Activation of Mitochondria in Mesenchymal Stem Cells by Mitochondrial Delivery of Coenzyme Q10.

The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using a microfluidic device to encapsulate Coenzyme Q10 (CoQ10) on a large scale. The current study aimed to confirm if treatment with CoQ10 encapsulated by MITO-Porter enhanced mitochondrial functions in MSCs, with the potential to improve MSC transplantation therapy. We used highly purified human bone marrow-derived MSCs, described as rapidly expanding clones (RECs), and attempted to control and increase the amount of CoQ10 encapsulated in the MITO-Porter using microfluidic device system. We treated these RECs with CoQ10 encapsulated MITO-Porter, and evaluated its cellular uptake, co-localization with mitochondria, changes in mitochondrial respiratory capacity, and cellular toxicity. There was no significant change in mitochondrial respiratory capacity following treatment with the previous CoQ10 encapsulated MITO-Porter; however, mitochondrial respiratory capacity in RECs was significantly increased by treatment with CoQ10-rich MITO-Porter. Utilization of a microfluidic device enabled the amount of CoQ10 encapsulated in MITO-Porter to be controlled, and treatment with CoQ10-rich MITO-Porter successfully activated mitochondrial functions in MSCs. The MITO-Porter system thus provides a promising tool to improve MSC cell transplantation therapy.

Human cardiosphere-derived cells with activated mitochondria for better myocardial regenerative therapy.

Cell transplantation is a promising therapeutic strategy for myocardial regeneration therapy. To improve therapeutic effects, we developed a culture medium additive that enhances the mitochondrial function of cardiomyocytes for transplantation. A mitochondrial targeting drug delivery system (MITO-Porter system) was used to deliver mitochondrial activation molecules to mouse-derived cardiac progenitor cells. In this study, we investigated whether the mitochondrial function of human-derived myocardial precursor cells could be enhanced using MITO-Porter. Human cardiosphere-derived cells (CDCs) were isolated from myocardium which was excised during surgery for congenital heart disease. MITO-Porter was added to the cell culture medium to generate mitochondrial activated CDCs (human MITO cells). The human MITO cells were transplanted into myocardial ischemia-reperfusion model rat, and the effect was investigated. The transplanted human MITO cells improved the cardiac function and suppressed myocardial fibrosis compared to conventional cell transplantation methods. These effects were observed not only with myocardial administration but also by intravenous administration of human MITO cells. This study is the first study that assessed whether the mitochondrial delivery of functional compounds improved the outcome of human-derived myocardial cell transplantation therapy.

A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene.

Barth syndrome (BTHS) is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and 3-methylglutaconic aciduria. The causative pathogenic variants for BTHS are in TAZ, which encodes a putative acyltransferase named tafazzin and is involved in the remodeling of cardiolipin in the inner mitochondrial membranes. Pathogenic variants in TAZ result in mitochondrial structural and functional abnormalities. We report a case of infantile BTHS with severe heart failure, left ventricular noncompaction, and lactic acidosis, having a missense c.640C>T (p.His214Tyr) variant in TAZ, which is considered a pathogenic variant based on the previously reported amino acid substitution at the same site (c.641A>G, p.His214Arg). However, in this previously reported case, heart function was compensated and not entirely similar to the present case. Silico prediction analysis suggested that c.640C>T could alter the TAZ messenger RNA (mRNA) splicing process. TAZ mRNAs in isolated peripheral mononuclear cells from the patient and in vitro splicing analysis using minigenes of TAZ found an 8 bp deletion at the 3' end of exon 8, which resulted in the formation of a termination codon in the coding region of exon 9 (H214Nfs*3). These findings suggest that splicing abnormalities should always be considered in BTHS.

Risk factors for hospitalisation due to respiratory syncytial virus infection in children receiving prophylactic palivizumab.

Respiratory syncytial virus (RSV) is a common pathogen that causes extremely severe respiratory symptoms in the first few weeks and months of life. In infants with cardiopulmonary diseases, RSV infections have a significant clinical impact. Palivizumab, a humanised monoclonal antibody for RSV, has been shown to significantly reduce the rate of hospitalisation of high-risk infants diagnosed with RSV. However, we have experienced a significant number of RSV infections in our institution that required hospitalisation or intensive care, despite the administration of palivizumab. This study aimed to analyse the risk factors associated with severe RSV despite the use of palivizumab. We retrospectively reviewed the medical records of 688 patients who visited or were admitted to our hospital and received palivizumab. Thirty-seven (5.4%) patients required hospitalisation for RSV, despite receiving palivizumab. In addition, 31 of these patients (83.8%) required hospitalisation out of season for palivizumab injection. Preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia (BPD), and trisomy 21 were risk factors for RSV-related hospitalisation in infected patients, despite receiving palivizumab. Furthermore, subgroup analysis of 69 patients with RSV revealed that hemodynamically significant congenital heart disease (CHD) was also a risk factor for RSV-related hospitalisation.Conclusion: Preterm birth (≤ 28 weeks of gestation), BPD, trisomy 21, hemodynamically significant CHD, and CHD requiring surgery or cardiac catheterisation/intervention during infancy could be considered when determining whether year-round administration of palivizumab is appropriate. What is Known: • Respiratory syncytial virus causes severe respiratory symptoms in infants, particularly those with cardiopulmonary diseases. • The use of palivizumab has reduced the rate of hospitalisation of infants diagnosed with RSV. Despite this, the rate of hospitalisation is still high. What is New: • We identified that preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia, trisomy 21, and hemodynamically significant congenital heart disease were risk factors for RSV-related hospitalisation, even after receiving palivizumab treatment. • High-risk infants should be closely monitored and the prolonged use of palivizumab should be considered.

Inter-brain synchronization during a cooperative task reflects the sense of joint agency.

People feel the sense of 'joint agency', which is the sense that 'we' did it, during a mutually cooperative action. Previous studies have reported that the inter-brain synchronization occurs during a mutually cooperative action, nevertheless the neural correlates of the sense of joint agency remains unclear. Here, we investigated whether the sense of joint agency reflects the inter-brain synchronization during a joint action. The pairs of participants engaged in constant rhythm tapping tasks with alternative (turn-taking) or sequential (non-turn-taking) coordination. Electroencephalograms (EEGs) of the participant pair during the tasks were simultaneously measured (hyperscanned), and the participants were subsequently asked to rate the sense of joint agency. The results showed that the participants felt strong sense of joint agency in the turn-taking cooperative actions, but not in the non-turn-taking actions. Moreover, EEG theta (4-7 Hz) oscillations were more synchronized between the frontal region in the leader, who tapped the first, and the right temporo-parietal region in the follower, who tapped following the leader, during the turn-taking cooperative actions than during the non-turn-taking cooperative actions. Furthermore, the degree of inter-brain synchronization was significantly correlated with the sense of joint agency, as well as the temporal accuracy of the tapping actions of the pair. These results indicate that the sense of joint agency strongly reflects the inter-brain synchronization, which depends on the quality of mutual cooperation during a joint action.

The accuracy of central blood pressure obtained by oscillometric noninvasive method using Mobil-O-Graph in children and adolescents.

OBJECTIVES: Central blood pressure (CBP) can now be reliably measured noninvasively with a number of devices in adult; however, noninvasive assessment of CBP has not been validated in children and adolescents. The purpose of this study was to clarify the accuracy of noninvasive oscillometric CBP measurements in children and adolescents. METHODS: This study included 60 patients with an average age of 7.9 ±â€Š4.4 years (range 1-18 years) who underwent a cardiac catheterization. We compared CBP, estimated with a noninvasive oscillometric method using a Mobil-O-Graph, with simultaneous invasive recordings using a catheter in children and adolescents. RESULTS: Comparison of the SBP values measured by the two methods, showing a linear correlation (r = 0.85; P < 0.0001) with the mean difference aortic SBP minus estimated central SBP of 2.0 ±â€Š5.6 mmHg (95% limits of agreement = -9.0-13.1). In DBP values, there was a correlation (r = 0.72; P < 0.0001) with the mean difference aortic DBP minus estimated central DBP of -0.1 ±â€Š6.4 mmHg (95% limits of agreement = -12.6-12.4). Sex and cardiac function did not affect central SBP estimation; however, the correlation between aortic and estimated central SBP in adolescents was better than that in children (r = 0.93, P < 0.0001 vs. r = 0.77, P < 0.0001), though the difference was not statistically significant (P = 0.483). CONCLUSION: Estimated CBP using Mobil-O-Graph in children and adolescents shows a certain degree of accuracy, which will be helpful in future for evaluating CBP in children and adolescents.

[A case of severe acute flaccid myelitis requiring continuous mechanical ventilation].

Many cases of acute flaccid paralysis occurred during an enterovirus D68 (EV-D68) outbreak in North America in the fall of 2014, and this epidemic has been newly defined as a distinct disease entity named acute flaccid myelitis (AFM). This disease entity is relatively popular among pediatricians, whereas it remains little-known among neurologists in Japan. We reported a 7-year-old girl with AFM, in whom severe limb weakness and respiratory failure developed five days after appearance of respiratory symptoms. Clinical features of our case were mimicked by those of acute axonal motor neuropathy at early stage of the disease, and this resulted in delayed diagnosis of AFM. DNA of EV-D68 was not detected. There are few reported cases of severe AFM, in which artificial ventilation is needed for a long time including both acute and recovery phases of the illness, and functional prognosis of AFM is discussed by literature.

Impact of Pulmonary Valve Regurgitation on Pressure Difference of Pulmonary Valve Stenosis in Patients with Tetralogy of Fallot After Repair.

Pressure difference (PD) is an important parameter in evaluating the degree of stenotic lesion. However, PD is influenced by the blood flow volume passing through the stenosis. In patients with tetralogy of Fallot (TOF), pulmonary valve regurgitation (PR) and pulmonary valve stenosis (vPS) are common post-operative complications. The aim of this study was to evaluate the influence of PR on the PD. First, we examined the relationship between the peak-to-peak PD and the valve orifice area in 7 patients with vPS from their cardiac catheterization data. Second, an estimated PD, i.e., PD assuming no PR, was calculated in 8 patients with TOF with vPS and PR from their valve orifice area using the relational equation in patients with vPS. Moreover, an excess of PD, equating to the difference between the measured and estimated PD, was calculated. Finally, the relationship between the regurgitant fraction (RF) and the excess PD was analyzed. There was a strong relationship between the reciprocal of the valve orifice area and the PD in patients with vPS (r = 0.904, p = 0.0053). The excess PD showed a significant correlation with the RF in patients with TOF (r = 0.889, p = 0.0032). PR of over 25% in RF augmented the PD depending on the regurgitant volume. Severity of vPS could be overestimated in post-operative patients with TOF who had significant PR when their RF was above 25%.

Attenuation of Pulse Pressure Amplification in Patients with Complete Transposition of the Great Arteries After an Arterial Switch Operation in Children.

Although the arterial switch operation has become the standard procedure for infants with complete transposition of the great arteries, possible late adverse events after surgery have not been fully elucidated. One such problem may be the postoperative function of the aorta that is radically manipulated. The current study enrolled 12 patients aged 4-9 years who had undergone an arterial switch operation. The ascending and descending aortic pressure waveforms were recorded by a catheter-mounted pressure sensor. The pressure values were compared with those of 28 age-matched controls. The mean patient age was 6.5 ± 1.0 years, and the mean age at the time of surgery was 15.2 ± 8.7 days. The pulse pressure in the ascending aorta was greater in the patients than in the controls (37.7 ± 5.7 vs. 33.5 ± 5.3 mmHg, p = 0.042), while no difference was observed at the descending aorta between the two groups (39.5 ± 5.1 vs. 37.4 ± 5.4 mmHg, respectively, p = 0.27). The pulse pressure amplification, defined as the pulse pressure in the descending aorta minus that in the ascending aorta, was significantly lower in patients who had undergone the arterial switch operation than in control patients (1.8 ± 1.6 vs. 4.0 ± 2.3 mmHg, p = 0.0052). The augmented pulse pressure in the ascending aorta and attenuated pulse pressure amplification observed in children treated with arterial switch surgery for complete transposition of the great arteries may implicate the procedure as a cause of future cardiovascular disease.