Fatal Coronary Artery Anomaly Concealed in Young Athletes with Exertional Syncope.

Background: Syncope is a common symptom in children, many of which are benign and do not require treatment. Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital malformation but can be a risk for serious cardiovascular events, including sudden death as well as cardiogenic syncope. Case Report. We describe the case of a 14-year-old boy who suffered an initial syncope and afebrile seizure during a soccer game. A detailed medical history and imaging studies led to the diagnosis of the anomalous aortic origin of the left main coronary artery with an intramural course (AAOLCA-IM). Conclusion: Symptomatic AAOLCA-IM has the highest risk of sudden death among AAOCA, and surgical repair may be performed. Onset during exercise or preceding chest symptoms are suspicious signs of cardiogenic syncope and should be considered for cardiovascular imaging evaluation.

Acute Esophageal Necrosis Secondary to Cyanotic Spells Associated with Unrepaired Tetralogy of Fallot.

Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart disease. Cyanotic spells occur more frequently after infancy in unrepaired cases. Acute esophageal necrosis (AEN) is a rare disease that causes circumferential mucosal necrosis in the distal esophagus. We report the case of a 26-year-old man who was admitted due to coffee-ground emesis, black stools, and decreased oxygen saturations. The patient had an unrepaired ToF and a congenital portosystemic venous shunt. An upper gastrointestinal endoscopy revealed AEN, which could be due to unstable hemodynamics of cyanotic spells. This is the first adult case presenting these 2 conditions occurring simultaneously.

Congenital portosystemic venous shunt associated with 22q11.2 deletion syndrome: a case report.

BACKGROUND: 22q11.2 deletion syndrome (22qDS) is the most common chromosomal microdeletion syndrome and is associated with a high rate of congenital heart disease (CHD) and neurodevelopmental abnormalities. Congenital portosystemic venous shunts (CPSS) are rare developmental abnormalities of the portal venous system. The clinical manifestations of CPSS are varied, and some patients have CHD or genetic chromosomal abnormalities, but their relationship remains unknown. We report the first case of CPSS associated with 22qDS. CASE PRESENTATION: A newborn boy referred to our institution was diagnosed with 22qDS due to characteristic facial features and complications of tetralogy of Fallot. A subsequent newborn screening test indicated hypergalactosemia and high blood levels of ammonia and bile acids. Upon closer examination, these abnormalities were found to be caused by the CPSS. Abdominal contrast-enhanced computed tomography and angiography confirmed that abnormal blood vessels ascended from the splenic vein and short-circuited to the left renal vein. Intracardiac repair for CHD was performed at 1 year of age, followed by transcatheter occlusion of the CPSS using a multilayer device (vascular plug) and detachable coil at 2 years of age. After treatment, the abnormal blood parameters promptly normalized. CONCLUSIONS: As the blood flow of CPSS bypasses the liver, the levels of galactose, bile acids, and ammonia in the systemic veins can increase. Some patients with CPSS have CHD, and these toxic substances may cause liver and lung lesions as well as portosystemic encephalopathy (PSE). Several genetic chromosomal abnormalities, including 22qDS, and CPSS have similar symptoms, and neurodevelopmental abnormalities, particularly those caused by PSE, may be difficult to diagnose. Blood tests, such as newborn screening, and abdominal imaging are useful in the early diagnosis of CPSS.

Bordetella pertussis is a common pathogen in infants hospitalized for acute lower respiratory tract infection during the winter season.

INTRODUCTION: There is some evidence that Bordetella pertussis (B. pertussis) can co-infect with viral respiratory infections in young infants. METHODS: B. pertussis infection was studied by culture, polymerase chain reaction (PCR), and loop-mediated isothermal amplification (LAMP) from nasopharyngeal swabs (NPSs) in 49 infants < 12 months of age, who were admitted for lower respiratory tract infections during the winter season. Seven other possible viral pathogens were documented by antigen detection or PCR in NPSs. The clinical feature of infants with mixed infection of B. pertussis and respiratory viruses were examined. RESULTS: Overall, B. pertussis infection was found in 10 (20.4%) cases, nine were less than 6 months of age and seven were unvaccinated. Viral etiology was found in 41 (84%) cases and pertussis-viral co-infection was present in eight patients, five of whom had mixed infection with respiratory syncytial virus. Only the presence of staccato coughing, cyanosis, and lymphocytosis were significantly different in B. pertussis-positive cases compared with B. pertussis-negative cases. Of the 10 pertussis cases, only the culture-positive cases showed the typical symptoms and laboratory findings of pertussis in addition to virus-associated respiratory symptoms with severe hospital course, whereas cases identified as DNA-positive lacked the characteristics of pertussis and their clinical severities were the same as B. pertussis-negative cases. CONCLUSION: In the absence of typical paroxysmal cough and lymphocytosis, we should carefully consider diagnosis of pertussis in young children hospitalized for presumed viral respiratory illness according to local epidemiological surveillance.

The combination of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as a novel predictor of intravenous immunoglobulin resistance in patients with Kawasaki disease: a multicenter study.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to be a predictor for intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD) recently. The objective of the present study was to elucidate the predictive validity of this new marker in a multicenter study. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 520 consecutive KD patients (development data set) and 332 subsequent patients (validation data set) at 7 hospitals in Japan. RESULTS: Both NLR and PLR were significantly higher in the IVIG-resistant group than in the IVIG-responsive group. When we set the cut-off point as NLR ≥ 4.11 and PLR ≥ 119, multiple logistic regression analyses showed that a high NLR and PLR before initial IVIG were independent predictors of IVIG resistance, and their combination was a stronger predictor than either alone. The sensitivity and specificity of the combination of NLR ≥ 4.11 and PLR ≥ 119 were 0.58 and 0.73 in the development data set. Validated using an independent data set, they were 0.54 and 0.72 in the validation data set. On comparing the AUC of this predictor with those of the Gunma and Kurume scores, the AUC was highest for this predictor, followed by the Gunma score and Kurume score (0.70, 0.68, and 0.64, respectively). DISCUSSION: The predictive validity of the combination of a high NLR and PLR, which is a simple and convenient indicator, was equal to or better than that of the existing scoring systems. The new predictive marker may be a suitable indicator for predicting IVIG resistance in KD patients.

Unexpected Ventriculitis Complication of Neonatal Meningitis Caused by Streptococcus gallolyticus Subsp. pasteurianus: a Case Report.

Streptococcus gallolyticus subsp. pasteurianus, previously recognized as S. bovis biotype II/2, is an uncommon yet important cause of invasive infection in young infants. Here, we report the first case of ventriculitis that was unexpectedly diagnosed in the course of neonatal meningitis due to S. gallolyticus subsp. pasteurianus, and we review the relevant literature. A 28-day-old male infant from Japan presented with fever, lethargy, and irritability. S. bovis was isolated from blood and the cerebrospinal fluid culture and was then identified as S. gallolyticus subsp. pasteurianus. Intravenous antibiotic therapy was initiated, which helped improve the clinical course of the disease; however, the patient presented ventriculitis-related complications diagnosed using follow-up magnetic resonance imaging (MRI) on day 12 of hospitalization. Ampicillin was administered for 21 days and discontinued after the patient showed improvement, according to MRI findings. The patient was discharged without sequelae. Ventriculitis is a rare complication of childhood meningitis due to S. gallolyticus subsp. pasteurianus. However, it may have been underdiagnosed, especially in cases with no specific manifestations similar to the present case. We suggest that MRI should be performed to screen for ventriculitis in the course of meningitis to avoid failure in treatment.

Umbilical hernia: Influence of adhesive strapping on outcome.

BACKGROUND: Adhesive strapping for umbilical hernia has been re-evaluated as a promising treatment. We evaluated the influence of adhesive strapping on the outcome of umbilical hernia. METHODS: We retrospectively evaluated patients with umbilical hernia referred to the present institution from April 2011 to December 2015. Patients who were treated with adhesive strapping were compared with an observation alone group. The adhesive strapping group was also subdivided into two groups: the cure group and the treatment failure group. RESULTS: A total of 212 patients with umbilical hernia were referred to the present institution. Eighty-nine patients were treated with adhesive strapping, while 27 had observation only. The cure rate in the adhesive strapping group was significantly higher than that in the observation group. The duration of treatment of the adhesive strapping group was significantly shorter than that of the observation group. In the adhesive strapping group, the patients in the cure group were treated significantly earlier than those in the treatment failure group (P < 0.001). Furthermore, even in cases of umbilical hernia non-closure, surgical repair was easier after adhesive strapping. CONCLUSION: Adhesive strapping represents a promising treatment for umbilical hernia. To achieve the best results, adhesive strapping should be initiated as early as possible.

Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study.

BACKGROUND: Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. METHODS AND RESULTS: We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17-0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38-0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20-0.44; P<0.001). CONCLUSIONS: UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

Multicenter prospective evaluation of a novel rapid immunochromatographic diagnostic kit specifically detecting influenza A H1N1 2009 virus.

BACKGROUND: Definitive diagnosis is crucial in reducing morbidity and mortality from pandemic influenza A H1N1 2009 (A/H1N1/2009), especially in high-risk populations. We recently developed a rapid diagnosis kit (RDK) capable of specifically detecting A/H1N1/2009. OBJECTIVES: To evaluate the diagnostic capability of the RDK in a multicenter, prospective trial. STUDY DESIGN: Samples were obtained by nasal swab from patients with suspected influenza. The diagnostic capability of the RDK was compared with that of the standard, real-time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: Of 266 patients who met the criteria, 122 and 92 were positive for A/H1N1/2009 influenza by PCR and by the newly developed RDK, respectively. The sensitivity, specificity and positive and negative predictive values of the RDK were 73.0%, 97.9%, 96.7% and 81.0%, respectively. A/H1N1/2009 detection rates by the RDK were significantly lower in samples obtained from patients more than 3 days after onset than in samples obtained between 1 and 2 days. CONCLUSIONS: The A/H1N1/2009-specific RDK is a reliable test that can be used easily at a patient's bedside for rapid diagnosis of A/H1N1/2009. This test will be of key importance in the control of A/H1N1/2009.

In vitro and in vivo pharmacological characterization of PF-01354082, a novel partial agonist selective for the 5-HT(4) receptor.

The pharmacological profile of PF-01354082, a selective 5-HT(4) receptor partial agonist, was investigated. PF-01354082 displayed high affinity for human 5-HT(4d) and dog 5-HT(4h) receptors in binding studies, having Ki values of 2.0 nM and 4.2 nM, respectively. By contrast, PF-01354082 did not show significant affinity for several other 5-HT receptors (5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(3A), and 5-HT(7)) or the dopamine D(2long) receptor. Functional assays using either cells expressing human recombinant 5-HT(4d) receptors or rat tunica muscularis mucosae demonstrated that PF-01354082 exhibited partial agonist activity at the 5-HT(4) receptor. The effects of PF-01354082 on in vitro receptor binding, ion channel activity, and sites of uptake were further investigated. PF-01354082 did not show biologically relevant binding activity at concentrations up to 10 microM except for binding to the 5-HT(4e) receptor. Furthermore, PF-01354082 decreased I(HERG) current by only 11% at a concentration of 300 microM, indicating that the compound had greater than 150,000-fold selectivity for the human 5-HT(4d) receptor over hERG channels. An in vivo study using a gastric motility model in conscious dogs demonstrated that oral administration of PF-01354082 resulted in marked and sustained stimulation of gastric motility in a dose-dependent manner. These results indicate that PF-01354082 is an orally active, highly selective, partial agonist of the human 5-HT(4) receptor that is expected to exert a favorable effect on gastrointestinal motor disorders with reduced adverse effects mediated by other related receptors.

Garcinone B reduces prostaglandin E2 release and NF-kappaB-mediated transcription in C6 rat glioma cells.

In the course of our survey of natural compounds inhibiting prostaglandin E2 release and/or lipopolysaccharide (LPS)-induced transcriptional stimulation via NF-kappaB, a central regulator of inflammatory genes, from natural resources, we found garcinone B, a xanthone from callus tissue culture of Hypericum patulum, as a compound with such pharmacological activities, that is a derivative of gamma-mangostin which potently inhibits COX-1 and COX-2 activities to reduce PGE2 release from C6 rat glioma cells, and inhibits IKK activity to prevent NF-kappaB-dependent COX-2 gene transcription. Garcinone B, to a lesser extent, reduced A23187-induced increase in prostaglandin E2 release than gamma-mangostin and its structurally related compound, patulone, in C6 cells. This compound also prevented LPS-induced stimulation of NF-kappaB-dependent transcription. These results suggest that garcinone B becomes a unique pharmacological tool to investigate intracellular signaling pathways involved in inflammation.

Standard-dose and short-term corticosteroid therapy in immunoglobulin-resistant Kawasaki disease.

Six patients with Kawasaki disease (KD) were treated with prednisolone (1 to 2 mg/kg/day) for 3 days (from days 10 to 12 after the onset of the illness) after apparently unsuccessful treatment with intravenous immunoglobulin (IVIG, 2 g/kg/dose and additional 1 g/kg/dose). Five patients responded immediately to the first course of prednisolone infusion. One patient failed to respond to the first course of prednisolone therapy, but he did respond to the second 3-day course of therapy. None of the patients demonstrated a further progression of coronary artery dilatation or any adverse effects. Standard-dose and short-term corticosteroid therapy therefore appears to be a safe and effective treatment for patients with IVIG-resistant KD.

Intravenous immunoglobulin preparations promote apoptosis in lipopolysaccharide-stimulated neutrophils via an oxygen-dependent pathway in vitro.

Since prolonged survival of activated neutrophils has an autotoxic potential, neutrophil apoptosis plays an important role in the rapid resolution of inflammation. Intravenous immunoglobulin (IVIG) preparations, which are beneficial therapeutic agents for the treatment of autoimmune diseases and systemic inflammatory diseases, have been reported to induce apoptosis of lymphocytes and endothelial cells in vitro. In the present study, we investigated whether IVIG may induce apoptosis of neutrophils cultured in vitro. After neutrophils prestimulated with or without lipopolysaccharide (LPS) were cultured in the presence or absence of IVIG, the number of apoptotic cells, intracellular H2O2 and GSH were measured by a flow cytometer. IVIG induced apoptosis of LPS-stimulated neutrophils dose dependently, but not in unstimulated neutrophils. Although anti-Fas monoclonal antibodies (mAbs) had no effect on the IVIG-induced apoptosis in the LPS-stimulated neutrophils, anti-Fc gamma receptor (Fc gammaR) II- and III-blocking mAbs significantly inhibited the IVIG-induced apoptosis. IVIG increased the production of intracellular H2O2, while it decreased the production of GSH, in the LPS-stimulated neutrophils. Furthermore, a specific NADPH oxidase inhibitor and anti-oxidants inhibited the IVIG-induced neutrophil apoptosis. Therefore, these findings indicate that IVIG preparations induce apoptosis of LPS-stimulated neutrophils and suggest that the IVIG-induced apoptosis may be mediated by an oxygen-dependent pathway via Fc gammaRII and III.

gamma-Mangostin inhibits inhibitor-kappaB kinase activity and decreases lipopolysaccharide-induced cyclooxygenase-2 gene expression in C6 rat glioma cells.

We investigated the effect of gamma-mangostin purified from the fruit hull of the medicinal plant Garcinia mangostana on spontaneous prostaglandin E(2) (PGE(2)) genase release and inducible cyclooxy-2 (COX-2) gene expression in C6 rat glioma cells. An 18-h treatment with gamma-mangostin potently inhibited spontaneous PGE(2) release in a concentration-dependent manner with the IC(50) value of approximately 2 microM, without affecting the cell viability even at 30 microM. By immunoblotting and reverse-transcription polymerase chain reaction, we showed that gamma-mangostin concentration-dependently inhibited lipopolysaccharide (LPS)-induced expression of COX-2 protein and its mRNA, but not those of constitutive COX-1 cyclooxygenase. Because LPS is known to stimulate inhibitor kappaB (IkappaB) kinase (IKK)-mediated phosphorylation of IkappaB followed by its degradation, which in turn induces nuclear factor (NF)-kappaB nuclear translocation leading to transcriptional activation of COX-2 gene, the effect of gamma-mangostin on the IKK/IkappaB cascade controlling the NF-kappaB activation was examined. An in vitro IKK assay using IKK protein immunoprecipitated from C6 cell extract showed that this compound inhibited IKK activity in a concentration-dependent manner, with the IC(50) value of approximately 10 microM. Consistently gamma-mangostin was also observed to decrease the LPS-induced IkappaB degradation and phosphorylation in a concentration-dependent manner, as assayed by immunoblotting. Furthermore, luciferase reporter assays showed that gamma-mangostin reduced the LPS-inducible activation of NF-kappaB-and human COX-2 gene promoter region-dependent transcription. gamma-Mangostin also inhibited rat carrageenan-induced paw edema. These results suggest that gamma-mangostin directly inhibits IKK activity and thereby prevents COX-2 gene transcription, an NF-kappaB target gene, probably to decrease the inflammatory agent-stimulated PGE(2) production in vivo, and is a new useful lead compound for anti-inflammatory drug development.

Tricholomalides A-C, new neurotrophic diterpenes from the mushroom Tricholoma sp.

Three new diterpenes, tricholomalides A-C (1-3), were isolated from the methanol extract of the fruiting body of Tricholoma sp. Their structures were elucidated on the basis of their spectral data, and the absolute configuration of 1 was determined by CD spectrum. Tricholomalides 1-3 significantly induced neurite outgrowth in rat pheochromocytoma cells (PC-12) at concentrations of 100 microM.

Baicalein inhibits Raf-1-mediated phosphorylation of MEK-1 in C6 rat glioma cells.

Baicalein is a flavonoid derived from the Scutellaria root. In investigations of the inhibitors of prostaglandin synthesis in C6 rat glioma cells, we found that baicalein had a potent inhibitory activity on prostaglandin synthesis induced by either histamine or A23187, a Ca(2+) ionophore. Baicalein inhibited histamine- or A23187-induced phosphorylation of p42/p44 extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), which causes the phosphorylation of cytosolic phospholipase A(2) (PLA(2)). Baicalein also inhibited the phosphorylation of MAPK kinase-1 (MEK-1) induced by histamine or A23187 in the cells. To examine the site of action of baicalein, MEK-1 and Raf-1 were prepared by immunoprecipitation with anti-MEK-1 and anti-Raf-1 antibodies, respectively. Baicalein inhibited the phosphorylation of exogenous MEK-1 by Raf-1 under cell-free conditions, while it did not change the phosphorylation of exogenous p42 MAPK by MEK-1. These results imply that baicalein inhibits the ERK/MAPK cascade, acting on the phosphorylation of MEK-1 by Raf-1.

Inhibitions of histamine release and prostaglandin E2 synthesis by mangosteen, a Thai medicinal plant.

The fruit hull of mangosteen, Garcinia mangostana L. has been used as a Thai indigenous medicine for many years. However, its mechanism of action as a medicine has not been elucidated. The present study was undertaken to examine the effects of mangosteen extracts (100% ethanol, 70% ethanol, 40% ethanol and water) on histamine release and prostaglandin E2 synthesis. We found that the 40% ethanol extract of mangosteen inhibited IgE-mediated histamine release from RBL-2H3 cells with greater potency than the water extract of Rubus suavissimus that has been used as an anti-allergy crude drug in Japan. All extracts of mangosteen potently inhibited A23187-induced prostaglandin E2 synthesis in C6 rat glioma cells, while the water extract of Rubus suavissimus had no effect. The 40% ethanol extract of mangosteen inhibited the prostaglandin E2 synthesis in a concentration-dependent manner with relatively lower concentrations than the histamine release. In addition, passive cutaneous anaphylaxis (PCA) reactions in rats were significantly inhibited by this ethanol extract as well as by the water extract of Rubus suavissimus. These results suggest that the 40% ethanol extract of mangosteen has potent inhibitory activities of both histamine release and prostaglandin E2 synthesis.