Detection of Pediatric Pulmonary Arterial Hypertension by School Electrocardiography Mass Screening.

Rationale: To detect pulmonary arterial hypertension (PAH) at any early stage is a promising approach to optimize the outcome. Objectives: To investigate the impact of school ECG-based screening on detecting idiopathic or heritable (I/H)-PAH in the general pediatric population. Methods: This was a nationwide survey of patients with I/H-PAH newly diagnosed at 3 months to 18 years of age in Japan during 2005-2012. Measurements and Main Results: Eighty-seven eligible patients (age range, 1-16 yr) were recruited. Among 68 (78%) patients diagnosed at greater than or equal to 6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (screening group) and 40 (59%) were recognized by their symptoms (n = 37) or coincidental occasions (n = 3; nonscreening group). In the screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs. 60%; P < 0.001), plasma brain natriuretic peptide level was lower (149 ± 290 vs. 398 ± 559 pg/ml; P = 0.045), and 6-minute-walk distance was longer (420 ± 109 vs. 327 ± 104 m; P < 0.001) than the nonscreening group, despite similar values in mean pulmonary artery pressure (58 ± 17 vs. 61 ± 17 mm Hg; P = 0.42) and pulmonary vascular resistance index (18 ± 8 vs. 21 ± 11 Wood units ⋅ m2; P = 0.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the screening group than the nonscreening group (14% vs. 50; P = 0.004). Conclusions: These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric patients with I/H-PAH that is associated with already established pulmonary hypertension but without obvious right heart failure and warrants investigating the prognostic significance of this system.

Chronotropic incompetence to exercise in anorexia nervosa patients during the body-weight recovery phase as an index of insufficient treatment.

Resting bradycardia is an important symptom for early diagnosis of anorexia nervosa (AN) during weight loss, and it improves with body-weight recovery. However, chronotropic incompetence (CI) in exercise is observed in some patients with AN despite amelioration of resting bradycardia in the recovery phase. We examined the relationship between CI in exercise and other parameters in patients with AN during the recovery phase. Ninety-two girls with AN (aged 13-20 years, median 15 years) performed cardiopulmonary exercise tolerance tests with a bicycle ergometer in the post-treatment recovery phase. Subjects with a peak-heart rate (HR) of < 160 beats/min (bpm) on subjective maximum loading were assigned to the CI+ group (n = 7), and those with a peak-HR of ≥ 160 bpm were assigned to the CI- group (n = 85). The peak-oxygen uptake (VO2) of both groups was below the normal range. Although there was no difference in peak-VO2 between these groups, both the resting-HR and ΔHR (peak-HR - resting-HR) were significantly lower in the CI+ group than in the CI- group (82 ± 8 vs. 93 ± 16 bpm, respectively; 72 ± 14 vs. 89 ± 13 bpm, respectively), suggesting lower exercise tolerance in patients with CI during the recovery phase of AN. Interestingly, the ΔVO2/ΔHR value was higher in the CI+ group than in the CI- group (0.31 ± 0.13 vs. 0.26 ± 0.06, respectively), suggesting excessive stroke volume for maintaining the cardiac output in patients with CI during their recovery phase. These data suggest that CI could be an index of insufficient recovery of AN and utilized for ideal exercise treatments of patients with AN during the recovery phase.

Homozygosity for moyamoya disease risk allele leads to moyamoya disease with extracranial systemic and pulmonary vasculopathy.

Moyamoya disease is characterized by diffuse distal intracranial stenosis. Recently, RNF213 has been identified as a susceptibility gene in the development of this condition. Pulmonary hypertension is a rare progressive vasculopathy with an unknown etiology. The co-occurrence of pulmonary hypertension and Moyamoya disease has been described in four patients; however, whether this co-occurrence represents a chance association or a common vascular pathology has remained unknown. Here, we report two unrelated male patients who presented during their childhood with dyspnea on exertion. Systemic vascular imaging studies revealed the presence of pulmonary hypertension and Moyamoya disease in both patients. Medical exome sequencing revealed that both patients had a homozygous mutation for p.Arg4810Lys in RNF213. We suggest that homozygosity in RNF213 may lead to a novel entity involving the brain and lung. Interestingly, when present in a heterozygous state, this mutation causes a classic cerebral vascular disease, Moyamoya disease. In the homozygous state, the exact same mutation led to Moyamoya disease with extracranial systemic vasculopathy in at least two patients. From a clinical standpoint, cerebrovascular or pulmonary vascular investigations may be warranted in patients with pulmonary hypertension or Moyamoya disease, respectively. © 2016 Wiley Periodicals, Inc.

A neonatal prolonged QT syndrome due to maternal use of oral tricyclic antidepressants.

UNLABELLED: It is known that tricyclic antidepressants induce long QT intervals associated with forms of life-threatening arrhythmia such as torsades de pointes (TdP), and these adverse effects may also occur in neonates whose mothers take tricyclic antidepressants. We report a neonatal case of prolonged QT interval and TdP caused by clomipramine that was transferred transplacentally from the mother. Administration of magnesium sulfate was effective to abolish TdP. CONCLUSION: When mothers take tricyclic antidepressants during pregnancy, their newborns should be watched carefully for drug-induced long QT syndrome and TdP. WHAT IS KNOWN: •Tricyclic antidepressant can prolong the QT interval. It may be used for depression in pregnancy. What is New: •This is the first neonatal case report of prolonged QT interval and TdP caused by clomipramine transferred transplacentally from the mother.

Periodic Protrusion of Right Coronary Cusp into Left Ventricular Outflow Tract Due to Detachment from the Aortic Annulus Complicated with Infective Endocarditis.

We describe the imaging of unusual dislocation of right coronary cusp into left ventricular outflow tract (LVOT) due to the infective endocarditis. Although the two-dimensional echocardiography identified a protruding mass in LVOT, the three-dimensional echocardiography precisely demonstrated the spatial anatomy of the aortic root, which was confirmed by the surgical operation, implicating the usefulness of three-dimensional echocardiography in this rare anomaly.

Update on medical treatment of patients with eisenmenger syndrome.

Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) associated with congenital heart defects. ES greatly affects functional capacity, quality of life, and survival of patients. Clinical management of patients with ES has been dramatically changed and developed in a new therapeutic era of PAH, approximately a century after the first ES case described by Dr. Eisenmenger. Targeted drugs for PAH improve functional capacity and quality of life of patients with ES. In addition, these drugs may also provide a benefit for patients' survival. To achieve further development in medical treatment of patients with ES, they will need to be individualized according to functional classes, underlying cardiac defects, and underlying systemic diseases.

Effectiveness of inactivated influenza and COVID-19 vaccines in hospitalized children in 2022/23 season in Japan - The first season of co-circulation of influenza and COVID-19.

We have analyzed the inactivated vaccine effectiveness (VE)for preventing influenza hospitalization by test-negative design in the 2022/23 season. This is the first season of co-circulation of influenza and COVID-19, and a unique period because all inpatients received COVID-19 screening. Among 536 children hospitalized with fever, none were positive for both influenza and SARS-CoV-2. The adjusted VE for preventing influenza A for all children, the 6-12-year-old group, and those with underlying diseases was 34 % (95 ％CI, -16 %-61 %, n = 474), 76 % (95 ％ CI, 21 %-92 %, n = 81), and 92 % (95 ％ CI, 30 %-99 %, n = 86), respectively. Only 1 out of 35 hospitalized cases with COVID-19, and 42 out of 429 controls, had been immunized with COVID-19 vaccine. This is the first report showing influenza VE by age group in children in this limited season. We still recommend the inactivated influenza vaccine for children based on the significant VE in subgroup analysis.

Congenital corneal staphyloma as a complication of Kabuki syndrome.

Kabuki syndrome has long been clinically defined based mainly on its characteristic eye features. The recent discovery of MLL2 as a causative gene of Kabuki syndrome has enabled the extreme end of the phenotype to be explored. We herein report on two patients with striking visible congenital staphyloma at birth. A diagnosis of Kabuki syndrome was subsequently made in both patients based on a constellation of characteristic eye features, cardiac abnormalities and severe developmental delay, and finally by the confirmation of MLL2 mutations. In conclusion, congenital corneal staphyloma is a complication of Kabuki syndrome with MLL2 mutations.

Ce-doping effect on dosimetric properties of mullite single crystals synthesized by the floating zone method.

We synthesized the 0.1, 0.5, 1.0, and 1.5% Ce-doped mullite single crystals by the floating zone method and evaluated their photoluminescence (PL) and thermally stimulated luminescence (TSL) properties. The single-phase orthorhombic structure was confirmed in all the samples from powder X-ray diffraction patterns. The transmittance spectra of all the samples showed the absorption related to the 4f-5d transitions of Ce3+ ions and optical band gap of mullite. The Ce-doped mullite single crystals had the PL attributed to the 5d-4f transitions of Ce3+ ions. In TSL properties, TSL glow curves had the glow peaks at 250 and 370 °C, and TSL spectra heated at 250 and 370 °C had the peak at around 390 nm owing to the Ce3+ ions. TSL dose response functions showed linear response from 0.01 mGy to 10 Gy for the 1.0% Ce-doped mullite single crystal and from 0.1 mGy to 10 Gy for the 0.1, 0.5, and 1.5% Ce-doped ones. The 1.0% Ce-doped mullite single crystal could be used multiple times for dosimetry. In addition, the TSL intensity of the 1.0% Ce-doped mullite single crystal after 7 days from X-ray irradiation was about 82.4% from immediately one after X-ray irradiation.

Clinical features and treatment strategies of febrile urinary tract infection caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: a multicenter retrospective observational study in Japan.

OBJECTIVES: The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. METHODS: A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL-producing bacteria were compared. RESULTS: Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). CONCLUSION: ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic.

Clinical characteristics of pediatric febrile urinary tract infection in Japan.

BACKGROUND: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. METHODS: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. RESULTS: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. CONCLUSIONS: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.

Effect of glucocorticoid on the biosynthesis of growth hormone-containing secretory granules in pituitary cells.

Recent studies have suggested that treatment of glucocorticoid to immature growth hormone (GH)-producing cell line, MtT/S cells, dramatically induced the accumulation of GH-containing secretory granules in the cytosol and differentiated into mature GH-producing cells. However, the molecular mechanism of glucocorticoid-induced GH-containing secretory granule biogenesis in the MtT/S cells remains unknown. In the present study, we found that GH mRNA expression was facilitated by application of glucocorticoid. We artificially increased GH synthesis by transfection of green fluorescent protein-tagged GH (GH-GFP) gene. We found that the artificial elevation of GH expression in the cells did not accumulate the secretory granules in the cytosol, whereas glucocorticoid-induced the biogenesis of granules in GH-GFP-expressing MtT/S cells. We next performed DNA microarray and real-time RT-PCR analysis and found that glucocorticoid significantly altered the expression of membrane trafficking-related protein, syntaxin11 (Syx11). Immunocytochemical analysis further demonstrated that Syx11 positive structures were well colocalized with GH-containing granules in both MtT/S cells and rat anterior pituitary gland. Our findings indicate that glucocorticoid regulate the expression of Syx11 and facilitate the biogenesis and the trafficking of GH-containing granules in the MtT/S cells.

Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A2 and prostacyclin.

Patients with Down syndrome (DS) and a left-to-right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A(2) and prostacyclin (PGI(2)) in four groups of infants, cross-classified as shown below, by measuring the urinary excretion levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha): DS infants with a left-to-right shunt and PH (D-PH, n = 18), DS infants without congenital heart defect (D-C, n = 8), non-DS infants with a left-to-right shunt and PH (ND-PH, n = 12), and non-DS infants without congenital heart defect (ND-C, n = 22). The urinary excretion ratios of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) in the D-PH, D-C, ND-PH, and ND-C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA(2) over PGI(2), leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left-to-right shunt.

Specific induction and long-term maintenance of high purity ventricular cardiomyocytes from human induced pluripotent stem cells.

Currently, cardiomyocyte (CM) differentiation methods require a purification step after CM induction to ensure the high purity of the cell population. Here we show an improved human CM differentiation protocol with which high-purity ventricular-type CMs can be obtained and maintained without any CM purification process. We induced and collected a mesodermal cell population (platelet-derived growth factor receptor-α (PDGFRα)-positive cells) that can respond to CM differentiation cues, and then stimulated CM differentiation by means of Wnt inhibition. This method reproducibly generated CMs with purities above 95% in several human pluripotent stem cell lines. Furthermore, these CM populations were maintained in culture at such high purity without any further CM purification step for over 200 days. The majority of these CMs (>95%) exhibited a ventricular-like phenotype with a tendency to structural and electrophysiological maturation, including T-tubule-like structure formation and the ability to respond to QT prolongation drugs. This is a simple and valuable method to stably generate CM populations suitable for cardiac toxicology testing, disease modeling and regenerative medicine.

Navigator-triggered and breath-hold 3D MRCP using compressed sensing: image quality and method selection factor assessment.

PURPOSE: To examine whether MRCP using a combination of compressed sensing and sensitivity encoding with navigator-triggered and breath-hold techniques (NT C-SENSE and BH C-SENSE, respectively) have comparable image quality to that of navigator-triggered MRCP using only sensitivity encoding (NT SENSE) at 1.5-T. METHODS: Fifty-one participants were enrolled in this prospective study between July and October 2018 and underwent the three 3D MRCP sequences each. The acquisition time and relative duct-to-periductal contrast ratios (RC values) of each bile duct segment were obtained. Visualization of the bile and main pancreatic ducts, background suppression, artifacts, and overall image quality were scored on 5-point scales. Mean and median differences in RC values and qualitative scores of NT C-SENSE and BH C-SENSE relative to NT SENSE were calculated with 95% confidence intervals (CIs). RESULTS: Acquisition time of NT SENSE, NT C-SENSE, and BH C-SENSE were 348, 143 (mean for both), and 18 s (for all participants), respectively. The RC value of each bile duct segment was inferior, but the lower limits of the 95% CIs of the mean differences were ≥ - 0.10, for both NT C-SENSE and BH C-SENSE. The visualization score of the intrahepatic duct in BH C-SENSE was inferior to that in NT SENSE (lower 95% CI limit, - 1.5). In both NT C-SENSE and BH C-SENSE, the 95% CIs of the median differences in the other qualitative scores were from - 1.0 to 0.0. CONCLUSION: NT C-SENSE and BH C-SENSE have comparable image quality to NT SENSE at 1.5-T.

Living-donor lung transplantation after surgical repair of transposition of the great arteries.

Pediatric pulmonary hypertension after surgery for congenital heart disease is a significant complication. We present a case of living-donor lung transplantation for a 12-year-old girl with pulmonary hypertension after surgical repair of transposition of great arteries. Despite repairing the transposition of great arteries, her growth was severely restricted because of progressive pulmonary hypertension; thus, lung transplantation was discussed. Standard bilateral lobar transplantation seemed unfeasible due to oversized grafts, so we performed a single lobar transplantation. Unexpectedly, she developed complications and died 3 months postoperatively despite another emergent lobar transplantation. We discussed the challenges and potential solutions regarding lobar size mismatching.

Three-component coupling using arynes and aminosilanes for ortho-selective double functionalization of aromatic skeletons.

Arynes were found to couple with aminosilanes and carbonyl compounds in the presence of benzoic acid to provide 2-aminobenzhydrols. Sulfonylimines could also be applied to the reaction, enabling amino and aminomethyl moieties to be incorporated into contiguous positions of aromatic skeletons. Only a small amount of the three-component coupling product was obtained in the absence of benzoic acid, which confirms its vital role in the present reaction.