Activation of Mitochondrial Oxygen Consumption Rate by Delivering Coenzyme Q10 to Mitochondria of Rat Skeletal Muscle Cell (L6).

Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q10 (CoQ10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery.

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.

Usefulness of Prolonged PR Interval to Predict Atrial Tachyarrhythmia Development Following Surgical Repair of Tetralogy of Fallot.

Atrial tachyarrhythmias (ATAs), which may occur after tetralogy of Fallot (TOF) surgery, can cause sudden cardiac death. However, ATAs may also develop in response to electrical substrates. This study aims to examine the predictive factors for ATAs by identifying electrical substrates in the atrium obtained from 12-lead electrocardiogram in patients who underwent TOF repair. A total of 144 patients aged >15 years (median, 31.6 years) who underwent TOF repair at Hokkaido University were enrolled. We investigated the correlation between the development of ATAs with age, time interval after initial corrective surgery, brain natriuretic peptide levels, cardiac magnetic resonance parameters (right ventricular end-diastolic volume index, right ventricular end-systolic volume index, right ventricular ejection fraction, right atrial volume index, left ventricular end-diastolic volume index, left ventricular ejection fraction), and 12-lead electrocardiogram parameters (P wave maximum voltage, PR interval, QRS width, number of fragmented QRS). Of the 144 patients, 44 patients (30.6%) developed ATAs. Multivariate analysis revealed time interval after initial corrective surgery (odds ratio 6.7, 95% confidence interval 1.78 to 12.6) and PR interval (odds ratio 2.7, 95% confidence interval: 1.17 to 4.20) as independent risk factors for the development of ATAs. The receiver operating characteristic curve revealed a PR interval cut-off value of >200 milliseconds as predictive of the development of ATAs in patients more than 15 years after initial corrective surgery (area under the curve, 0.658; sensitivity, 71.4%; specificity, 66.4%). The present study demonstrated that a prolonged PR interval is a simple and convenient predictor for the development of ATAs in patients who underwent TOF repair.

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.

Hybrid Assistive Limb® for sporadic inclusion body myositis: A case series.

We evaluated the efficacy of rehabilitation therapy with Hybrid Assistive Limb® (HAL; hereafter HAL therapy) in three patients diagnosed with sporadic inclusion body myositis (sIBM) who were hospitalized to undergo HAL therapy. Among them, one patient participated in eight courses and the other two in two courses of HAL therapy between 2017 and 2020. We determined the mean rate of improvement in two-minute walking distance and 6 m walking speed at the time of hospital discharge. After HAL therapy, we confirmed the patients' desire to continue the use of HAL. In one patient, we observed improvements of 146.0% and 120.0% in two-minute walk and 6 m walking speed, respectively, after the first course of HAL therapy; these values are 133.7% and 130% after the eighth course of HAL therapy. These values exceeded 90% in the other two patients after the second course of HAL therapy. HAL therapy maintained both quantity and quality of ambulation and showed positive psychological effects on patient conditions because it reduces exercise load and facilitates safety. While HAL therapy might be effective in maintaining and improving ambulation in patients with sIBM, we should consider to discontinue HAL therapy as it increased risk of falling.