methods and Results: Before CABG, we applied three quantitative techniques using (18)F-fluorodeoxyglucose-PET and (99m)technetium-tetrofosmin-SPECT with a software tool to measure defects with hypoperfused but viable and non-viable myocardium in 15 patients. One method used solely PET, two others combined PET and SPECT at different thresholds. As a reference, we used change in left-ventricular (LV) function and volume by MRI. Preoperatively, ischaemic but viable areas detected by the method with a 10% threshold combining PET-SPECT and the PET-only method correlated significantly with preoperative regional wall thickening (WT; P = 0.03 and P = 0.005, respectively). When compared with global functional outcome (change in LV ejection fraction) and LV remodelling (change in end-diastolic volume) 1 year postoperatively, no correlation appeared with preoperative PET- or PET-SPECT-derived viable or non-viable tissue. Neither was any correlation observable between local change in WT and local preoperative defect size evaluated by any of these three methods., Conclusion: Preoperatively, PET and PET-SPECT with 10% threshold detected dysfunctional myocardium, but all analysis methods failed to predict 1-year functional outcome assessed by MRI. In patients with three-vessel disease and heart failure, SPECT perfusion and PET viability study results show substantial heterogeneity; this should be considered when selecting patients for revascularization., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Long-term results regarding treatment of chronic ischemic heart failure with bone marrow mononuclear cells (BMMCs) have been few. We received encouraging results at the 1-year follow-up of patients treated with combined coronary artery bypass grafting (CABG) and BMMCs, so we decided to extend the follow-up., Methods: The study patients had received injections of BMMCs or vehicle into the myocardial infarction border area during CABG in a randomized and double-blind manner. We could contact 36 of the 39 patients recruited for the original study. Pre-operatively and after an extended follow-up period, we performed magnetic resonance imaging, measured pro-B-type amino-terminal natriuretic peptide, reviewed patient records from the follow-up period, and determined current quality of life with the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey., Results: The median follow-up time was 60.7 months (interquartile range [IQR], 45.1-72.6 months). No statistically significant difference was detected in change of pro-B-type amino-terminal natriuretic peptide values or in quality of life between groups. The median change in left ventricular ejection fraction was 4.9% (IQR, -2.1% to 12.3%) for controls and 3.9% (IQR, -5.2% to 10.2%) for the BMMC group (p = 0.647). Wall thickening in injected segments increased by a median of 17% (IQR, -5% to 30%) for controls and 15% (IQR, -12% to 19%) for BMMC patients (p = 0.434). Scar size in injected segments increased by a median of 2% (IQR, -7% to 19%) for controls but diminished for BMMC patients, with a median change of -17% (IQR, -30% to -6%; p = 0.011)., Conclusions: In the treatment of chronic ischemic heart failure, combining intramyocardial BMMC therapy with CABG fails to affect cardiac function but can sustainably reduce scar size, even in the long-term., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Although cell therapy of the failing heart by intramyocardial injections of myoblasts to results in regenerative benefit, it has also been associated with undesired and prospectively fatal arrhythmias. We hypothesized that intramyocardial injections of myoblasts could enhance inflammatory reactivity and facilitate electrical cardiac abnormalities that can be reduced by epicardial myoblast sheet delivery. In a rat model of ischemic heart failure, myoblast therapy either by intramyocardial injections or epicardial cell sheets was given 2 weeks after occlusion of the coronary artery. Ventricular premature contractions (VPCs) were assessed, using an implanted three-lead electrocardiograph at 1, 7, and 14 days after therapy, and 16-point epicardial electropotential mapping (EEPM) was used to evaluate ventricular arrhythmogenicity under isoproterenol stress. Cardiac functioning was assessed by echocardiography. Both transplantation groups showed therapeutic benefit over sham therapy. However, VPCs were more frequent in the Injection group on day 1 and day 14 after therapy than in animals receiving epicardial or sham therapy (p < 0.05 and p < 0.01, respectively). EEPM under isoproterenol stress showed macroreentry at the infarct border area, leading to ventricular tachycardias in the Injection group, but not in the myoblast sheet- or sham-treated groups (p = 0.045). Both transplantation types modified the myocardial cytokine expression profile. In animals receiving epicardial myoblast therapy, selective reductions in the expressions of interferon gamma, interleukin (IL)-1β and IL12 were observed, accompanied by reduced infiltration of inflammatory CD11b- and CD68-positive leukocytes, compared with animals receiving myoblasts as intramyocardial injections. Intramyocardial myoblast delivery was associated with enhanced inflammatory and immunomodulatory reactivity and increased frequency of VPCs. In comparison to intramyocardial injection, the epicardial route may serve as the preferred method of skeletal myoblast transplantation to treat heart failure.

Objectives: We present here a sub-study of our prospective, randomized, double-blinded trial of bone marrow mononuclear cell (BMMC) transplantation with coronary artery bypass surgery (CABG) (ClinicalTrials.gov Identifier: NCT00418418), evaluating our secondary end-point concerning hospital stay as well as perioperative morbidity. Injecting a substantial amount of biologically active cells into a diseased myocardium inspires concerns for safety, a concern overlooked in previous trials., Methods: We evaluated the immediate perioperative effects of intramyocardial injection of autologous BMMCs combined with CABG. In a randomized double-blinded manner, 39 patients received injections either of BMMCs (n = 20) or of vehicle medium (n = 19). The patients' haemodynamics, arterial blood gases, systemic vein oxygen level, blood glucose, acid-base balance, lactate, haemoglobin, body temperature and diuresis, as well as medications needed, were recorded in the operating theatre and in the intensive care unit (ICU) every 4 h throughout the first postoperative 24 h., Results: No dissimilarities in these parameters were detectable. In the ICU, the median need for adrenaline was 0.0086 µg/kg/min (first quartile 0.0000, third quartile 0.0204) for controls and 0.0090 µg/kg/min (0.0000, 0.0353) for BMMC patients (P = 0.757); for noradrenaline, 0.0586 µg/kg/min (0.0180, 0.0888) for controls and 0.0279 µg/kg/min (0.0145, 0.0780) for BMMC patients (P = 0.405). The median stay at the ICU was 2 days for both groups (1, 2 for controls; 1, 3 for BMMCs; P = 0.967). Within the first postoperative day, one control patient had an elevated level of creatine kinase-myocardial band fraction mass (CK-MBm) up to >100 µg/l; no BMMC patient showed elevated CK-MBm levels (P = 0.474)., Conclusions: Both intramyocardial BMMC and placebo injections appear safe during surgery and immediate ICU stay after treatment of heart failure., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)