Taichi Kato

Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial

BACKGROUND Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. METHODS We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. FINDINGS We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. INTERPRETATION Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. FUNDING Japanese Ministry of Health, Labour and Welfare.

THE 1994 SUPEROUTBURST OF THE NEW SU UMA-TYPE DWARF NOVA, SX LEONIS MINORIS

We present observations of SX LMi obtained during the 1994 long outburst at Ouda Station. Superhumps, with a period of 0.06950 (± 0.00002) d, are detected. This confirms SX LMi as a new member of the SU UMa-type dwarf novae. We measured the recurrence cycle of normal outbursts and superoutbursts to be about 35 d and 250 d, repsectively, from outburst records by RoboScope (Indiana University) and amateur observers. These recurrence cycles are typical values for normal SU UMa stars. However, the outburst amplitude (~3.8 mag) of SX LMi is small for an SU UMa star and close to those of ER UMa stars. This small outburst amplitude might be understood if the viscosity at quiescence and the mass-transfer rate are slightly high in SX LMi.

Thrombocytopenia in patients with 22q11.2 deletion syndrome and its association with glycoprotein Ib-β

Purpose: To elucidate whether thrombocytopenia in 22q11.2 deletion syndrome patients is associated with the hemizygosity of glycoprotein Ib-β and to clarify the correlation of phenotype and genotype of this gene in 22q11.2 deletion syndrome patients with thrombocytopenia.Methods: Platelet number, mean platelet volume, platelet agglutination, and the protein level of glycoprotein Ib-β were measured in 22q11.2 deletion syndrome patients and controls. Phenotypes other than that of thrombocytopenia were also analyzed in these patients.Results: The 22q11.2 deletion syndrome patients with thrombocytopenia had a larger mean platelet volume, lower agglutination to ristocetin, and lower protein level of glycoprotein Ib-β than control patients. The 22q11.2 deletion syndrome patients with thrombocytopenia showed an increased risk of developing schizophrenia.Conclusions: Thrombocytopenia in 22q11.2 deletion syndrome patients is associated with decreased expression of glycoprotein Ib-β because of the hemizygosity. 22q11.2 deletion syndrome patients with thrombocytopenia require total management, especially for schizophrenia.

Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis

It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3-5 wk (early study) or during 5-8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.

The POU-domain protein Oct-1 is widely expressed in adult rat organs

The cDNA encoding a rat Oct-1 POU-domain was cloned by the reverse transcription-polymerase chain reaction method and subsequently Oct-1 mRNA expression was investigated. Our results show that the POU-domain of Oct-1 has been highly conserved during vertebrate evolution and that Oct-1 mRNA is widely expressed in various organs of adult rat.

Estrogen-like activity and dual roles in cell signaling of an Agaricus blazei Murrill mycelia-dikaryon extract

Agaricus blazei (A. blazei) Murrill mycelia-dikaryon has attracted the attention of scientists and clinicians worldwide owing to its potential for the treatment of cancer. However, little is known about its effect on other pathologies. This study sought to extend the potential medical usefulness of A. blazei for preventing vascular damage and to unravel its mechanism of action. The A. blazei extract showed estrogen-like activity in both gene expression profiling and a luciferase assay. Indeed, the extract inhibited oxidized low-density lipoprotein-stimulated activation of Erk1/2, Akt and p38 in HUVECs and macrophage-derived TIB-67 cells. Moreover, the extract enhanced transcription of the glutathione peroxidase 3 (GPX3), α-synuclein (SNCA) and endothelial nitrogen-oxide synthase (eNOS) genes. Furthermore, atherosclerotic lesions in rabbits were reduced by intake of A. blazei powder. Therefore, A. blazei may be useful for preventing atherosclerosis via dual roles in cell signaling, suppression of macrophage development and the recovery of endothelial cells from vascular damage.

Coronary arterial ectasia in a 2-year-old boy showing two symptoms of Kawasaki disease without manifesting fever

We read with great interest the recent clinical cases of incomplete Kawasaki disease with remarkable paucity of signs and symptoms reported by Thapa et al. [1] and Yilmazer et al. [2]. In the present letter, we describe a case of coronary arterial ectasia in a patient showing two symptoms of Kawasaki disease without fever. A 2-year-old boy was referred to our hospital with an 8-day history of arthralgia without fever. An elevated white blood cell count (11,500/ l) and elevated C-reactive protein (CRP) (4.1 mg/dl) were documented. Magnetic resonance imaging revealed Xuid collection in the right hip joint. Antibiotics were administered until joint Xuid culture revealed no bacterial infection. Although arthralgia improved within 7 days, CRP and erythrocyte sedimentation rate remained elevated. Further examination including chest X-ray, blood and stool cultures, viral serology, and autoantibodies revealed no abnormalities. Echocardiography was conducted to survey the focus of inXammation and revealed coronary arterial ectasia in segments 1, 5, and 6 with pericardial eVusion. Although incomplete Kawasaki disease was considered in the diVerential diagnosis, only conjunctival injection and desquamation contributed to the diagnostic criteria for Kawasaki disease, and no fever was evident during the clinical course. Aspirin was administered but immunoglobulin was not because of the unknown etiology of the coronary arterial abnormality. Echocardiography after administration of aspirin for 1 month showed deteriorated coronary arterial ectasia, especially in the right coronary artery, despite a gradual decrease in CRP (Fig. 1a). CRP normalized 45 days after disease onset and was followed by improvement of coronary arterial ectasia (Fig. 1b). Cardiac catheterization 1 year after disease onset showed no abnormalities of the coronary arteries (Fig. 2). This result prompted discontinuation of aspirin administration, after which the patient showed neither recurrence of coronary arterial ectasia nor reelevation of CRP. Accumulating data indicate that some cases of Kawasaki disease do not fulWll the classical diagnostic criteria. This so-called “incomplete Kawasaki disease” can also cause coronary arterial aneurysms or ectasia [3, 4]. Although no evidence-based diagnostic criteria have been determined for incomplete Kawasaki disease, an algorithm has been advocated for evaluation of incomplete Kawasaki disease in patients with persistent fever associated with two or three of the principal symptoms of Kawasaki disease [5]. However, the patient described herein presented with two symptoms of Kawasaki disease and persistently elevated CRP without manifesting fever during the entire clinical course, and developed coronary arterial ectasia. CRP is an acute-phase reactant, and persistent elevation has been reported as a risk T. Kato (&) Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: ktaichi@med.nagoya-u.ac.jp

Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.

We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

The diameter of the inferior vena cava provides a noninvasive way of calculating central venous pressure in neonates.

To explore a less invasive way of assessing preload in neonates than fitting catheters to measure central venous pressure (CVP). This study evaluated the relationship between inferior vena cava (IVC) measurements and gestational age (GA) or body weight (BW) in term and premature infants and the correlation between those measurements and CVP in sick infants under mechanical ventilation.

Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial

We compared the efficacy and safety of infliximab with intravenous immunoglobulin (IVIG), a standard therapy, in a phase 3 trial (NCT01596335) for Japanese patients with Kawasaki disease (KD) showing persistent fever after initial IVIG. Patients with initial IVIG-refractory KD, aged 1–10 years, received a single dose of IV infliximab 5 mg/kg or IV polyethylene glycol-treated human immunoglobulin (VGIH) 2 g/kg on day 0. Primary outcome was defervescence rate within 48 h after the start of treatment. Safety was evaluated through day 56. Overall, 31 patients were randomized (infliximab, n = 16; VGIH, n = 15); 31.3% and 60.0% patients discontinued due to worsening KD. Defervescence rate within 48 h was greater with infliximab (76.7%) than VGIH (37.0%) (p = 0.023), and defervescence was achieved earlier with infliximab (p = 0.0072). Coronary artery lesions occurred in 1 (6.3%) and 3 (20.0%) patients receiving infliximab and VGIH, respectively, up to day 21. Adverse events occurred in 15 (93.8%) and 15 (100.0%) patients in the infliximab and VGIH groups, respectively. No serious adverse events in the infliximab group and one in the VGIH group were observed. Infliximab improved the defervescence rate within 48 h and time to defervescence versus standard therapy, and was well tolerated in patients with IVIG-refractory KD.