[A CASE OF CHILDHOOD-ONSET EOSINOPHILIC GRANULOMATOUS POLYANGIITIS WITH ASYMPTOMATIC MYOCARDIAL INVOLVEMENT WHO WAS DIAGNOSED AT MORE THAN 5 YEARS AFTER ONSET OF ATOPIC DERMATITIS AND BRONCHIAL ASTHMA].

Atopic dermatitis and bronchial asthma are common diseases in children. We report the development of eosinophilic polyangiitis granulomatosis (EGPA) in a young girl being treated for both atopic dermatitis, diagnosed at 1 year of age, and bronchial asthma, diagnosed at 4 years of age. Her eruption did not result in lichenification and was not fully responsive to corticosteroid ointment. Asthma lightened by treatment of inhalational steroids. Hypereosinophilia was detected at 5 years of age, at least 20% of white blood cells, and 44% at 8 years of age. At 10 years of age, she was diagnosed with anti-neutrophil cytoplasmic antibody-negative EGPA. The diagnosis was based on findings of eosinophil-infiltrating granulomatous vasculitis of the skin accompanied by notable peripheral blood eosinophilia, sinusitis, and pulmonary nodules on radiographic evaluation. Asymptomatic myocardial involvement was also detected utilizing dual perfusion and metabolic scintigraphy with 201Tl/123I-BMIPP, which was relieved by 1-year treatment of glucocorticoid combined with immunosuppressive drugs. EGPA is an extremely rare vasculitis that develops several years after preceding allergic disorders. Pediatric-onset EGPA has a poorer prognosis than adult-onset EGPA, which can be attributed to a high prevalence of cardiac involvement. Therefore, accurate diagnosis is critical for improving prognosis. EGPA should be considered when atypical findings are noted in management of atopic dermatitis and bronchial asthma.

Different responses to exercise between Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia.

Aims: Andersen-Tawil Syndrome (ATS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are both inherited arrhythmic disorders characterized by bidirectional ventricular tachycardia (VT). The aim of this study was to evaluate the diagnostic value of exercise stress tests for differentiating between ATS and CPVT. Methods and results: We included 26 ATS patients with KCNJ2 mutations from 22 families and 25 CPVT patients with RyR2 mutations from 22 families. We compared the clinical and electrocardiographic (ECG) characteristics, responses of ventricular arrhythmias (VAs) to exercise testing, and the morphology of VAs between ATS and CPVT patients. Ventricular arrhythmias were more frequently observed at baseline in ATS patients compared with CPVT patients [the ratio of ventricular premature beats (VPBs)/sinus: 0.83 ± 1.87 vs. 0.06 ± 0.30, P = 0.01]. At peak exercise, VAs were suppressed in ATS patients, whereas they were increased in CPVT patients (0.14 ± 0.40 vs. 1.94 ± 2.71, P < 0.001). Twelve-lead ECG showed that all 25 VPBs and 15 (94%) of 16 bidirectional VTs were right bundle branch block (RBBB) morphology in ATS patients, whereas 19 (86%) of 22 VPBs had left bundle branch block (LBBB), and 12 (71%) of 17 bidirectional VT had LBBB and RBBB morphologies in CPVT patients. Conclusion: In patients with ATS, VAs with RBBB morphology were frequently observed at baseline and suppressed at peak exercise. In contrast, exercise provoked VAs with mainly LBBB morphology in patients with CPVT. In adjunct to clinical and baseline ECG assessments, exercise testing might be useful for making the diagnosis of ATS vs. CPVT, both characterized by bidirectional VT.

Tissue Motion Annular Displacement of the Mitral Valve Can Be a Useful Index for the Evaluation of Left Ventricular Systolic Function by Echocardiography in Normal Children.

As the important role of longitudinal shortening in ventricular function has been well recognized over the past decade, evaluation of longitudinal systolic function of the left ventricle has become a subject of growing interest. Tissue motion annular displacement of the mitral valve (TMAD) is a new parameter of longitudinal systolic function. Although some studies have reported that this new parameter correlates with left ventricular ejection fraction (LVEF) in adults, little is known about TMAD in normal children. In this work, we investigated 94 children with no history of cardiovascular disease. TMAD was measured in the apical four-chamber view using the two-dimensional speckle tracking technique. Three points for tracking were selected in a diastolic frame: the lateral mitral valve annulus, medial mitral valve annulus, and left ventricular apex. The value was expressed as the percentage of displacement of the midpoint of the mitral valve annulus, using software to correct for left ventricular length at end-diastole. Pearson's coefficient was used to estimate the correlation between TMAD and left ventricular systolic function parameters including the biplane modified Simpson method-derived ejection fraction and global longitudinal strain (GLS). We also analyzed the correlation between TMAD and heart rate (HR), height, age, and body surface area (BSA). TMAD was found to correlate significantly with LVEF (r = 0.71, p < 0.01) and GLS (r = -0.77, p < 0.01). However, no correlation was revealed for HR (r = -0.14, p = 0.19), height (r = -0.17, p = 0.10), age (r = -0.19, p = 0.09), or BSA (r = -0.19, p = 0.08). These results indicate that TMAD is useful for assessing LVEF and longitudinal systolic function in normal children, and is not influenced by changes in HR, height, age, or BSA.

Tolerance to ischemia reperfusion injury in a congenital heart disease model.

BACKGROUND: Open heart surgery-associated ischemia/reperfusion (I/R) injury affects postoperative outcome, and a leading cause of this is lipid peroxidation. Congenital heart disease (CHD) patients, however, are less sensitive to I/R injury. Although little is known about the underlying molecular mechanisms, CHD-associated hypoxia alters the polyunsaturated fatty acid (PUFA) composition of membranes, which are the preferential targets for reactive oxygen species (ROS) generated during I/R. Here, using an animal model, we investigated the molecular mechanisms underlying I/R tolerance in CHD. METHODS: In order to reproduce I/R injury in vitro, we used a working heart perfusion model, isolated from juvenile control and CHD model rats (CHD rats), and examined the recovery of cardiac function during a period of I/R. PUFA composition of the plasma membrane was determined on gas chromatography/mass spectrometry. Oxidative stress-related cellular responses were investigated on immunoblotting, using antibodies against nuclear factor erythroid 2-related factor (Nrf-2), hemeoxygenase-1 (HO-1), and 4-hydroxy-2-hexanal (4-HHE)-modified protein. RESULTS: Ischemia/reperfusion-induced cardiac dysfunction was markedly suppressed in CHD rats, compared with the control rats. n-3/n-6 PUFA ratio was significantly increased in both the pre- and post-I/R phase in CHD rats, but not in the controls. Four-HHE-modified protein, Nrf-2, and HO-1 were significantly increased in CHD rats as well, compared with the controls. CONCLUSIONS: Following open heart surgery in CHD patients, the increased n-3/n-6 PUFA ratio may lead to the upregulation of cellular antioxidative system components through the oxidation product, 4-HHE, resulting in an increased tolerance to I/R injury.

Asymptomatic spinal arteriovenous fistula presenting only as continuous murmur.

Spinal arteriovenous fistula is extremely rare in children. Weakness and sensory disturbance in the lower extremities are the specific clinical presentations. Children, however, commonly have no subjective symptoms; in rare cases, a continuous murmur is the only physical finding. An 18-month-old boy was referred for evaluation of a continuous murmur audible at the back. He had no motor or sensory disorder; only a Levine 3/6 continuous murmur audible at the back was found. Echocardiography showed a structurally normal heart but indicated ascending continuous blood flow behind the aortic arch and dilatation of the innominate vein. We suspected spinal arteriovenous fistula, and it was visualized on computed tomography angiography. Spinal arteriovenous fistula was detected using only auscultation and echocardiography. Suspicion of this anomaly on careful auscultation and simple examination, and confirmation on detailed examination, even in the absence of motor or sensory disturbance, is important.

Combination of double aortic arch and interruption of aortic arch in pulmonary atresia with ventricular septal defect.

No reports on pulmonary atresia with ventricular septal defect with the combination of double aortic arch and interruption between left and right carotid arteries have been published so far.

A case of Fabry nephropathy with histological features of oligonephropathy.

UNLABELLED: Newborn screening studies indicate the expected high incidence of later-onset Fabry disease with silent Fabry nephropathy while, with recent improved clinical care of premature infants, children with congenital oligonephropathy caused by premature embryonal development of the kidney are thought to be increasing. However, the coexistence of Fabry nephropathy and oligonephropathy has not been reported previously. We present the case of a 13-year-old boy who was diagnosed with Fabry nephropathy accompanied with histological features of oligonephropathy. He was born as a preterm baby, and a renal biopsy was performed because of mild renal dysfunction and mild proteinuria. He had neither characteristic early symptoms nor a family history of Fabry disease. Histologic findings demonstrated diffuse global enlargement and foamy change of podocytes with markedly decreased number and enlargement of the glomeruli. Both his plasma and leukocyte α-galactosidase A (GLA) activities were markedly decreased, and the plasma globotriaosylsphingosine and urine globotriaosylceramide levels were increased. Gene analysis revealed a missense mutation, R112H, in the GLA gene, which had been reported in the later-onset phenotype of Fabry patients. He is now under treatment with enzyme replacement therapy and an angiotensin-converting enzyme inhibitor. CONCLUSION: This case indicated the possible co-occurrence of Fabry nephropathy and oligonephropathy. For early diagnosis and timely management, careful examinations for proteinuria and renal function, in addition to establishing an effective screening system for Fabry disease, will be necessary.

Modulation of C16:0-ceramide in hypertrophied immature hearts by losartan.

BACKGROUND: The angiotensin type 2 receptor plays a unique role in growth inhibition in adult myocardium via modulation of ceramide synthesis. Angiotensin type 1 (AT1 )-receptor blockade results in increased angiotensin type 2 receptor activation by angiotensin II, and AT1 -receptor blockers are sometimes prescribed to children for the treatment of cardiac hypertrophy or heart failure. We investigated the changes of ceramide lipid components in hypertrophied immature rabbit hearts after chronic administration of the AT1 -receptor blocker, losartan. METHODS: One-week-old Japanese white rabbits were randomly divided into three groups: sham-operated control rabbits (Group S), rabbits given distilled water orally for 21 days after aortic constriction (Group H), and rabbits given losartan orally for 21 days after aortic constriction (Group H + L). RESULTS: Compared with Group S, the hypertrophy index and left ventricular posterior wall thickness were significantly increased in Group H, but were not different in Group H + L. Total myocardial ceramide levels in Group H and Group H + L were suppressed compared with Group S. The relative fatty acid components of myocardial ceramide in Group H were the same as those in Group S, but Group H + L showed a significant increase in the C16 :0 component. CONCLUSIONS: The total cardiac ceramide levels are depressed by pressure overload of immature rabbit hearts. Losartan reduced the hypertrophy with selective increase of the relative amount of C16:0 -ceramide.

Changes in cerebral oxygen saturation and blood flow during hypoxic gas ventilation therapy in HLHS and CoA/IAA complex with markedly increased pulmonary blood flow.

BACKGROUND: Hypoxic gas ventilation therapy has recently been performed to prevent post-birth increased pulmonary blood flow in cases of congenital heart diseases with increased pulmonary blood flow. However, how the oxygen supply to the tissues changes during breathing a hypoxic gas mixture, remains unknown. The changes in cerebral oxygen saturation and blood supply during hypoxic gas ventilation therapy using a nitrogen gas mixture were studied. METHODS AND RESULTS: Cerebral regional oxygen saturation (cerebral rSO(2)) was measured by near-infrared spectroscopy, and changes in middle cerebral artery (MCA) blood flow and an index of vascular resistance (RI) were assessed in 8 consecutive patients having congenital heart diseases with increased pulmonary blood flow. In all patients, urinary volume increased significantly, and the respiratory rate showed a clear decrease. Percutaneous oxygen saturation showed no significant change. The average of cerebral rSO(2) was 67.3% before hypoxic gas ventilation, but increased to 69.4%, 69.1%, and 70.7% within 1, 12, and 24 h after initiation of treatment, respectively. MCA blood flow significantly increased in the diastolic phase, and RI significantly improved from 0.80 to 0.68 within 12 h after initiation of therapy. CONCLUSIONS: These results indicate that hypoxic gas ventilation therapy does not decrease cerebral oxygen saturation, but safely improves the cerebral blood supply in cases of congenital heart diseases with increased pulmonary blood flow.

Matrix metalloproteinase-9 in vascular lesions and endothelial regulation in Kawasaki disease.

BACKGROUND: Matrix metalloproteinases (MMPs) contribute to extracellular remodeling in Kawasaki disease (KD). MMP-9 is an essential vasculature-remodeling factor but its role in the vascular lesions of KD is not understood. This study focused on MMP-9 regulation via cytokines in endothelial cells (ECs). METHODS AND RESULTS: Plasma and peripheral blood mononuclear cells were obtained from 30 KD patients, and 15 non-febrile and 25 febrile children. Plasma MMP-1, -2, -9, and tissue inhibitor of MMP (TIMP)-1 and -2 were measured by 2-step sandwich ELISA. Immunohistology was performed on coronary arterial lesions (CAL) from a patient who died of KD in the acute phase. MMP-9 mRNA expression in human umbilical ECs (HUVECs) treated with plasma or cytokines, and in mononuclear cells was measured by semi-quantitative reverse transcription-polymerase chain reaction. Plasma MMP-1, -2 and TIMP-2 levels were normal for KD. Plasma MMP-9 and TIMP-1 levels increased during the acute phase of the disease (P<0.001 vs each control). MMP-9 stained diffusely in CAL. MMP-9 mRNA levels were higher in HUVECs treated with plasma in the acute and convalescent phases. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha stimulated MMP-9 expression, whereas interferon (IFN)-gamma suppressed it. There was no MMP-9 mRNA elevation in mononuclear cells. CONCLUSIONS: ECs are a source of MMP-9 in the vascular lesions of KD. MMP-9 is regulated by cytokines IL-1beta, IL-6, TNF-alpha and IFN-gamma.

Kidney injury biomarkers after cardiac angiography in children with congenital heart disease.

OBJECTIVE: This study aims to investigate the changes in renal function and levels of urinary biomarkers before and after cardiac angiography in children with congenital heart disease (CHD). SETTING: Children with CHD are at a risk for kidney injury during contrast exposure in cardiac angiography. OUTCOME MEASURES: We measured urinary protein, albumin, N-acetyl-ß-D-glucosaminidase (NAG), ß2-microglobulin (BMG), and liver-type fatty acid-binding protein (L-FABP) levels, as well as serum creatinine and cystatin C levels, before and after cardiac angiography in 33 children with CHD. RESULTS: No significant decrease was noted in either the creatinine-based or cystatin C-based estimated glomerular filtration rate at 24 hours after angiography compared with that before angiography. Urinary protein, NAG, BMG, and L-FABP levels were significantly increased at 24 hours after angiography, all of which returned to baseline levels at more than 7 days after angiography. An increase in urinary level of protein, albumin, NAG, or BMG was mostly associated with increased urinary L-FABP level. An increase in both urinary BMG and L-FABP, but not that in urinary L-FABP alone, was associated with increased levels of urinary protein and NAG, as well as the greater dose of contrast media. CONCLUSIONS: Transient increases of kidney injury biomarkers following cardiac angiography are not necessarily associated with the impairment of renal function in a short time period; however, the increase in urinary protein, albumin, NAG, or BMG level may indicate greater stresses to the kidneys than the increase in urinary L-FABP alone in children with CHD.

Patient safety education using an arts and health approach in Japanese university hospitals: a pilot study.

BACKGROUND: Recently, arts and health activities have been introduced into health care, and evidence of their effectiveness has been accumulating. However, few studies have examined this subject in Japan. METHODS: In this practice-based report, faculty of a Japanese school of medicine and a university of arts and design collaborated to explore the effectiveness of an arts and health approach in three different patient safety educational programs implemented in different university hospitals in Japan. RESULTS: The results of the programs demonstrated the effectiveness of integrating arts and health into patient safety management. CONCLUSIONS: Additional research is required to understand this further.

High incidence of GalNAc disialosyl lactotetraosylceramide in metastatic renal cell carcinoma.

BACKGROUND: In renal cell carcinoma (RCC), glycosphingolipids monosialosyl globopentaosylceramide (MSGb5) and GalNAc disialosyl lactotetraosylceramide (GaINAcDSLc4) were shown to be predictors of metastasis. Here we extended the research using a larger cohort of patients with a longer follow-up period, and reevaluate their relationship to malignant potential, metastasis and prognosis in patients with RCC. PATIENTS AND METHODS: MSGb5 and GalNAcDSLc4 were examined in 114 primary RCCs by immunohistochemical method on cryostat sections. RESULTS: GalNAcDSLc4 was detected in 13.2% of RCCs and was associated with a significantly higher incidence of metastasis at the time of primary visit (60.0% vs. 31.3%, p=0.0419) as well as de novo metastasis during followup (33.3% vs. 14.7%), and a shorter survival (p=0.0399). MSGb5 was detected in 51.8% of tumors and was not related to clinocopathological characteristics or survival. CONCLUSION: RCC patients with tumors positive for GalNAcDSLc4 are at higher risk of metastasis at the time of diagnosis and during follow-up.

Influence of Geometric Changes in the Thoracic Aorta due to Arterial Switch Operations on the Wall Shear Stress Distribution.

BACKGROUND: The transposition of the great arteries (TGA) is one of the most severe congenital heart diseases. The arterial switch operation (ASO) is the preferred procedure to treat TGA. Although numerous reports have shown good results after ASOs, some patients suffer from circulatory system problems following the procedure. One reason for problems post-ASO is the local changes in the curvature and torsion of the thoracic aorta. OBJECTIVE: The influence of these geometric changes on the blood flow field needs to be investigated in detail to consider possible cardiovascular problems after an ASO. METHOD: In this study, we conduct blood flow simulations in the thoracic aorta post-ASO, evaluate geometric changes in the aorta due to the ASO in terms of curvature and torsion, and consider the effect of geometric changes on blood flow in the aorta. RESULTS: It was found that a large curvature near the aortic root causes an increase in the maximal wall shear stress value in the middle systole. Moreover, a large torsion results in a circumferential change in the maximal wall shear stress region. It was also found that the maximal wall shear stress in the post-ASO models is significantly higher than that in the normal models. This indicates that the aortic aneurysm initiation risk for a post-ASO artery may be higher than that of a normal artery. CONCLUSION: To reduce the risk of initiating an aneurism, it is suggested that the curvature near the aortic root should be decreased during the ASO.

Efficacy and safety of tolvaptan for pediatric patients with congestive heart failure. Multicenter survey in the working group of the Japanese Society of PEdiatric Circulation and Hemodynamics (J-SPECH).

BACKGROUND: Tolvaptan, a vasopressin V2-receptor antagonist, has been reported to improve congestion in adult patients with heart failure. However, it has not been fully clarified whether tolvaptan is also effective and safe for pediatric patients as well as adult. METHODS: This trial was a multicenter, retrospective, observational study, and was led by the Japanese Society of PEdiatric Circulation and Hemodynamics (J-SPECH). Thirty-four pediatric patients who received tolvaptan to treat congestive heart failure were enrolled in this study. RESULTS: An increment in the urinary volume and decrease in the body weight from baseline were significant at day 1 (+106.7 ± 241.5%, p = 0.008 and -2.30 ± 4.17%, p = 0.01), day 3 (+113.5 ± 261.9%, p = 0.02 and -2.30 ± 4.17%, p = 0.01), week 1 (+56.3 ± 163.5%, p = 0.01 and -1.55 ± 4.09%, p = 0.03) and month 1 (+91.1 ± 171.6%, p = 0.01 and -2.95 ± 5.98, p = 0.03). The significant predictive factors in responders, who was defined as patients who achieved an increase in the urinary volume at day 1, were older age (p = 0.03), larger body weight before exacerbation (p = 0.04), higher weight at one day before the first administration of tolvaptan (p = 0.03), higher aspartate aminotransferase levels (p = 0.03) and higher urinary osmolality levels (p = 0.03). A logistic regression analysis showed that the urinary osmolality was the only significant predictive factor for responders to tolvaptan. Adverse drug reactions were observed in 7 patients (20.6%). Six patients had thirst and a dry month, and 1 had a mild increase in the alanine aminotransferase and aspartate aminotransferase. CONCLUSION: Tolvaptan can be effectively and safely administered in pediatric patients. Because the kidneys in neonates and infants are resistant to arginine vasopressin, the efficacy of tolvaptan may be less effective compared to older children.

[Persistent müllerian duct Syndrome in brothers].

Persistent Müllerian duct syndrome is associated with cryptorchidism and transverse testicular ectopia. Such gonads are at an increased risk of malignant transformation. Furthermore, most patients have azoospermia. Here in we report about two brothers with persistent Müllerian duct syndrome. The diagnosis was made during surgical operation for testicular cancer in younger brother. In the other one, persistent Müllerian duct syndrome was diagnosed during examination for infertility.

A pilot study of Bifidobacterium breve in neonates undergoing surgery for congenital heart disease.

BACKGROUND: Probiotics have currently been widely used in patients undergoing various types of surgeries and improved their clinical outcomes, while data in pediatric cardiac surgery have been lacking. We investigated the safety and effects on the intestinal microbiota of the probiotic Bifidobacterium breve in neonates undergoing surgery for congenital heart disease. METHODS: This pilot, randomized study was performed in a single-center, university hospital-based pediatric intensive care unit (PICU). Twenty-one neonates undergoing surgery for congenital heart disease at >7 days after birth were randomly allocated to two groups: group A received 3 × 10(9) colony-forming units (CFU)/day of enteral B. breve strain Yakult (BBG-01), which was started 1 week before and terminated 1 week after surgery (n = 10), and group B did not receive BBG-01 (n = 11). RESULTS: The characteristics of the patients were similar in both groups. The postoperative days until fulfillment of the criteria for discharge from the PICU tended to be fewer in group A (8 [7-8] days) than in group B (9 [8-14] days) (p = 0.10). Likewise, the postoperative days to enteral nutrition or achievement of caloric goal tended to be fewer in group A than in group B. The Bifidobacterium in fecal samples after initiating BBG-01 in group A were significantly higher in number than that in group B. Enterobacteriaceae were significantly fewer in group A than in group B immediately (7.0 [3.9-7.7] vs. 8.5 [8.0-9.1] log10 cells/g) and 1 week (7.7 [7.0-8.1] vs. 9.3 [8.6-9.5] log10 cells/g) after surgery (p < 0.05 for both comparisons). The number of Pseudomonas after 1 week was significantly lower in group A than in group B (p = 0.04). The concentrations of total organic and acetic acids were also significantly higher in group A than in group B. The postoperative course was uncomplicated and all neonates were discharged alive from the PICU. CONCLUSIONS: The perioperative administration of a probiotic to neonates undergoing surgery for congenital heart disease was safe and significantly improved their intestinal environment. The positive effects of this treatment on clinically significant outcomes remain to be investigated.

Noninvasive estimation of central venous pressure after Fontan procedure using biochemical markers and abdominal echography.

OBJECTIVES: Patients may develop liver dysfunction, including liver fibrosis, over the long term following Fontan procedure. Therefore, early detection of liver dysfunction is essential to identify those patients who are at risk. We evaluated various laboratory parameters, including liver biochemical markers, hepatic echography findings, and cardiac catheterization outcomes, at an early stage after undergoing Fontan procedure. METHODS: A total of 56 patients who underwent Fontan procedure were included in the study. All patients underwent cardiac catheterization and biochemical markers were evaluated from the samples. Abdominal echography was performed on a subgroup of patients (n = 20) to observe the structure of liver tissues and to measure blood flow in the hepatic vein, portal vein, and hepatic artery. RESULTS: The mean period of time since Fontan procedure was 2.8 ± 2.1 years. There was a significant correlation between venous pressure and serum levels of γ-glutamyltranspeptidase and type IV collagen 7s domain, which indicated a high probability of liver consolidation. The other biochemical markers were normal. Stepwise regression analyses suggested that by using the ratio of hepatic venous flow and type IV collagen 7s collagen domain concentration, inferior vena cava pressure can be predicted. CONCLUSIONS: Our study showed that we can predict inferior vena cava pressure using noninvasive abdominal echography and biochemical markers at an early stage after Fontan procedure.