Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice.

The p53 tumor suppressor protein is a potent activator of proliferative arrest and cell death. In normal cells, this pathway is restrained by p53 protein degradation mediated by the E3-ubiquitin ligase activity of MDM2. Oncogenic stress releases p53 from MDM2 control, so activating the p53 response. However, many tumors that retain wild-type p53 inappropriately maintain the MDM2-p53 regulatory loop in order to continuously suppress p53 activity. We have shown previously that single point mutations in the human MDM2 RING finger domain prevent the interaction of MDM2 with the E2/ubiquitin complex, resulting in the loss of MDM2's E3 activity without preventing p53 binding. Here, we show that an analogous mouse MDM2 mutant (MDM2 I438K) restrains p53 sufficiently for normal growth but exhibits an enhanced stress response in vitro. In vivo, constitutive expression of MDM2 I438K leads to embryonic lethality that is rescued by p53 deletion, suggesting MDM2 I438K is not able to adequately control p53 function through development. However, the switch to I438K expression is tolerated in adult mice, sparing normal cells but allowing for an enhanced p53 response to DNA damage. Viewed as a proof of principle model for therapeutic development, our findings support an approach that would inhibit MDM2 E3 activity without preventing MDM2/p53 binding as a promising avenue for development of compounds to activate p53 in tumors with reduced on-target toxicities.

A Case of Successful Biventricular Repair of the Transposition of the Great Arteries with a Coronary Anomaly Associated with an Atrioventricular Septal Defect.

The transposition of the great arteries (TGA) associated with a complete atrioventricular septal defect is a rare and serious congenital cardiac anomaly. In this report, we describe the successful biventricular repair of a TGA with a complete atrioventricular septal defect in an infant. Due to the low body weight of the patient and a complex coronary pattern anomaly, an arterial switch operation was executed, with the Mee procedure and pulmonary arterial banding as initial palliative measures when the infant was 22 days old and weighed 2.5 kg. Subsequently, atrioventricular septal defect repair using the modified one-patch method was performed when the patient was 1.3 years old and weighed 8.8 kg. Remarkably, the postoperative course of the patient demonstrated no notable incidents. To our knowledge, this is the first time a two-stage strategy was applied to repair these complex defects, presenting a promising approach for managing similar cases in future medical practice.

Association between the dynamic movement of hyperechoic foci and patients'/sonographic outcomes among pediatric patients with portal venous gas following a cardiac event.

OBJECTIVES: To demonstrate the association between the dynamic movements of hyperechoic foci in portal venous gas (PVG) and patients'/sonographic outcomes after congenital heart disease or cardiac events. METHODS: Thirty-one pediatric patients requiring management of congenital heart diseases or cardiac events who had PVG on ultrasound were included in this retrospective study. The patient outcome was prognosis: dead or alive. The sonographic outcome was recovery from PVG, measured as days from PVG detection to when it diminished on ultrasound. The following sonographic findings of hyperechoic foci in PVG were compared between patients: detection within the mesenteric vein, having to-and-fro movements within the intrahepatic portal vein, distribution (left segment or both left and right segments) and shape (line or punctate) in the liver, and detection within the portal and hepatic veins. Comparisons were made using Fisher's exact/Mann-Whitney U test. RESULTS: Four patients died without having recovered from PVG. A significant difference was observed in terms of the to-and-fro movement (with/without to-and-fro movement in dead vs. alive patients: 3/1 vs. 1/26, respectively; P = 0.003). Furthermore, a significant difference in sonographic outcomes was observed regarding patients with/without hyperechoic foci within the mesenteric vein (days with vs. without this finding: 2.0 ± 1.24(1-5) vs.1 ± 0(1), respectively; P = 0.011). CONCLUSIONS: In our small limited cohort, when PVG was visualized on ultrasound, close evaluation of the dynamic movement of hyperechoic foci, especially their to-and-fro movement within the intrahepatic portal vein and detection of hyperechoic foci within the mesenteric vein, were useful in predicting patients' outcomes and the time to PVG diminishment.

Fluorographic findings of diaphragmatic paralysis with spontaneous recovery.

BACKGROUND: Postoperative diaphragmatic paralysis is an unavoidable complication of cardiovascular surgery. Although diaphragmatic plication, as a surgical treatment, can be performed, spontaneous recovery is possible. We aimed to identify differences in fluorographic findings of diaphragmatic paralysis between pediatric patients with and without spontaneous recovery within 1 year of intrathoracic surgery. METHODS: Ten children, who had been followed-up for at least 1 year post-surgery and who had not received diaphragmatic plication were included and classified into those with or without spontaneous recovery. The presence or absence of the paradoxical movement of the diaphragm and mediastinum was evaluated based on fluorographic findings. Fisher's exact test was used to compare the presence or absence of paradoxical movement between the groups. RESULTS: Eight patients experienced spontaneous recovery. The mean ± standard deviation time to spontaneous recovery was 150 ± 114 days (range, 18-338 days). In the spontaneous recovery group, no patient had paradoxical movement of the mediastinum, and a significant between-group difference was observed in the presence of the paradoxical movement of the mediastinum (present/absent in patients with vs. without spontaneous recovery: 0/8 vs. 2/0, P = 0.02). There was no significant between-group difference in paradoxical movement of the diaphragm (present/absent in patients with vs. without spontaneous recovery: 1/7 vs. 2/0, P = 0.07). Pediatric patients without paradoxical movement of the mediastinum spontaneously recovered within 1 year of intrathoracic surgery. CONCLUSIONS: Pediatric patients without paradoxical movement of the mediastinum, based on fluorography findings, spontaneously recovered within 1 year of surgery. The timing of spontaneous recovery varied between cases.

De Vega Tricuspid Annuloplasty for Pediatric Patients: Growth Potential of the Plicated Annulus.

Although De Vega annuloplasty is an important option for pediatric patients with functional tricuspid regurgitation (TR), little is known about its long-term results, including the future of the plicated annulus. We retrospectively reviewed our experience with pediatric patients who underwent the De Vega annuloplasty between 2005 and 2020. Tricuspid valve assessments were performed by transthoracic echocardiography. The targeted diameter of annular plication was 80 to 90% of normal tricuspid diameter, according to the patient's condition. The study included 55 patients (41 with biventricular physiology (group B), 14 with univentricular physiology (group U)) with a median follow-up of 5.0 years. Median age at operation was 5.0 years. There was one late death due to severe mitral regurgitation. Tricuspid valve reoperation was required in five patients and the 10-year freedom from reoperation was 91.9% for the entire cohort. The 10-year freedom from the composite adverse outcome of death, reoperation, and significant TR was 79.2% in group B versus 56.6% in group U (p = 0.034). TR grade significantly decreased after surgery (p < 0.001), without significant aggravation during the postoperative follow-up. No patients presented tricuspid stenosis. Mean Z-scores of annular diameter immediately after operation and at the latest follow-up were - 0.65 ± 0.56 versus - 0.47 ± 0.65 (p = 0.57). De Vega annuloplasty is a safe, efficient, and durable procedure for functional TR in pediatric patients including those with univentricular physiology, allowing adequate growth of the plicated annulus without the progression of tricuspid stenosis.

Oblique coronary transfer technique in arterial switch operation for transposition of the great arteries.

BACKGROUND: Mortality rates after the arterial switch operation (ASO) for transposition of the great arteries (TGA) are still suboptimal mainly due to postoperative myocardial ischemia. The present study aimed to investigate the clinical impact of our modification of coronary transfer technique, wherein the coronary cuffs are transferred oblique to the pulmonary trunk to avoid torsion of the coronary arteries. METHODS: From September 2010 to August 2020, all 37 consecutive patients who underwent ASO for TGA with our modification, that is, the oblique coronary transfer technique, were retrospectively reviewed. Cardiac dimensions and patency of the coronary arteries were examined by cineangiography, and hemodynamic parameters were measured by cardiac catheterization and transthoracic echocardiography. RESULTS: During a median 5.3 years of postoperative follow-up, there were no deaths and no patient required mechanical circulatory support. Median left ventricular ejection fraction was 68.8% (interquartile range 66.8-71.0, minimum 54.6). All patients maintained normal sinus rhythm without arrhythmia, except in the early postoperative period. Five patients underwent unplanned re-intervention for peripheral pulmonary stenosis, but none for coronary insufficiency. The 8-year freedom from re-intervention rate was 85.6%. Among a total of 110 transplanted coronary arteries, 108 (98.2%) remained patent, and two circumflex arteries were occluded much later after surgery, although with preserved ventricular function due to compensatory growth of other coronary branches. CONCLUSION: The oblique coronary transfer technique, which aims to avoid torsion of the coronary arteries, provides good patency of the coronary arteries and subsequent improvement of postoperative mortality rates following ASO.

Effect of Continuous Feeding of Ayu-Narezushi on Lipid Metabolism in a Mouse Model of Metabolic Syndrome.

Ayu-narezushi, a traditional Japanese fermented food, comprises abundant levels of lactic acid bacteria (LAB) and free amino acids. This study aimed to examine the potential beneficial effects of ayu-narezushi and investigated whether ayu-narezushi led to improvements in the Tsumura Suzuki obese diabetes (TSOD) mice model of spontaneous metabolic syndrome because useful LAB are known as probiotics that regulate intestinal function. In the present study, the increased body weight of the TSOD mice was attenuated in those fed the ayu-narezushi-comprised chow (ayu-narezushi group) compared with those fed the normal rodent chow (control group). Serum triglyceride and cholesterol levels were significantly lower in the Ayu-narezushi group than in the control group at 24 weeks of age. Furthermore, hepatic mRNA levels of carnitine-palmitoyl transferase 1 and acyl-CoA oxidase, which related to fatty acid oxidation, were significantly increased in the ayu-narezushi group than in the control group at 24 weeks of age. In conclusion, these results suggested that continuous feeding with ayu-narezushi improved obesity and dyslipidemia in the TSOD mice and that the activation of fatty acid oxidation in the liver might contribute to these improvements.

Computed tomography findings of mediastinitis after cardiovascular surgery.

BACKGROUND: To our knowledge, no systematic study has been conducted on computed tomography (CT) imaging of mediastinitis in children post-cardiovascular surgery. We aimed to assess the CT findings of pediatric patients diagnosed with mediastinitis after cardiovascular surgery. METHODS: We included 28 pediatric patients with suspected mediastinitis after undergoing cardiovascular surgery and who underwent CT. Patients were divided into a group with mediastinitis requiring antibiotic therapy (n = 15) confirmed by positive bacterial culture from the mediastinum and a group without mediastinitis (n = 13). Fisher's exact test was used to compare the following CT findings between the two groups: (i) mediastinal fluid collection; (ii) free gas bubble within fluid collection; (iii) sternal destruction; and (iv) capsular ring enhancement. The enhancement extent was categorized into the following four grades: whole rim enhancement, >50% of the rim enhancement, <50% of the rim enhancement, and no rim enhancement. A receiver operating characteristic curve analysis was performed to establish a cut-off point for obtaining the maximum diagnostic accuracy. RESULTS: A significant difference was observed between patients, with and without mediastinitis in sternal destruction (73.6% vs 0%, P = <0.0001) and capsular ring enhancement (100.0% vs 38.5%, P = 0.0004). By using a cut-off grade of the whole rim enhancement, the estimated sensitivity and specificity for mediastinitis diagnosis were 100% and 92.3%, respectively. CONCLUSION: Computed tomography findings of sternal destruction and capsular ring enhancement were observed more in patients with mediastinitis than in those without mediastinitis, and should be assessed carefully to diagnose mediastinitis accurately in pediatric patients who have undergone cardiac surgery.

[Modified Warden Procedure for Correction of Partial Anomalous Pulmonary Venous Connection and Sinus Venosus Atrial Septal Defect in an Adult].

A 32-year-old woman was referred to our hospital for the surgical indication of sinus venosus-type atrial septal defect. Preoperative computed tomography scan revealed that the right upper pulmonary vein returned to the high superior vena cava. We performed a modified Warden procedure using a pedicle flap of the right atrial appendage along with a fresh autologous pericardium. Her postoperative course was uneventful with no venous obstruction or sinus node dysfunction. This technique is a useful surgical option for a partial anomalous pulmonary venous connection especially in adults.

Activated Microglia Desialylate and Phagocytose Cells via Neuraminidase, Galectin-3, and Mer Tyrosine Kinase.

Activated microglia can phagocytose dying, stressed, or excess neurons and synapses via the phagocytic receptor Mer tyrosine kinase (MerTK). Galectin-3 (Gal-3) can cross-link surface glycoproteins by binding galactose residues that are normally hidden below terminal sialic acid residues. Gal-3 was recently reported to opsonize cells via activating MerTK. We found that LPS-activated BV-2 microglia rapidly released Gal-3, which was blocked by calcineurin inhibitors. Gal-3 bound to MerTK on microglia and to stressed PC12 (neuron-like) cells, and it increased microglial phagocytosis of PC12 cells or primary neurons, which was blocked by inhibition of MerTK. LPS-activated microglia exhibited a sialidase activity that desialylated PC12 cells and could be inhibited by Tamiflu, a neuraminidase (sialidase) inhibitor. Sialidase treatment of PC12 cells enabled Gal-3 to bind and opsonize the live cells for phagocytosis by microglia. LPS-induced microglial phagocytosis of PC12 was prevented by small interfering RNA knockdown of Gal-3 in microglia, lactose inhibition of Gal-3 binding, inhibition of neuraminidase with Tamiflu, or inhibition of MerTK by UNC569. LPS-induced phagocytosis of primary neurons by primary microglia was also blocked by inhibition of MerTK. We conclude that activated microglia release Gal-3 and a neuraminidase that desialylates microglial and PC12 surfaces, enabling Gal-3 binding to PC12 cells and their phagocytosis via MerTK. Thus, Gal-3 acts as an opsonin of desialylated surfaces, and inflammatory loss of neurons or synapses may potentially be blocked by inhibiting neuraminidases, Gal-3, or MerTK.

[Hemorrhagic Shock due to an Aortoesophageal Fistula in an Infant with a Double Aortic Arch；Report of a Case].

We experienced a case of a female infant with a double aortic arch (DAA) which formed an aortoesophageal fistula, leading to hemorrhagic shock. The patient had severe dyspnea at birth, and was intubated and tube-feeding was started through a nasogastric tube immediately after birth. A DAA was diagnosed by contrast-enhanced computed tomography. Due to abdominal organ malformation, we proceeded with abdominal surgery. Forty-nine days after birth, she suddenly developed massive hematemesis and went into hemorrhagic shock. The bleeding was stopped using an endoscope and was shown to have originated from the esophagus membrane. Compression of the esophageal wall by both the inserted nasogastric tube and vascular ring led to the development of ulceration, resulting in a fistula associated with massive hematemesis. An operation for a DAA was performed on the 53rd day after birth. The inferior side of the DAA was cut, to decompress the bronchus and esophagus and close the fistula. The patient's postoperative course was good and there was no further bleeding. In severe cases of a DAA who require respiratory intubation and tube feeding from a nasogastric tube it is important to carry out surgery as soon as possible.

Massive hemorrhage after Kasai portoenterostomy in a patient with a congenital extrahepatic portosystemic shunt, malrotation and a double aortic arch: report of a case.

A newborn female was transferred to our hospital presenting with severe respiratory distress. She underwent tracheal intubation and nasogastric tubing. Investigations revealed a congenital extrahepatic portosystemic shunt (CEPS) type 1, biliary atresia, heterotaxia, polysplenia, malrotation and a double aortic arch (DAA). She underwent the Kasai portoenterostomy and the Ladd procedure when she was 29 days old. On postoperative day 20, she developed sudden hematemesis with bright red blood. Endoscopy showed massive bleeding from an esophageal ulcer, and endoscopic therapy was performed successfully. During left thoracotomy, an aortoesophageal fistula (AEF) was detected and repaired by direct suturing. The postoperative course was uneventful. CEPS type 1 is commonly associated with other congenital malformations; however, there have been no previous reports of an association between CEPS and DAA. Nasogastric tube insertion in a patient with DAA can result in catastrophic AEF. The treatment strategy should be carefully considered in patients with CEPS type 1 and multiple congenital fetal anomalies.

[Mid-aortic syndrome in 2-year old boy presenting with severe left ventricular dysfunction; report of a case].

Mid aortic syndrome is uncommon acquired or congenital condition characterized by segmental narrowing of the abdominal or distal descending thoracic aorta. If left untreated, it result in life threatening complications. We described the case of 2-year-old boy admitted to our hospital for hypertension and heart failure. Diagnosis of mid aortic syndrome was made with severe stenosis in distal descending aorta. With consideration of growth, we avoided bypass grafting and implantation with prothesic graft. For severe adhesion, we performed patch aortoplasty with 0.4 mm expanded polytetrafluoroethylene (ePTFE) patch. Postoperative course was unevetful. His blood pressure and left ventricular function was normalized. He was discharged on the 20st day after the surgery.

The Prevalence of Scoliosis after Fontan Circulation Surgery Followed-Up to Adolescence.

Introduction: The advancement of surgical techniques and perioperative management for congenital heart disease (CHD) has increased life expectancy. The surgical creation of the Fontan circulation maintains pulmonary blood flow without relying on an effective pump from the abnormal heart, relying on peripheral vascular resistance to maintain effective flow through the lungs. Unfortunately, this delicate mechanism is compromised when scoliosis restricts ventilation, leading to Fontan failure and a poor prognosis for life. This report describes the prevalence of scoliosis with Fontan completion surgery and the role of screening and surgical correction. Methods: Ninety-six consecutive Japanese patients undergoing Fontan completion surgery for CHD between 2000 and 2017 were identified in our institutional records. The inclusion criterion was at least 7 years of follow-up after Fontan completion surgery, while the exclusion criteria were congenital, syndromic, and neuromuscular scoliosis. Radiographic and clinical parameters, including cardio-thoracic ratio (CTR) for cardiomegaly and cyanosis saturation, were compared between with and without scoliosis. Results: There were 23 and 40 patients in the scoliosis and no scoliosis groups, respectively. The mean age at the final follow-up was 18.5 and 16.7 years in the scoliosis and no scoliosis groups, respectively (p=0.02). Mean CTR was 43.7% and 39.4% in the scoliosis and no scoliosis groups (p=0.016), and the mean saturation in room air at the final follow-up was 88.8% and 93.2%, respectively (p=0.036). There were no significant differences to clarify the risk factors with multivariate logistic regression analysis. Conclusions: The prevalence of scoliosis with Fontan completion surgery was 36.5%. Screening for scoliosis is important for children with Fontan circulation surgery as part of their routine follow-up at least until they reach adolescence.Evidence Level: 4.

Ten-year outcomes of congenital cataract surgery performed within the first six months of life.

PURPOSE: To investigate the long-term outcomes of congenital cataract surgery performed within the first 6 months of life. SETTING: 11 ophthalmic surgical sites in Japan. DESIGN: Retrospective chart review. METHODS: Medical charts were retrospectively reviewed for 216 eyes of 121 patients. The age at surgery was 2.9 ± 1.7 months, with follow-up duration 13.0 ± 2.3 years. The cohort consisted of 83 cases with bilateral aphakia, 12 with bilateral pseudophakia, 20 with unilateral aphakia, and 6 with unilateral pseudophakia. RESULTS: Surgical intervention within the critical period of visual system development (10 weeks for bilateral and 6 weeks for unilateral cases) led to significantly better final visual acuity than surgery conducted after this time frame. The incidence of secondary glaucoma was similar between groups while the occurrence of visual axis opacification was more frequent with earlier surgery. A forward stepwise multiple regression analysis revealed that the final visual acuity was significantly associated with laterality of cataract (better outcomes in bilateral cases), phakic status (with pseudophakia outperforming aphakia), presence of systemic and ocular comorbidities, and development of secondary glaucoma. Secondary glaucoma was significantly more prevalent in aphakic eyes than pseudophakic eyes. CONCLUSIONS: In patients with genuine congenital cataract, surgery within the critical period of visual development results in better final visual acuity, albeit with an increased risk of visual axis opacification. The use of IOL with sophisticated surgical techniques shows promise even in congenital cataract surgery.

Corrigendum: Use of the index of pulmonary vascular disease for predicting longterm outcome of pulmonary arterial hypertension associated with congenital heart disease.

[This corrects the article DOI: 10.3389/fcvm.2023.1212882.].

[Clinical course of retinopathy of prematurity and other neonatal complications in Kobe Children's Hospital].

PURPOSE: To report changes in retinopathy of prematurity (ROP) and other neonatal complications for the last 15 years CASES AND METHOD: 638 cases with a birth weight of less than 1000 g were categorized into two groups in oxygen management changes based on reduced oxygen protocol before and after change (Group A: 218 cases from 1997 to 2001, Group B: 420 cases from 2002 to 2011). Prematurity and the clinical course of ROP were reviewed. In addition, the incidence of 5 main neonatal complications before and after oxygen control criterion change was compared. RESULTS: The differences in birth weight and gestational age among the two groups were not significant (A: 765 138 g/26.5 +/- 2.2 weeks, B: 753 +/- 158 g/26.1 +/- 2.3 weeks). The incidence of ROP and the rate of treatment for ROP in Group B were significantly less than in Group A (A: 83.0%/32.6% VS B: 54.8%/ 10.0%; p < 0.01). The rate of forming a cicatricial phase severer than grade 3 was 4.1% in Group A and 1.7% in Group B (p = 0.06). The incidence of neonatal complications before and after oxygen management change was not significantly different. CONCLUSION: Incidence and treatment of ROP were improved after changing to the reduced oxygen protocol. There was no increase in neonatal complications after the management change.

Long-term surgical outcomes of pediatric cataract-multivariate analysis of prognostic factors.

We assessed the 10-year postoperative outcomes of pediatric cataract patients who underwent surgery at the age of 6 years or younger. A retrospective review of medical charts was conducted for 457 eyes of 277 patients, with the age at surgery averaging 1.3 ± 1.5 years (mean ± SD) and the follow-up duration averaging 12.8 ± 2.4 years (ranging from 10 to 17 years). The cohort included 250 eyes of 125 cases with bilateral aphakia (age at surgery 0.5 ± 0.8 years), 110 eyes of 55 cases with bilateral pseudophakia (1.9 ± 1.6 years), 42 cases with unilateral aphakia (1.1 ± 1.3 years), and 55 cases with unilateral pseudophakia (2.6 ± 1.7). A forward stepwise multiple regression analysis revealed that the best-corrected visual acuity at the final visit was significantly associated with laterality of cataract (with bilateral cases showing better results compared to unilateral cases), presence of systemic comorbidities, presence of ocular comorbidities, development of glaucoma, and phakic status (with better results in the pseudophakia group than the aphakia group). The age at surgery did not significantly affect visual acuity outcomes. A multiple logistic regression analysis demonstrated that the incidence of secondary glaucoma was significantly linked to younger age at surgery, phakic status (higher in aphakic than pseudophakic eyes), and presence of systemic comorbidities. In conclusion, after pediatric cataract surgery, final visual acuity was better in patients with bilateral cataracts, those treated with an intraocular lens, and cases without systemic or ocular comorbidities and secondary glaucoma. The development of secondary glaucoma was linked to younger age at surgery, aphakic status, and presence of systemic comorbidities.