Time course of peripheral immunophenotypes of multisystem inflammatory syndrome in children.

The etiology of multiple inflammatory syndrome in children (MIS-C) remains poorly understood. As clues to elucidate the pathogenic condition, several characteristic peripheral immunophenotypes have been reported in MIS-C. However, no report has demonstrated the time course of the peripheral immunophenotype along with the clinical course in the same patient. Herein, we clarified the immunological characteristics of a Japanese patient with MIS-C. There was an initial cytokine storm followed by T-cell activation, especially of CD8+ T cells, with the expansion of T-cell receptor Vß 21.3-expressing cells, which suggests superantigen-mediated T-cell activation. In addition, we also found an increase in IgG-producing cells (plasmablasts and switched memory B cells), which were accompanied by elevated serum levels of anti-SARS-CoV-2 spike antigen-specific IgG antibodies. These time course of peripheral immunophenotypes support that immunological activation against SARS-CoV-2 spike protein plays a central role in the etiology of MIS-C.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Abdominal aortic thrombus formation in a neonate with an interrupted aortic arch.

We note the risk of paradoxical embolism in patients with congenital heart defects with a right-to-left shunt. These patients should be managed to ensure that abdominal aortic thrombi are not overlooked when their clinical conditions change.

Successful trans-maternal nadolol pharmacotherapy in a fetus presenting with long QT syndrome type 2 complicated by torsade de pointes.

Fetuses with congenital long QT syndrome (LQTS) may experience life-threatening arrhythmias, such as torsade de pointes (TdP), and/or functional atrioventricular block. However, trans-maternal pharmacotherapy for these cases is rarely reported and management practices have yet to be established. The fetus of a mother with genetically-confirmed LQTS type 2 (LQT2) presented with complex arrhythmias, diagnosed via magnetocardiography as ventricular arrhythmias (including TdP), at 28 weeks of gestation. After initiation of trans-maternal nadolol administration at 15 mg/d initial dosage and 30 mg/d subsequent dosage, the frequency of fetal ventricular arrhythmias decreased and almost disappeared within several days. The mother gave birth to the baby at full term without significant complications in either the mother or fetus. This is the first report that demonstrates the efficacy and safety of trans-maternal administration of nadolol for treatment of symptomatic LQT2 fetuses with TdP. .

An autopsy case of acute myocarditis with unique lymph node findings characterized by the proliferation of reactive plasmablasts.

We report an autopsy case of acute myocarditis, in which the mediastinal lymph nodes exhibited unique findings. A 15-year-old Japanese boy was diagnosed with the secondary onset of acute myocarditis. No viruses were identified. Autopsy confirmed acute lymphocytic myocarditis. Lymphadenopathy was observed, especially in pulmonary hilar/mediastinal areas. Microscopically, interfollicular areas were uniformly filled with medium-sized, round cells that resembled lymphocytes. They were immunohistochemically CD3- CD5- CD19+ CD20- CD79a- Pax-5- CD138+ MUM1+ LMP1- EBNA2- cytoplasmic IgG+ IgA- and IgM-. No monotypia was observed for kappa and lambda light chains, and multiplex polymerase chain reaction analyses of immunoglobulin heavy chain variable region diversity demonstrated oligoclonal peaks, suggesting reactive change. IgG+ or VS38c+ cells frequently co-expressed Ki-67 (up to 80%). We considered these cells abundantly present in lymph nodes to be reactive plasmablasts because they were early plasma cells with proliferative activity.

How to Safely Prevent Venous Thromboembolism in Severe Trauma Patients.

Venous thromboembolism (VTE) is a life-threatening complication after trauma. Several studies have reported VTE prophylaxis using low-molecular-weight heparin; however, there is no consensus for prophylaxis after trauma. This study aimed to assess the efficacy and safety of our new anticoagulation therapy protocol using unfractionated heparin (UFH) plus intermittent pneumatic compression (IPC) to prevent post-traumatic VTE in high-risk trauma patients.This study enrolled 70 trauma patients who were admitted to the emergency medical center of Nagasaki University Hospital and had Risk Assessment Profile (RAP) scores ≥ 5. After stopping bleeding at the trauma site, all patients received intravenous UFH (10,000 U/day) plus IPC, which was continued for 14 days or until the patients could walk. On days 7 and 14, all patients underwent lower extremity sonography for deep-vein thrombosis screening. VTE incidences between patients with the above intervention and historical controls with IPC alone were compared.No significant differences in age, sex, and the RAP score were observed between the 105 controls and intervention patients. VTE occurrence was fewer in patients with the intervention (14.3%) than in the controls (28.6%; P = 0.029). No hemorrhagic complications occurred after UFH administration. Multivariable logistic analysis revealed a significant association between the intervention and low incidence of VTE (odds ratio: 0.390; 95% confidence interval: 0.163-0.913; P = 0.030).Routine UFH administration with IPC may prevent post-traumatic VTE without adverse events.

Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a Ryanodine Receptor Type 2 Missense Mutation.

BACKGROUND: Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the sameryanodine receptor type 2(RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC .Methods and Results:Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the sameRYR2-R169Q missense mutation and no other CPVT- or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca2+imaging and [3H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca2+release from the sarcoplasmic reticulum and increased fractional Ca2+release. CONCLUSIONS: The rare association of LVNC and CPVT phenotypes withRYR2mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.

Mexiletine infusion challenge test for neonatal long QT syndrome with 2:1 atrioventricular block.

For applying a genotype-based treatment in neonatal long QT syndrome (LQTS), early detection of the genotype becomes an important issue. We report a case of a neonate with LQTS type 3 that presented with 2:1 atrioventricular block and underwent a mexiletine infusion challenge test, and achieved shortening of the QTc and 1:1 atrioventricular conduction. The mexiletine infusion challenge test was helpful to make an early detection of the genotype of the LQTS and predicted the drug efficacy in a neonatal patient.

Effects of a trauma center on early mortality after trauma in a regional city in Japan: a population-based study.

BACKGROUND: Although the effects of the trauma center(TC) were researched in several studies, there have been few studies on changes in the regional mortality due to the implementation of a TC. An emergency medical center (EMC) and TC were implemented at Nagasaki University Hospital (NUH) for the first time in the Nagasaki medical region of Japan in April 2010 and October 2011, respectively, and they have cooperated with each other in treating trauma patients. The purpose of this study was to investigate the effects on the early mortality at population level of a TC working in cooperation with an EMC. METHODS: This is a retrospective study using standardized regional data (ambulance service record) in Nagasaki medical region from April 2007 through March 2017. We included 19,045 trauma patients directly transported from the scene. The outcome measures were prognosis for one week. To examine the association between the implementation of the EMC and TC and mortality at a region, we fit adjusted logistic regression models. RESULTS: The number of patients of each fiscal year increased from 1492 in 2007 to 2101 in 2016. The number of all patients transported to NUH decreased until 2009 to 70, but increased after implementation of the EMC and TC. Overall mortality of all patients in the region improved from 2.3% in 2007 to 1.0% in 2016. In multivariate logistic regression model, odds ratio of death was significantly smaller at 2013 and thereafter if the data from 2007 to 2011 was taken as reference. CONCLUSIONS: Implementation of the EMC and TC was associated with early mortality in trauma patients directly transported from the scene by ambulance. Our analysis suggested that the implementation of EMC and TC contributed to the improvement of the early mortality at a regional city with 500000 populations. LEVEL OF EVIDENCE: Level III.

Endothelial Dysfunction of Conduit Arteries in Patients with Repaired Coarctation of the Aorta.

Adult patients with repaired coarctation of the aorta (r-CoA) show high prevalence of late hypertension, but the exact mechanisms of this phenomenon are unknown. Endothelial dysfunction has been implicated in this paradoxical hypertension. We evaluated the endothelial function of both conduit and resistance arteries by using flow-mediated dilation (FMD) and digital peripheral artery tonometry (PAT).Seventeen patients with r-CoA and one patient with repaired interrupted aortic arch (r-CoA group) aged 22.0 ± 6.9 years (5 females) underwent FMD of the right brachial artery, PAT of the right finger, blood marker tests, ambulatory blood pressure monitoring, echocardiography, carotid ultrasonography, and brachio-ankle pulse wave velocity measurement. The median age at aortic arch reconstruction was 2.0 months (interquartile range: 15 days to 7.0 years). Results were compared with 17 age-matched healthy subjects (control group).Eight (44%) patients of the r-CoA group were hypertensive (5 received antihypertensive drugs). Patients in the r-CoA group showed significantly lower FMD (3.8 ± 1.5 versus 6.6 ± 2.5%, P < 0.001), larger intima-media thickness (0.63 ± 0.17 versus 0.47 ± 0.09 mm, P = 0.001), and higher left ventricular mass index (91.4 ± 24.6 versus 73.4 ± 17.3 g/m2, P = 0.017) than those in the control group. There were no significant differences in PAT (refractory hyperemia index, 1.86 ± 0.43 versus 1.99 ± 0.59, P = 0.48) and brachio-ankle pulse wave velocity between the two groups.Vascular dysfunction in r-CoA patients, particularly endothelial dysfunction, tends to occur more significantly in conduit arteries than in resistance arteries.

Ultrasonographic diagnosis of diaphragm paralysis in a neonate during mechanical ventilation after cardiac surgery.

Diaphragm excursion method is unsuitable for diagnosis of diaphragm paralysis during positive pressure ventilation. We diagnosed diaphragm paralysis in a neonate, without interrupting positive pressure respiratory support after cardiac surgery, using the diaphragm thickness fraction, which could be evaluated during mechanical ventilation and was unaffected by bowel gases. The diaphragm thickness fraction method can help diagnose diaphragm dysfunction using only echography.

Prenatal Diagnosis of Atrioventricular Block and QT Interval Prolongation by Fetal Magnetocardiography in a Fetus with Trisomy 18 and SCN5A R1193Q Variant.

We report a case of fetal trisomy 18 with SCN5A R1193Q variant that presented with sinus bradycardia, 2 : 1 atrioventricular block (AVB), and QT interval prolongation. These complex arrhythmias were diagnosed by fetal magnetocardiography combined with ultrasound findings. Advanced AVB and ventricular arrhythmias were confirmed after birth. Genetic testing of the baby revealed a SCN5A R1193Q variant, which we considered could account for the various arrhythmias in this case.

Pravastatin reduces steroid-induced osteonecrosis of the femoral head in SHRSP rats.

BACKGROUND AND PURPOSE: Although the definite cause of steroid-induced osteonecrosis of the femoral head (ONFH) is unknown, peripheral circulatory failure, lipid metabolism disturbance, and increased oxidative stress are considered to be possible causes. We investigated whether pravastatin as a statin treatment reduces (1) the incidence of ONFH, (2) the adipocyte area, and (3) bone marrow changes in the femoral head. METHODS: We divided up 81 thirteen-week-old spontaneously hypertensive stroke-prone (SHRSP)/Izm male rats into 4 groups: a control group (group C), a group given pravastatin (group P), a group given steroid (group S), and a group given both pravastatin and steroid (Group PS). The steroid was administered at 15 weeks of age. Pravastatin, as a statin, was administered in the drinking water for 4 weeks. The rats were killed when 17 weeks old. Osteonecrosis was diagnosed based on histopathological examination. Oxidative stress was assessed from immunostaining. RESULTS: The incidence of histological osteonecrosis was lower in the groups given pravastatin. The percentage of adipocyte area in the bone marrow was lower in the PS group than in the S group. Immunohistochemical staining for oxidative stress showed that staining was less in the PS group than in the S group. Pravastatin had no effect on the blood-derived biochemical findings on lipid metabolism. However, it reduced the incidence of steroid-induced ONFH in these SHRSP rats. We presume that this occurred by reducing oxidative stress and by reducing the percentage of adipocyte area in the femoral heads. INTERPRETATION: Our data suggest that pravastatin may be effective in reducing steroid-induced ONFH.

Pentosan reduces osteonecrosis of femoral head in SHRSP.

Increased oxidative stress is considered one of the main causes of steroid-induced osteonecrosis of the femoral head (ONFH). The aim of this study was to evaluate the effects of a steroid hormone and pentosan polysulfate sodium (pentosan), a heparin analog, in stroke-prone spontaneously hypertensive rats (SHRSP) as a model of ONFH. One hundred twenty-three 13-week-old male SHRSP/Izm rats were divided into four groups: a control group (group C), pentosan-administered group (group P), steroid-administered group (group S), and group administered pentosan plus steroid (group PS). Methylprednisolone acetate, as the steroid hormone, at a dose of 4 mg (15 mg/kg) was administered at 15 weeks of age. Pentosan at a dose of 3 mg/day/kg was continuously administered intraperitoneally from 13 weeks of age for 4 weeks. Rats were sacrificed at 17 weeks of age, and heart blood and both femora were collected. Triglyceride levels were significantly lower in group PS than in group S, indicating that pentosan improves lipid metabolism. The incidence of histologic ONFH was significantly lower in group P, at 14.8% (10/71 femoral heads), than in group C, at 30.4% (17/56 femoral heads), and significantly lower in group PS, at 40.8% (29/71 femoral heads), than in group S, at 91.3% (42/46 femoral heads), indicating that pentosan markedly inhibits ONFH. Immunohistochemical staining for oxidative stress showed that the stainability was significantly lower in group PS than in group S. Pentosan seems to reduce the incidence of ONFH in SHRSP by improving lipid metabolism and decreasing oxidative stress.

MRI findings of an inflammatory variant of well-differentiated liposarcoma.

The inflammatory variant of well-differentiated liposarcoma (WDLPS) is a rare subtype. We present a 75-year-old woman who had a tumor that was difficult to diagnose preoperatively. Magnetic resonance imaging of the tumor revealed a large, lobulated heterogeneous soft tissue mass with a distinctive pattern of intermingled well-differentiated fatty elements and nodular areas of high T2-intensity tissue.

Effects of selective iNOS inhibition on type II collagen-induced arthritis in mice.

Nitric oxide as well as prostaglandins has been reported to play an important role in inflammatory diseases including arthritis. In the present study, the effects of iNOS inhibition on development of disease were examined in type II collagen-induced arthritis (CIA) in male DBA/1J mice. From 4 weeks after the first immunization with bovine type II collagen, 1400W (10 mg/kg/day, p.o.), a selective iNOS inhibitor, indomethacin (1 mg/kg/day, p.o.), a cyclooxygenase (COX) inhibitor, or 1400W + indomethacin was administered for 8 weeks. Immunization with type II collagen evoked arthritic inflammation of paws and bone destruction accompanied by increases in urinary nitrite/nitrate (NOx) excretion, plasma NOx and PGE2 levels. Administration of 1400W reduced urinary NOx excretion and increased plasma PGE2 levels, while it had no effect on arthritic inflammation or bone destruction. Indomethacin slightly reduced the inflammatory signs and bone destruction with marked reduction of plasma PGE2. Combination of 1400W and indomethacin reduced urinary NOx and PGE2 levels, and showed greater amelioration of inflammatory signs and bone destruction than either alone. In conclusion, 1400W, a selective iNOS inhibitor, failed to prevent CIA probably due to its increasing effect on PGE2 production, but showed a synergistic ameliorative effect in combination with indomethacin.