A nationwide survey of pediatric acquired demyelinating syndromes in Japan.

OBJECTIVE: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. METHODS: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. RESULTS: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34-0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58-0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04-0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. CONCLUSIONS: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.

Acute pericardial effusion representing the TNF-α-mediated severe inflammation but not the coronary artery outcome of Kawasaki disease.

OBJECTIVES: To establish the optimal inflammation control of Kawasaki disease (KD), we investigated the clinical and pathophysiological basis of pericardial effusion (PE) during the acute phase of KD. METHOD: Clinical and laboratory features of Japanese KD children with PE (PE group: n = 9) and without PE (non-PE group: n = 89) were studied retrospectively by using the medical records. Serum levels of soluble tumour necrosis factor receptor 1 (sTNFR1), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assays (ELISAs). RESULTS: PE group patients had coronary artery lesions (CALs) more frequently than non-PE group patients during the acute phase of KD (33% vs. 5.6%, p = 0.024). PE patients also showed lower levels of haemoglobin (p < 0.01) and serum albumin (p < 0.01) and higher platelet counts (p = 0.013) than non-PE patients. The proportion of neurological symptoms, but not other manifestations, in the PE group was higher than in the non-PE group (p = 0.022). All patients survived free from coronary artery aneurisms. Serum levels of sTNFR1, but not the other cytokines, in the PE group were higher than those in the non-PE group (p < 0.001). The sTNFR1 levels correlated positively with C-reactive protein (CRP) (r = 0.30, p = 0.019) or total bilirubin (r = 0.40, p < 0.01) levels. CONCLUSIONS: Acute PE in KD patients indicated the severity of TNF-mediated vascular inflammation and concurrent CALs. According to the progression, these patients might need more targeted therapy of anti-inflammation for a better coronary outcome.

Intravenous immunoglobulin does not increase FcγRIIB expression levels on monocytes in children with immune thrombocytopenia.

Intravenous immunoglobulin (IVIG) produces a rapid and prolonged increase in the platelet counts of children with immune thrombocytopenia (ITP). The mechanism of IVIG efficacy in a murine model of ITP has been reported to operate through an IVIG-mediated increase in the expression of the inhibitory Fc receptor FcγRIIB(CD32B) on splenic macrophages. This investigation examined whether IVIG administration results in a similar increase in FcγRIIB expression on peripheral blood CD14(+) monocytes in 20 children with ITP. FcγRIIB expression on peripheral blood monocytes was measured by flow cytometry in ITP patients, before and after IVIG therapy, as well as in control subjects. Peripheral blood monocytes were labelled with fluorescent-specific antibodies. There were no significant differences in the absolute number of [corrected] CD14(+) CD32B(+) monocytes, and [corrected] the percentages of CD14(+) CD32B(+) cells in mononuclear cells or monocytes. [corrected]. We suggest that IVIG does not increase FcγRIIB expression in peripheral blood monocytes in children with ITP.

Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells.

The activation of nuclear factor-kappa B (NF-κB) in vascular endothelial cells may be involved in vascular pathogeneses such as vasculitis or atherosclerosis. Recently, it has been reported that some amino acids exhibit anti-inflammatory effects. We investigated the inhibitory effects of a panel of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases in various cell types. The activation of NF-κB was determined in human coronary arterial endothelial cells (HCAECs) because NF-κB modulates the production of many cytokines and the expression of adhesion molecules. We examined the inhibitory effects of the amino acids cysteine, histidine and glycine on the induction of NF-κB activation, expression of CD62E (E-selectin) and the production of interleukin (IL)-6 in HCAECs stimulated with tumour necrosis factor (TNF)-α. Cysteine, histidine and glycine significantly reduced NF-κB activation and inhibitor κBα (IκBα) degradation in HCAECs stimulated with TNF-α. Additionally, all the amino acids inhibited the expression of E-selectin and the production of IL-6 in HCAECs, and the effects of cysteine were the most significant. Our results show that glycine, histidine and cysteine can inhibit NF-κB activation, IκBα degradation, CD62E expression and IL-6 production in HCAECs, suggesting that these amino acids may exhibit anti-inflammatory effects during endothelial inflammation.

Enhancement of activated beta1-integrin expression by prostaglandin E2 via EP receptors in isolated human coronary arterial endothelial cells: implication for the treatment of Kawasaki disease.

OBJECTIVE: Plasma prostaglandin E(2) (PGE(2)) levels are markedly elevated in acute Kawasaki disease (KD). We evaluated the function of the EP receptors in the expression of activated beta(1)-integrin stimulated by PGE(2) in human coronary arterial endothelial cells (HCAEC). METHODS: We determined the mRNA expression of the PGE(2) receptors, EP receptors (EP(1-4)) in HCAEC by RT-PCR and protein expression by Western blotting. We evaluated the function of the EP receptors in the expression of activated beta(1)-integrin stimulated by PGE(2) in HCAEC, using antagonists and agonists of the EP receptors, by flow cytometry. RESULTS: RT-PCR revealed mRNAs for all four EP receptors in HCAEC. Western blotting demonstrated EP(1), EP(2) and EP(3) expression in HCAEC. The EP(2) and EP(3) agonists enhanced the expression of activated beta(1)-integrin in HCAEC. The potency of the EP(2) agonist was significantly greater than that of the EP(3) agonist. Pretreatment with the EP(1), EP(2) and EP(3) antagonists inhibited the expression of activated beta(1)-integrin induced by PGE(2) in HCAEC. The potency of the EP(2) antagonist was significantly greater than that of the EP(1) and EP(3) antagonists. CONCLUSIONS: Our results suggest that PGE(2) mainly induces the activation of beta(1)-integrins via the EP(2) receptor in HCAEC. Our results further suggest that the EP(2) antagonist modulates the inflammatory response during KD vasculitis.

Acute encephalopathy associated with influenza and other viral infections.

Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthem subitum. It occurs worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are affected by influenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy. This article reviews various syndromes of acute encephalopathy by classifying them into three major categories. The first group caused by metabolic derangement consists of various inherited metabolic disorders and the classical Reye syndrome. Salicylate is a risk factor of the latter condition. The second group, characterized by a systemic cytokine storm and vasogenic brain edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome, and acute necrotizing encephalopathy. Non-steroidal anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid, may aggravate these syndromes. Severe cases are complicated by multiple organ failure and disseminated intravascular coagulation. Mortality is high, although methylprednisolone pulse therapy may be beneficial in some cases. The third group, characterized by localized edema of the cerebral cortex, has recently been termed acute encephalopathy with febrile convulsive status epilepticus, and includes hemiconvulsion-hemiplegia syndrome and acute infantile encephalopathy predominantly affecting the frontal lobes. Theophylline is a risk factor of these syndromes. The pathogenesis is yet to be clarified, but an increasing body of evidence points to excitotoxicity and delayed neuronal death.

Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is an important enzyme responsible for airway remodelling. Monocytes/macrophages have a cysteinyl leukotriene 1 (cysLT1) receptor, but its function is poorly understood. OBJECTIVE: To elucidate the function of the cysLT1 receptor of human monocytes/macrophages in MMP-9 production. METHODS: We examined the effect of cysLTs (LTC4, -D4 and -E4) on TNF-alpha-induced MMP-9 production in THP-1 cells, a human monocytic leukaemia cell line and peripheral blood CD14+ monocytes/macrophages. In addition, we examined the effect of pranlukast, a cysLT1 receptor antagonist, on the enhancement of TNF-alpha-induced MMP-9 production by cysLTs. RESULTS: ELISA revealed that LTC4 and -D4, but not -E4, enhanced TNF-alpha-induced MMP-9 production in THP-1 cells and peripheral blood CD14+ monocytes/macrophages. Real-time polymerase chain reaction demonstrated that LTC4 and -D4, but not -E4, increased MMP-9 mRNA expression induced by TNF-alpha in THP-1 cells. Moreover, we demonstrated that pranlukast completely inhibited the enhancement of TNF-alpha-induced MMP-9 production by LTC4 and -D4 in THP-1 cells and peripheral blood CD14+ monocytes/macrophages. CONCLUSION: LTC4 and -D4 enhanced the TNF-alpha-induced MMP-9 production via binding the cysLT1 receptor in human monocytes/macrophages. Pranlukast inhibited the enhancements by LTC4 and D4.

Acute encephalopathy associated with influenza and other viral infections.

Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthem subitum. It occurs worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are affected by influenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy. This article reviews various syndromes of acute encephalopathy by classifying them into three major categories. The first group caused by metabolic derangement consists of various inherited metabolic disorders and the classical Reye syndrome. Salicylate is a risk factor of the latter condition. The second group, characterized by a systemic cytokine storm and vasogenic brain edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome, and acute necrotizing encephalopathy. Non-steroidal anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid, may aggravate these syndromes. Severe cases are complicated by multiple organ failure and disseminated intravascular coagulation. Mortality is high, although methylprednisolone pulse therapy may be beneficial in some cases. The third group, characterized by localized edema of the cerebral cortex, has recently been termed acute encephalopathy with febrile convulsive status epilepticus, and includes hemiconvulsion-hemiplegia syndrome and acute infantile encephalopathy predominantly affecting the frontal lobes. Theophylline is a risk factor of these syndromes. The pathogenesis is yet to be clarified, but an increasing body of evidence points to excitotoxicity and delayed neuronal death.

Cysteinyl leukotrienes induce monocyte chemoattractant protein 1 in human monocytes/macrophages.

BACKGROUND: Monocytes/macrophages have a cysteinyl leukotriene 1 (CysLT1) receptor, but its function is poorly understood. Objective To elucidate the biological function of the CysLT1 receptor of human monocytes/macrophages. METHODS: We examined the production of TNF-alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, monocyte chemoattractant protein 1 (MCP-1), macrophage colony-stimulating factor (M-CSF), and eotaxin induced by CysLTs (leukotriene (LT)C4, -D4, and -E4) in THP-1 cells, a human monocytic leukaemia cell line, and peripheral blood CD14+ monocytes/macrophages. Moreover, we examined the effect of CysLTs on the expression of beta-chemokine receptor 2B (CCR2B) as the receptor of MCP-1 by Western blot analysis. RESULTS: ELISA revealed that CysLTs induced MCP-1 in THP-1 cells and peripheral blood CD14+ monocytes/macrophages, but not other cytokines. PCR demonstrated that CysLTs increased MCP-1 mRNA expression in THP-1 cells, and Western blotting showed that CysLTs increased the expression of CCR2B in THP-1 cells. Moreover, we demonstrated that pranlukast, a CysLT1 receptor antagonist, blocked MCP-1 production by CysLTs in THP-1 cells almost completely, and partially inhibited MCP-1 release by CysLTs in peripheral blood CD14+ monocytes/macrophages and CCR2B expression by CysLTs in THP-1 cells. CONCLUSION: CysLTs induce MCP-1 and increase CCR2B expression in human monocytes/macrophages.

Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease.

Kawasaki disease (KD) is an acute illness of early childhood characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and nonsuppurative lymphadenopathy. The histopathological findings in KD comprise panvasculitis with endothelial necrosis, and the infiltration of mononuclear cells into small and medium-sized blood vessels. The levels of many proinflammatory cytokines, chemokines and adhesion molecules can be elevated in sera from children with KD at the acute stage. Although many immunological studies on KD involving peripheral blood have been reported, the data obtained remain controversial. This review focuses on the immune response of peripheral blood lymphocytes and monocytes/macrophages during acute KD.

Intravenous immunoglobulin does not increase FcgammaRIIB expression on monocytes/macrophages during acute Kawasaki disease.

OBJECTIVES: Intravenous immunoglobulin (IVIG) therapy has been reported to be effective for reducing the incidence of coronary artery lesions in Kawasaki disease (KD), an acute febrile vasculitis of unknown aetiology. Regarding the mechanism of IVIG in immune thrombocytopenic purpura (ITP), it has been reported that IVIG increases the expression of the inhibitory Fc receptor, FcgammaRIIB (CD32B), on splenic macrophages in a murine ITP model. Regarding the mechanism of IVIG during acute KD, we investigated whether or not IVIG increases the expression of FcgammaRIIB in peripheral blood CD14+ monocytes/macrophages. METHODS: The expression of FcgammaRIIB in peripheral blood CD14+ monocytes/macrophages was determined before and after IVIG therapy in 13 patients with acute KD by flow cytometry. RESULTS: The percentage of CD14+ CD32B+ monocytes/macrophages among peripheral blood mononuclear cells, the absolute number of CD14+ CD32B+ monocytes/macrophages and the percentage of CD14+ CD32B+ monocytes/macrophages among CD14+ monocytes/macrophages in patients with acute KD before IVIG therapy were significantly increased compared with those after IVIG therapy and in controls. CD14+ CD32B+ monocytes/macrophages decreased to within the normal range soon after IVIG therapy. CONCLUSIONS: IVIG therapy in patients with KD did not increase the expression of FcgammaRIIB in peripheral blood CD14+ monocytes/macrophages during the acute stage.

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion.

OBJECTIVE: To clarify whether patients with clinical diagnoses of encephalitis/encephalopathy with a reversible lesion in the splenium of the corpus callosum (SCC) share common clinical features. METHODS: Possible encephalitis/encephalopathy patients with a reversible isolated SCC lesion on MRI were collected retrospectively. Their clinical, laboratory, and radiologic data were reviewed. RESULTS: Fifteen encephalitis/encephalopathy patients with a reversible isolated SCC lesion were identified among 22 patients referred for this study. All 15 patients had relatively mild clinical courses. Twelve of the 15 patients had disorders of consciousness. Eight patients had seizures, and three of them received antiepileptic drugs. All 15 patients clinically recovered completely within 1 month (8 patients within a week) after the onset of neurologic symptoms. The SCC lesion was ovoid in six patients; it extended irregularly from the center to the lateral portion of SCC in the other eight patients. Homogeneously reduced diffusion was seen in all seven patients who underwent diffusion-weighted imaging. There was no enhancement in the five patients so examined. The SCC lesion had completely disappeared in all patients at follow-up MRI exams between 3 days and 2 months after the initial MRI (within 1 week in eight patients). CONCLUSION: The clinical features among the affected patients were nearly identical, consisting of relatively mild CNS manifestations and complete recovery within 1 month.

Expression of CTLA-4 (CD152) in peripheral blood T cells of children with influenza virus infection including encephalopathy in comparison with respiratory syncytial virus infection.

Influenza virus and respiratory syncytial virus (RSV) are the most common causes of acute severe respiratory infection in children during the winter. There have been few reports about peripheral blood T cell activation in vivo in influenza virus infection and conflicting results concerning peripheral blood T cells activation in RSV infection. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) is a receptor present on T cells that plays a critical role in the down-regulation of antigen-activated immune responses. To clarify the status of peripheral blood T cells, we investigated intracellular CTLA-4 expression in T cells in patients with influenza virus and RSV infection. We collected blood samples from 15 patients with influenza virus infection, including three with complications of influenza virus-associated encephalopathy and 18 patients with RSV infection, as well as 44 healthy children. We determined the intracellular expression of CTLA-4 in CD4+ and CD8+ T cells by flow cytometry. There were no significant differences in the percentages of intracellular CTLA-4-positive CD4+ T cells and CD8+ T cells by age. The percentages of intracellular CTLA-4-positive CD4+ T cells in the patients with influenza virus infection were significantly higher than those in healthy children (P < 0.01). In particular, the patients with influenza virus-associated encephalopathy had sevenfold higher percentages of CTLA-4-positive CD4+ T cells than influenza patients without encephalopathy (P < 0.05). The patients with influenza virus-associated encephalopathy had increased percentages of CTLA-4-positive CD8+ cells at the acute stage in comparison with the convalescent stage and in control subjects (P < 0.01, respectively). RSV patients showed no increase in CTLA-4-positive CD4+ T cells or CD8+ T cells. The immunological status of peripheral T cell activation is substantially different in influenza virus infection and RSV infection. The patients with RSV infection did not show any increase in CTLA-4-positive peripheral blood T cells. There was a remarkable increase in intracellular CTLA-4 in CD4+ and CD8+ T cells in influenza virus-associated encephalopathy. Down-regulation of antigen-activated peripheral blood T cell activation might play an important role in the pathogenesis of influenza virus-associated encephalopathy and host defence against influenza virus infection.