HOIL-1L deficiency induces cell cycle alteration which causes immaturity of skeletal muscle and cardiomyocytes.

HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiated from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiated from control hiPSCs. Further analysis of hiPSC-derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results demonstrate that abnormal cell maturation possibly contribute to the development of myopathy and DCM. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.

Chloroquine decreases cardiac fibrosis and improves cardiac function in a mouse model of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because decreased autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes. METHODS: In this present study, we evaluated myocardial fibrosis and its mechanism in mdx mice, a model of DMD, and also evaluated changes in cardiac function. RESULTS: As assessed by LC3 immunohistochemistry, a small number of autophagosomes were detected in cardiomyocytes of both mdx mice and control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by 4 weeks of isoproterenol-induced cardiac stress in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine significantly decreased cardiomyocyte fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration. CONCLUSIONS: Heart failure in DMD patients is possibly treated with chloroquine, and the mechanism probably involves chloroquine's anti-inflammatory effects.

Influence of the bronchus on the vascular growth of major aortopulmonary collateral arteries.

OBJECTIVES: Patients with major aortopulmonary collateral arteries (MAPCAs) often require additional surgical or catheter intervention after unifocalization (UF) due to stenosis and poor growth. We hypothesized that the UF design influences vascular growth; assessment was based on the passing route related to the bronchus. METHODS: We enrolled 5 patients with pulmonary atresia (PA), ventricular septal defect and MAPCA who underwent UF and subsequent definitive repair at our institute from 2008 to 2020. Angiography and computed tomography scans were routinely performed before surgical intervention to clarify pulmonary circulation and the relationships between MAPCAs and the bronchus, which revealed peculiar MAPCAs directed to the pulmonary hilum passing behind the bronchus (defined as retro-bronchial MAPCAs; rbMAPCAs). Vascular growth of rbMAPCAs, non-rbMAPCAs and the native pulmonary artery were assessed using the angiograms before and after repair. RESULTS: The angiogram before UF [age 42 (24-76) days, body weight 3.2 (2.7-4.2) kg] showed that the diameter of the original unilateral PA, rbMAPCA and non-rbMAPCA was 19.95 ± 6.65, 20.72 ± 5.36 and 20.29 ± 7.42 mm/m2, respectively (P = 0.917). UF was completed in a single-stage with the placement of modified Blalock-Taussig shunt through median sternotomy at the age of 1.6 (1.0-2.5) months. Angiograms performed 3.0 (1.0-10.0) years after UF completion demonstrated a smaller rbMAPCA diameter at peri-bronchial region (3.84 ± 2.84 mm/m2) compared to the native unilateral PAs (16.11 ± 5.46 mm/m2, P < 0.0001) and non-rbMAPCA (10.13 ± 4.44 mm/m2, P = 0.0103). CONCLUSIONS: RbMAPCAs tend to be stenosed at the point where they cross the bronchus and emerge in the middle mediastinum after in situ UF.

Hemodynamic and Clinical Response to Liver Transplantation in Children and Young Adults POPH Patients.

Portopulmonary hypertension is an intractable form of pulmonary hypertension. Although liver transplantation is recommended for patients who respond poorly to treatments, the mechanisms by which liver transplantation improves pulmonary hypertension remain unclear. The present study investigated these mechanisms by retrospectively evaluating patients' data. This study retrospectively evaluated echocardiography and catheterization data before and after liver transplantation in 12 patients who underwent liver transplantation from 2001 to 2019. The 12 patients included one male and 11 females, of median age at liver transplantation of 10 years, 2 months. Nine patients underwent liver transplantation for congenital biliary atresia and three for portal vein aplasia or hypoplasia. Mean pulmonary arterial pressure was 44.1 ± 8.1 mmHg at the first cardiac catheter examination, 35.3 ± 7.8 mmHg before liver transplantation, and 29.5 ± 9.3 mmHg 6 months after liver transplantation. Pulmonary artery pressure was reduced by treatments of pulmonary hypertension and by liver transplantation. Pulmonary vascular resistance did not differ before and after liver transplantation, whereas the cardiac index decreased significantly, indicating that the significant reduction in mean pulmonary artery pressure was due to a decrease in cardiac index. Decreased cardiac index was thought to result from improvements in hyperdynamic conditions due to increased (normalized) systemic vascular resistance. Liver transplantation likely suppresses shear stress on pulmonary arteries, preventing further damage by hyper-circulation. A longer-term evaluation is required to determine the effect of improving pulmonary artery remodeling.

Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells.

For long QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance. This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening. We investigated the response of LQT2-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) following IKr blockade using a multi-electrode array, finding that the response to IKr blockade was significantly smaller than in Control-iPSC-CMs. Furthermore, we found that LQT1-iPSC-CMs and LQT3-iPSC-CMs could be distinguished from Control-iPSC-CMs by IKs blockade and INa blockade, respectively. This strategy might be helpful in compensating for the shortcomings of genetic testing of LQTS patients.

Successful living donor liver transplantation after stent implantation in a patient with Alagille syndrome and severe bilateral pulmonary artery stenosis.

Severe pulmonary hypertension is a contraindication for liver transplantation owing to high mortality. However, decision-making regarding the treatment approach for patients with bilateral peripheral pulmonary artery stenosis, typically complicated by elevated main pulmonary artery and right ventricle pressures, can be challenging. Here, we report successful living donor liver transplantation after bilateral pulmonary artery stent implantation in a patient with Alagille syndrome, severe bilateral peripheral pulmonary artery stenosis, and extremely high main pulmonary artery and right ventricle pressures.

Splenic irradiation as a component of a reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in myelofibrosis with massive splenomegaly.

Primary myelofibrosis is a hematologic neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. A similar clinical condition can occur at late stage of myeloproliferative neoplasms such as polycythemia vera and essential thrombocythemia. Although allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy for both conditions, massive splenomegaly frequently observed in patients with myelofibrosis is considered to be a risk factor for graft failure or engraftment delay after transplantation. A proportion of patients can benefit from splenectomy before transplantation but such procedures have been associated with substantial surgical morbidity. Here, we report two elderly patients with myelofibrosis who received scheduled splenic irradiation for massive splenomegaly immediately prior to allogeneic HSCT instead of undergoing splenectomy. The first patient was a 60-year-old woman who received peripheral blood stem cell transplantation for post-essential thrombocythemia myelofibrosis from an HLA-identical sibling; the second patient was a 60-year-old man who received unrelated bone marrow transplantation for primary myelofibrosis. After receiving fractionated splenic irradiation and fludarabine-based reduced-intensity conditioning regimens, these patients showed remarkable reduction of their splenomegaly at the time of transplantation. They attained successful donor cell engraftment without severe complications related to splenic irradiation, while improvement in splenomegaly was durable. Our experience suggests that splenic irradiation before allogeneic HSCT might be a safe and effective alternative to splenectomy for myelofibrosis patients with massive splenomegaly in terms of reducing the risk of surgical morbidity.

Left pulmonary artery banding to repair ipsilateral diffuse pulmonary arteriovenous fistula.

Congenital pulmonary arteriovenous fistula (PAVF) is a rare disease which causes hypoxemia by shunting deoxygenated blood from the pulmonary artery into pulmonary venous return. Lung transplantation is the most effective therapy to treat severe, diffuse PAVF. However, the availability of lungs for transplantation is limited in most parts in the world. For patients with diffuse PAVF affecting only one side of the lungs, ipsilateral pulmonary artery banding (PAB) is an effective treatment, but not yet standard of care. We report successful treatment of a patient with diffuse left-sided PAVF with PAB. We believe that PAB is an effective therapy for severe unilateral PAVF and may serve as a bridge to lung transplantation.

Multi-scale numerical simulations on piezoresistivity of CNT/polymer nanocomposites.

In this work, we propose a comprehensive multi-scale three-dimensional (3D) resistor network numerical model to predict the piezoresistivity behavior of a nanocomposite material composed of an insulating polymer matrix and conductive carbon nanotubes (CNTs). This material is expected to be used as highly sensitive resistance-type strain sensors due to its high piezoresistivity defined as the resistance change ratio divided by the mechanical strain. In this multi-scale 3D numerical model, three main working mechanisms, which are well known to induce the piezoresistivity of strain sensors fabricated from nanocomposites, are for the first time considered systematically. They are (a) the change of the internal conductive network formed by the CNTs, (b) the tunneling effect among neighboring CNTs, and (c) the CNTs' piezoresistivity. Comparisons between the present numerical results and our previous experimental ones were also performed to validate the present numerical model. The influence of the CNTs' piezoresistivity on the total piezoresistivity of nanocomposite strain sensors is explored in detail and further compared with that of the other two mechanisms. It is found that the first two working mechanisms (i.e., the change of the internal conductive network and the tunneling effect) play a major role on the piezoresistivity of the nanocomposite strain sensors, whereas the contribution from the CNTs' piezoresistivity is quite small. The present numerical results can provide valuable information for designing highly sensitive resistance-type strain sensors made from various nanocomposites composed of an insulating polymer matrix and conductive nanofillers.