G0S2 regulates innate immunity in Kawasaki disease via lncRNA HSD11B1-AS1.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis that is currently the most common cause of acquired heart disease in children. However, its etiology remains unknown. Long non-coding RNAs (lncRNAs) contribute to the pathophysiology of various diseases. Few studies have reported the role of lncRNAs in KD inflammation; thus, we investigated the role of lncRNA in KD inflammation. METHODS: A total of 50 patients with KD (median age, 19 months; 29 males and 21 females) were enrolled. We conducted cap analysis gene expression sequencing to determine differentially expressed genes in monocytes of the peripheral blood of the subjects. RESULTS: About 21 candidate lncRNA transcripts were identified. The analyses of transcriptome and gene ontology revealed that the immune system was involved in KD. Among these genes, G0/G1 switch gene 2 (G0S2) and its antisense lncRNA, HSD11B1-AS1, were upregulated during the acute phase of KD (P < 0.0001 and <0.0001, respectively). Moreover, G0S2 increased when lipopolysaccharides induced inflammation in THP-1 monocytes, and silencing of G0S2 suppressed the expression of HSD11B1-AS1 and tumor necrosis factor-α. CONCLUSIONS: This study uncovered the crucial role of lncRNAs in innate immunity in acute KD. LncRNA may be a novel target for the diagnosis of KD. IMPACT: This study revealed the whole aspect of the gene expression profile of monocytes of patients with Kawasaki disease (KD) using cap analysis gene expression sequencing and identified KD-specific molecules: G0/G1 switch gene 2 (G0S2) and long non-coding RNA (lncRNA) HSD11B1-AS1. We demonstrated that G0S2 and its antisense HSD11B1-AS1 were associated with inflammation of innate immunity in KD. lncRNA may be a novel key target for the diagnosis of patients with KD.

Indicators of unresponsiveness after initial i.v. immunoglobulin treatment in acute Kawasaki disease.

BACKGROUND: The aim of this study was to identify the indicators of unresponsiveness to initial i.v. immunoglobulin (IVIG) treatment for Kawasaki disease (KD). METHODS: One hundred and forty-five patients with KD, who had received initial treatment consisting of a single IVIG dose (1 g/kg or 2 g/kg) and oral aspirin (30 mg/kg), were studied. Laboratory parameters, including C-reactive protein (CRP) and serum sodium (Na), were measured before and after IVIG treatment, and during the convalescent phase, and the laboratory data compared with regards to IVIG response. Multiple logistic regression models, which included laboratory data obtained immediately after the IVIG treatment, were constructed to determine the indicators of IVIG unresponsiveness immediately after the completion of the initial treatment. RESULTS: On logistic regression analysis, serum Na after IVIG treatment was the only independent factor related to initial IVIG unresponsiveness (ß = 0.53, P < 0.01; OR, 1.69; 95%CI: 1.15-2.49). On receiver operating characteristic curve analysis, the optimal serum Na cut-off immediately after IVIG treatment was 135.5 mEq/L with a sensitivity of 0.75, and a specificity of 0.79. CONCLUSIONS: Prolonged hyponatremia after completion of the initial IVIG therapy was an indicator of the need for subsequent IVIG therapy. Treatment plans should be established for patients with acute KD that pay particular attention to prolonged hyponatremia.

Evaluation of longitudinal and radial left ventricular functions on 2-D and 3-D echocardiography before and after intravenous immunoglobulin in acute Kawasaki disease.

BACKGROUND: The relationship between left ventricular (LV) function and longitudinal or radial contraction has not yet been elucidated in acute Kawasaki disease (KD), especially before and after treatment with intravenous immunoglobulin (IVIG). METHODS: We studied 28 KD patients without coronary aneurysms (average age, 3.2 years). The LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), and ejection fraction (LVEF) were assessed on 3-D echocardiography before IVIG, after IVIG, and in the convalescent phase. LV fractional shortening (LVFS) and the mitral annular plane systolic excursion (MAPSE) z-score were measured as surrogates for radial and longitudinal LV wall motions, respectively. Serum brain natriuretic peptide (BNP) was also assessed as a heart failure indicator in acute KD patients. RESULTS: In all KD patients, LVEDV decreased in the acute phase with preservation of LVESV. Both LVSV and MAPSE z-score were lowest before IVIG and increased after IVIG. MAPSE z-score was highly correlated with LVEF before and after IVIG treatment. Although there was a good correlation between logBNP and LVEF before IVIG, it was lost after IVIG. CONCLUSIONS: LVEDV decreased longitudinally during the acute phase of KD with preservation of LVESV, reducing both LVSV and LVEF. Serum BNP is a useful marker for evaluating LV function only prior to IVIG treatment.

Z-score of Mitral Annular Plane Systolic Excursion is a Useful Indicator of Evaluation of Left Ventricular Function in Patients with Acute-Phase Kawasaki Disease.

We previously reported the clinical usefulness of the mitral annular plane systolic excursion (MAPSE) to evaluate the left ventricular (LV) function in patients with Kawasaki disease (KD) in the acute-phase. However, the feasibility of the MAPSE z-score has not been evaluated in patients with acute KD. We prospectively studied 60 KD patients without coronary aneurysms. The MAPSE z-scores were calculated using our standard MAPSE data. Brain natriuretic peptide (BNP) was measured as a parameter of LV function. In total, 281 healthy age- and body size-matched subjects were chosen as the control group. The MAPSE z-score decreased in the acute-phase (median value, -1.4) and increased in the convalescent phase (median value, 0.18; P < 0.0001). However, there was no significant difference in the MAPSE z-score between patients in the convalescent phase and the control patients (0.18 vs. 0.02, P = 0.199). Multivariate regression analysis revealed that BNP was an independent predictor of the MAPSE z-score (ß = 0.40, P < 0.005). According to the receiver operating characteristic (ROC) analysis, the optimal cutoff value for the MAPSE z-score to judge LV dysfunction was -0.9. The MAPSE z-score is a useful index to evaluate LV function, and the cutoff value of -0.9 can be an indicator to judge LV dysfunction in the patients with acute-phase KD.

Geometry-Related Right Ventricular Systolic Function Assessed by Longitudinal and Radial Right Ventricular Contractions.

The aim of our study was to evaluate the geometry-related right ventricular (RV) systolic function under normal hemodynamics by assessing the longitudinal and the radial RV contractions in children. We examined 953 healthy children. We measured tricuspid annular plane systolic excursion (TAPSE), RV anterior wall displacement from the interventricular septum (RVWD), and RV to left ventricular diameter ratio (RV/LV ratio) using M-mode echocardiography. The z-values were calculated as geometrical parameters of the TAPSE (z-TAPSE), the RVWD (z-RVWD), and the RV/LV ratio (z-RV/LV). The RV stroke volume (RVSV) was measured using Doppler echocardiography and standardized using the z-value (z-RVSV). The z-TAPSE was no or weakly negatively correlated with both the z-RVWD (r = -0.18, P < 0.0001) and the z-RV/LV (r = -0.12, P < 0.0001). In contrast, the z-RV/LV correlated positively with the z-RVWD (r = 0.61, P < 0.0001). The z-RVSV correlated only with the z-TAPSE (r = 0.30, P < 0.0001). Although the radial RV motion increases with the progression of RV dilatation, the RVSV is not associated with radial RV motion. In contrast, the RVSV relates to the longitudinal RV motion independently of the radial RV motion under the normal physiological condition. We presume that the RV contraction patterns change related to the RV geometry under various hemodynamic conditions.

Z-Value of Mitral Annular Plane Systolic Excursion Is a Useful Indicator to Predict Left Ventricular Stroke Volume in Children: Comparing Longitudinal and Radial Contractions.

BACKGROUND: The purpose of our study was to explore the pumping mechanism of the left ventricle (LV) and to examine the role of longitudinal LV contraction in LV stroke volume (LVSV) compared to a radial LV contraction. METHODS AND RESULTS: We examined 890 consecutive children without structural heart disease including 395 patients with a history of Kawasaki disease (KD). We measured the mitral annular plane systolic excursion (MAPSE), the LV end-diastolic and end-systolic dimension (LVDd), the LV radial wall displacement (LVRWD) and the LV stroke volume (LVSV). The LVSV was determined by the Doppler method. The z-values of MAPSE, LVDd, LVRWD and LVSV were calculated by the mean values and standard deviations (SDs) based upon BSA every 0.1 m(2) . We evaluated the relationship between the z-LVSV and the geometrical factors. The z-value of the MAPSE was the most powerful determinant for the z-values of the LVSV of all of the geometrical factors (ß = 0.36, P < 0.0001). However, the z-values of the LVRWD did not contribute to those of the LVSV. CONCLUSIONS: The longitudinal LV contraction contributes more to the LVSV than the radial LV contraction, even in subjects without heart failure. Evaluation of longitudinal LV contraction using the MAPSE z-value is useful for assessing global LV function in children with various body sizes.

Right to Left Ventricular Diameter Ratio ≥0.42 is the Warning Flag for Suspecting Atrial Septal Defect in Preschool Children: Age- and Body Surface Area-Related Reference Values Determined by M-Mode Echocardiography.

It is not always easy to observe and screen atrial septal defects (ASD) using echocardiography. In addition, there are no established echocardiographic reference indices for screening patients with ASDs. We retrospectively reviewed our database and recruited 151 isolated ASD patients and 2769 healthy subjects. In total, 307 echocardiographic studies were performed for ASD patients. Surgical repairs were done in 75 of the ASD patients. The ratio of right to left ventricular end-diastolic dimensions (RVD/LVD), which was determined by M-mode echocardiography, was used as an index of RV dilatation. After obtaining age- and body surface area (BSA)-related RVD/LVD nomograms in healthy subjects, we calculated the z-scores of RVD/LVD for all subjects and obtained the optimal cut-off values to differentiate patients with ASD from healthy subjects. The optimal cut-off values were high in neonates and gradually decreased with an increase in the age and BSA, but were almost constant in children aged >4 years or whose BSA was >0.65 m(2). The cut-off values of RVD/LVD for suspected ASD were ≥0.42 in children aged >4 years or those whose BSA was >0.65 m(2). Those for an ASD operation were ≥0.46 in those whose BSA > 0.65 m(2). The RVD/LVD determined by M-mode echocardiography is a useful index to evaluate RV dilatation in patients with ASDs. The RVD/LVD ≥ 0.42 is the warning flag for suspecting ASD in preschool children and that ≥0.46 may be a clinical important sign to determine ASD operation.

Adult classical glioblastoma with a BRAF V600E mutation.

The B-Raf proto-oncogene serine/threonine kinase (B-Raf) is a member of the Raf kinase family. The BRAF V600E mutation occurs frequently in certain brain tumors such as pleomorphic xanthoastrocytoma, ganglioglioma, and pilocytic astrocytoma, and less frequently in epithelioid and giant cell glioblastoma. BRAF V600E mutation in these cases has been canonically detected using Sanger sequencing or immunohistochemistry but not with next-generation sequencing (NGS). Moreover, to our knowledge, there is no detailed report of the BRAF V600E mutation in an adult glioblastoma with classical histologic features (c-GBM). Therefore, we performed NGS analysis to determine the mutational status of BRAF of 13 glioblastomas (GBMs) (11 primary and 2 secondary cases) and detected one tumor harboring the BRAF V600E mutation. We report here the detection of the BRAF V600E mutation in a patient with c-GBM and describe the patient's clinical course as well as the results of histopathological analysis.

Z-values of tricuspid annular plane systolic excursion in Japanese children.

BACKGROUND: The aim of this study was to establish growth-related standard values and z-values for tricuspid annular plane systolic excursion (TAPSE) for Japanese children. METHOD: We examined 953 consecutive healthy children and adolescents, ranging from newborn to 22.7 years of age (mean age, 4.4 ± 4.0 years). TAPSE was measured as the longitudinal tricuspid valve annular motion from the apex on M-mode echocardiography. The right ventricular (RV) stroke volume (RVSV) divided by the body surface area (RVSV/BSA) was used as an independent indicator of body size. RVSV was determined from the recordings of the ejection blood flow velocity and the diameter at the level of the pulmonary orifice in the RV outflow tract. RESULTS: TAPSE had positive correlations with age and BSA, ranging from 6.0 to 31.4 mm (mean, 19.1 ± 4.4 mm). The z-values ranged from -3.63 to 3.17. There was no significant difference in TAPSE between the genders (male, 19.0 ± 4.6 mm; female, 19.1 ± 4.2 mm). The z-values positively correlated with RVSV/BSA. CONCLUSIONS: Growth-related normal TAPSE was studied in healthy Japanese children to obtain the TAPSE z-value. TAPSE z-value is one of the parameters that can be used to assess RV systolic function independent of body size.

Impairment of Left Ventricular Longitudinal Contraction is Associated with Serum Brain Natriuretic Peptide Concentration in Patients with Acute-Phase Kawasaki Disease.

It is well known that brain natriuretic peptide (BNP) is elevated in the acute phase of Kawasaki disease (KD). We hypothesized that mitral annular plane systolic excursion (MAPSE) could identify LV dysfunction in the acute phase of KD. Fifty patients with KD were enrolled in this study. BNP sampling and an echocardiographic study were performed just before and after intravenous immunoglobulin administration. MAPSE was measured in M-mode in the apical four-chamber view. The %MAPSE was calculated as the MAPSE measured in the acute phase divided by that measured in the convalescent phase. We compared the acute and the convalescent phases of KD. The values of the MAPSE were significantly reduced (45 out of 50 patients) during the acute phase and immediately recovered in the convalescent phase (10.0 ± 1.9 vs. 12.7 ± 1.9 mm, P < 0.0001). Of the parameters tested, %MAPSE was the only echocardiographic parameter that was associated with Log-BNP. Additionally, %MAPSE had a significant negative correlation with Log-BNP (r = -0.45, P < 0.0039). Longitudinal LV contraction is impaired in the acute phase of KD, but it immediately recovers in the convalescent phase. Measuring the longitudinal LV contractility should be essential for evaluating LV function in the acute phase of KD, and MAPSE is useful for this evaluation.

Evaluation of right ventricular function using single-beat three-dimensional echocardiography in neonate.

Aim of our study was to evaluate right ventricular (RV) systolic function in neonate using newly developed single-beat three-dimensional echocardiography (sb3DE). We enrolled 15 healthy or premature neonates (0-53 days after birth). We scanned one beat full volume using Siemens ACUSON SC2000 (Siemens AG) echocardiography with 4Z1c full-volume transducer without ECG gating. RV end-diastolic volume (RVEDV) and RV end-systolic volume (RVESV) were computed with special software dedicated to analysis for RV volume. RV ejection fraction (RVEF) and RV stroke volume (3D-RVSV) were calculated. And RV stroke volume was also determined from the recordings of ejection blood flow velocity and diameter at the level of the pulmonary orifice in RV outflow tract (Doppler-RVSV). Tricuspid annular plane systolic excursion (TAPSE) was also measured by 2D echocardiography. RVEDV ranged from 5.1 to 10.7 ml (average 7.5 ml), RVESV ranged from 2.3 to 5.8 ml (average 3.9 ml). There was a good correlation between 3D-RVSV and Doppler-RVSV (r = 0.77). Bland-Altman plot revealed that 3D-RVSV became underestimation of an average of 1.78 ml compared to Doppler-RVSV. And TAPSE positively correlated with 3D-RVEF (r = 0.58, P = 0.038). Newly developed sb3DE enables us to perform three-dimensional acquisition of RV volume without ECG gating even in neonate. However, 3D-RVSV currently tends to be underestimated in neonatal measurement.

Alternation of right ventricular contraction pattern in healthy children-shift from radial to longitudinal direction at approximately 15 mm of tricuspid annular plane systolic excursion.

BACKGROUND: Many studies have investigated tricuspid annular plane systolic excursion (TAPSE) as a longitudinal right ventricular (RV) contraction. The aim of this study was to clarify the mechanism of RV systolic function compared with longitudinal and radial RV contractions in healthy children. METHODS AND RESULTS: A total of 815 consecutive healthy children and adolescents were enrolled. We measured TAPSE on M-mode echocardiography as a longitudinal RV contraction. RV wall displacement (RVWD) toward the center of the left ventricle (LV) was measured in the short-axis view on M-mode echocardiography. RV stroke volume (RVSV) was obtained using pulse Doppler echocardiography as an indicator of RV global systolic function. RVSV and TAPSE had a positive but non-linear correlation with a definite inflection point around 15 mm of TAPSE. Subjects were stratified into 2 groups according to TAPSE (≤ 15 mm or >15 mm). In subjects with TAPSE ≤ 15 mm, RVWD and TAPSE were identified as independent predictors of RVSV. In contrast, in subjects with TAPSE >15 mm, TAPSE were identified as an independent predictor of RVSV. CONCLUSIONS: Normal RV contraction pattern shifts from radial to longitudinal directions at approximately 15 mm of TAPSE. RVSV is primarily generated by longitudinal contraction, but in neonates, RVSV is supported not only by longitudinal contraction but also by radial contraction.

Quantitative imaging of spontaneous neuromagnetic activity for assessing cerebral ischemia using sLORETA-qm.

To image cerebral neural activity in ischemic areas, we proposed a novel technique to analyze spontaneous neuromagnetic fields based on standardized low-resolution brain electromagnetic tomography modified for a quantifiable method (sLORETA-qm). Using a 160-channel whole-head-type magnetoencephalographic system, cerebral magnetic fields were obtained pre- and postoperatively from 5 patients with unilateral internal carotid artery occlusive disease and 16 age-matched healthy volunteers. For quantitative imaging, voxel-based time-averaged intensities of slow waves in 4 frequency bands (0.3-2 Hz, 2-4 Hz, 4-6 Hz and 6-8 Hz) were obtained by the proposed technique based on sLORETA-qm. Positron emission tomography with (15)O gas inhalation ((15)O-PET) was also performed in these patients to evaluate cerebral blood flow and metabolism. In all 5 patients, slow waves in every frequency band were distributed in the area of cerebrovascular insufficiency, as confirmed by (15)O-PET preoperatively. In 4 patients, slow-wave intensities in theta bands (4-6 Hz, 6-8 Hz) decreased postoperatively along with improvements in cerebral blood flow and metabolism, whereas delta bands (0.3-2 Hz, 2-4 Hz) showed no significant differences between pre- and postoperatively. One patient with deterioration of cerebral infarction after surgery showed marked increases in slow-wave intensities in delta bands (0.3-2 Hz, 2-4 Hz) postoperatively, with distribution close to the infarct region. The proposed quantitative imaging of spontaneous neuromagnetic fields enabled clear visualization and alternations of cerebral neural conditions in the ischemic area. This technique may offer a novel, non-invasive method for identifying cerebral ischemia, although further studies in a larger number of patients are warranted.

A case of central nervous system lymphomatoid granulomatosis; characteristics of PET imaging and pathological findings.

Lymphomatoid granulomatosis (LYG) in the central nervous system (CNS) is an uncommon lymphoproliferative disorder with low grade malignant potential. Here we report a case of CNS-LYG, in particular, its characteristics of radioisotope imaging and pathological findings. A 65-year-old man complained of visual disturbance and homonymous hemianopsia was designated. CT and MRI revealed an edematous, enhanced irregular and nodular lesion in the right occipital and parietal lobes. Although 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan showed low uptake in the lesion, Methionine (MET)-PET scan indicated high uptake. Proton magnetic resonance spectroscopy ((1)H-MRS) at 3T revealed a decrease of the peak of the N-acetylaspartate (NAA), suggesting a possible neoplastic lesion. The patient was diagnosed with CNS-LYG based on the surgically removed material showing perivascular infiltration of CD3-positive small T-lymphocytes with granulomatous lesions. The post-operative steroid therapy was effective and the recurrence or exacerbation has not been observed by radiological imaging until now.

Prediction of seizure outcome following epilepsy surgery: asymmetry of thalamic glucose metabolism and cerebral neural activity in temporal lobe epilepsy.

OBJECTIVE: The objective of this retrospective study is to analyze whether preoperative functional imaging studies using FDG-PET and MEG enable prediction of postoperative seizure outcomes. METHODS: Thirty-six patients with intractable temporal lobe epilepsy were studied. Asymmetry index of tCMRgluc (PET-AI) and the equivalent current dipole intensity of first response of SEF (SEF-AI) were determined preoperatively using (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and magnetoencephalography (MEG), respectively. Seizure outcomes were evaluated according to the classification proposed by the International League Against Epilepsy (ILAE) at least 24 months after resection of epileptic focuses. Twelve healthy volunteers were included in this study to determine the normal value. RESULTS: Quantitative analysis revealed mean PET-AI in the patients was 5.4+/-5.2% (significantly different from normal controls); mean SEF-AI was 25.2+/-20.6% (not significantly different). PET-AI was positive (indicative of epileptic focus) in 29 of 36 patients (80.6%), while SEF-AI was positive in 17 of 36 patients (47.2%). Although no significant correlation between PET-AI and SEF-AI was noted (r=0.43), concordant asymmetry in both PET-AI and SEF-AI was significantly associated with better seizure outcome than discordant or paradoxical asymmetry of both factors (p<0.01). CONCLUSIONS: The results suggest that quantitative analysis of tCMRgluc with SEF may be helpful in characterizing the preoperative epileptogenic condition and predicting postoperative seizure outcome in patients with temporal lobe epilepsy, although a constellation of developmental brain abnormalities and environmental factors that together produce epilepsy need to be further explored.