Cerebral Insufficiency Caused by Diazoxide in a Premature Neonate with Congenital Hyperinsulinism.

Diazoxide is a peripheral vasodilator that has been used for intravenous treatment of hypertensive emergencies. However, it is currently used mainly for hyperinsulinemic hypoglycemia in lower dose orally, and its major side effects are edema and pulmonary hypertension. Herein, we report the first association between periventricular leukomalacia (PVL) and intractable hypotension due to diazoxide. A Japanese female premature infant showed hypoglycemia concomitant with hyperinsulinemia. She was diagnosed with congenital hyperinsulinism, and oral diazoxide was started. Six days after starting diazoxide, she suddenly showed peripheral coldness, oliguria, and severe hypotension. The hypotension was refractory to general vasopressor therapies and persisted even after the discontinuation of diazoxide. Cranial echography showed periventricular echodensities followed by cystic PVL. Low-dose vasopressin effectively treated the hypotension. This single case reminds us the serious adverse events of diazoxide that have been forgotten, especially in premature neonates.

Assessing the Efficacy of Very Early Motor Rehabilitation in Children with Down Syndrome.

Among children with Down syndrome, the frequency of motor rehabilitation intervention and the age at the start of this intervention are independently related to the age at onset of independent walking. Early motor rehabilitation, before age 6 months, may be effective in reducing motor delay in children with Down syndrome.

Case Report: Kawasaki disease associated with acute generalized exanthematous pustulosis secondary to carbocysteine.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption characterized by sterile pustules on an erythematous background, which is usually associated with drugs. AGEP is described as a self-limiting disease with favorable prognosis. We reported a case of Kawasaki Disease (KD) following AGEP. A 3-year-old male, who was admitted with pustules and five days of fever at our hospital, was diagnosed with AGEP. Despite the skin lesions and fever improving drastically after prednisolone therapy, the fever recurred on hospitalization day 5. The following symptoms suggestive of KD also appeared: bulbar conjunctival hyperemia, cervical lymphadenopathy, erythema of the lips, eruption on his trunk, and erythema and edema of the hands and feet. He was diagnosed with KD and treated with intravenous immunoglobulin. He was discharged on the thirteenth day of hospitalization without cardiac complications. Drug-induced lymphocyte stimulation test revealed carbocysteine as the suspected cause of AGEP, which consequently triggered KD. Because a mucosal lesion is uncommon in AGEP, bulbar conjunctival hyperemia suggested that KD sequentially occurred after AGEP. Since AGEP is benign and self-limited in most cases, it is necessary to differentiate other diseases, including KD, when recurrent fever or rash occurs in the course of AGEP.

Leukotriene D4 enhances tumor necrosis factor-α-induced vascular endothelial growth factor production in human monocytes/macrophages.

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic mitogens specific for vascular endothelial cells. It also induces vascular hyperpermeability and protein leakage into the extracellular space. Leukotriene D(4) (LTD(4)), one of the cysteinyl leukotrienes (CysLTs), is known to be one of the key molecules of allergic inflammation. The interaction between LTD(4) and VEGF production in human monocytes/macrophages is not well characterized. METHODS: We examined VEGF production by THP-1 cells, a human monocytic leukemia cell line, and human peripheral blood CD14+monocytes/macrophages stimulated with LTD(4) and/or tumor necrosis factor-α (TNF-α). We also determined the inhibitory effects of pranlukast, a CysLT(1) receptor antagonist, on VEGF production by LTD(4) stimulation. RESULTS: LTD(4) significantly induced VEGF production and enhanced TNF-α-induced VEGF release in THP-1 cells and human peripheral blood CD14+monocytes/macrophages. VEGF mRNA expression was also induced by stimulation of THP-1 cells with LTD(4) and TNF-α. In addition, 10(-7)-10(-10)M pranlukast completely inhibited VEGF production enhanced by LTD(4). The 50% inhibitory concentration (IC50) for VEGF production in THP-1 cells was 10(-10)-10(-11)M. CONCLUSIONS: LTD(4) induced VEGF production and enhanced VEGF release induced by TNF-α via CysLT(1) receptors in human monocytes/macrophages. These effects were completely inhibited by pranlukast.

Characteristics of atopic children with pandemic H1N1 influenza viral infection: pandemic H1N1 influenza reveals 'occult' asthma of childhood.

The number of human cases of pandemic H1N1 influenza viral infection has increased in Japan since April 2009, as it has worldwide. This virus is widespread in the Yamaguchi prefecture in western Japan, where most infected children exhibited respiratory symptoms. Bronchial asthma is thought to be one of the risk factors that exacerbate respiratory symptoms of pandemic H1N1-infected patients, but the pathogenesis remains unclear. We retrospectively investigated the records of 33 children with pandemic H1N1 influenza viral infection who were admitted to our hospital between October and December 2009 and analyzed their clinical features. The percentage of children with asthma attack, with or without abnormal findings on chest radiographs (pneumonia, atelectasis, etc.), caused by pandemic H1N1 influenza infection was significantly higher than that of children with asthma attack and 2008-2009 seasonal influenza infection. Of the 33 children in our study, 22 (66.7%) experienced an asthma attack. Among these children, 20 (90.9%) did not receive long-term management for bronchial asthma, whereas 7 (31.8%) were not diagnosed with bronchial asthma and had experienced their first asthma attack. However, the severity of the attack did not correlate with the severity of the pulmonary complications of pandemic H1N1 influenza viral infection. The pandemic H1N1 influenza virus greatly increases the risk of lower respiratory tract complications such as asthma attack, pneumonia, and atelectasis, when compared to the seasonal influenza virus. Furthermore, our results suggest that pandemic H1N1 influenza viral infection can easily induce a severe asthma attack, pneumonia, and atelectasis in atopic children without any history of either an asthma attack or asthma treatment.

Human thymic stromal lymphopoietin enhances expression of CD80 in human CD14+ monocytes/macrophages.

OBJECTIVE: Human thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, promotes inflammatory T helper type 2 cell (Th2) differentiation of naive CD4(+) T cells. TSLP is highly produced in keratinocytes of patients with atopic dermatitis and bronchial epithelia of patients with asthma and was thought to be a master switch for allergic inflammation. We sought to examine the effect of TSLP in human monocytes/macrophages. METHODS: The effect of TSLP on the expression of cell surface antigens (CD11c, CD16, CD54, CD80, CD86, and HLA-DR) in peripheral blood CD14(+) monocytes/macrophages was examined. RESULTS: TSLP enhanced the expression of CD80 in peripheral blood CD14(+) monocytes/macrophages but not that of other cell surface antigens. It was associated with an increased percentage of CD14(dim/-), CD80(+), CD11c(+), and HLA-DR(+) cells, which was consistent with the increased differentiation of myeloid dendritic cells. CONCLUSIONS: TSLP induces CD80 expression in human peripheral blood CD14(+) monocytes/macrophages; this indicates monocyte/macrophage activation. This may be associated with their differentiation into myeloid dendritic cells.

Amino acids exhibit anti-inflammatory effects in human monocytic leukemia cell line, THP-1 cells.

OBJECTIVE: The elemental diet is one of the effective therapies for inflammatory bowel disease. However, the mechanism remains unclear, and there have never been reports about the inhibitory effects of amino acids in human monocytes/macrophages. We investigated the inhibitory effects of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases, in human monocytes/macrophages. METHODS: We examined the inhibitory effects of cysteine, histidine or glycine on the induction of nuclear factor-κB (NF-κB) activation, expression of intracellular adhesion molecule-1 (ICAM-1, CD54) and production of interleukin-8 (IL-8) in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood mononuclear cells (PBMCs) stimulated with tumor necrosis factor-α (TNF-α). RESULTS: Cysteine, histidine and glycine significantly reduced the activation of NF-κB in THP-1 cells stimulated with TNF-α. In addition, cysteine and histidine significantly inhibited the expression of ICAM-1 and production of IL-8 in THP-1 cells and PBMCs. CONCLUSIONS: Our results suggest that cysteine and histidine exhibit anti-inflammatory effects in THP-1 cells, and may be responsible for the efficacy of treatment in inflammatory bowel diseases.

Prostaglandin E2 suppresses beta1-integrin expression via E-prostanoid receptor in human monocytes/macrophages.

Beta1-integrins mediate cell attachment to different extracellular matrix proteins, intracellular proteins, and intercellular adhesions. Recently, it has been reported that prostaglandin E2 (PGE2) has anti-inflammatory properties such as inhibition of the expression of adhesion molecules or production of chemokines. However, the effect of PGE2 on the expression of beta1-integrin remains unknown. In this study, we investigated the effects of PGE2 on the expression of beta1-integrin in the human monocytic cell line THP-1 and in CD14+ monocytes/macrophages in human peripheral blood. For this, we examined the role of four subtypes of PGE2 receptors and E-prostanoid (EP) receptors on PGE2-mediated inhibition. We found that PGE2 significantly inhibited the expression of beta1-integrin, mainly through EP4 receptors in THP-1 cells and CD14+ monocytes/macrophages in human peripheral blood. We suggest that PGE2 has anti-inflammatory effects, leading to the inhibited expression of beta1-integrin in human monocytes/macrophages, and that the EP4 receptor may play an important role in PGE2-mediated inhibition.

Functional expression of cysteinyl leukotriene receptors on human platelets.

Normal peripheral blood leukocytes, such as basophils, eosinophils, B lymphocytes and monocytes/macrophages, have a cysteinyl leukotriene 1 (CysLT1) receptor, while the cysteinyl leukotriene 2 (CysLT2) receptor is expressed in cardiac Purkinje cells, endothelium, brain and leukocytes. However, it is unknown whether or not platelets express the CysLT1 or CysLT2 receptor. In this study we identify and characterize the biological function of the CysLT receptor of human platelets. We determined the CysLT1 or CysLT2 receptor mRNA expression in normal human platelets by RT-PCR and determined protein expression by Western blotting and flow cytometry. Moreover, we examined the effect of cysteinyl leukotrienes (CysLTs) in platelets on the induction of RANTES (Regulated on Activation, Normal T Expressed, and presumably Secreted). We also investigated whether the CysLT1 receptor antagonist pranlukast inhibits CysLT-induced RANTES release. In conclusion, we showed the functional expression of CysLT receptors on human platelets and demonstrated that CysLTs induced the release of significant amounts of RANTES, which suggests a novel role for human platelets in CysLT-mediated allergic inflammation.

Kawasaki Disease Following Severe Sunburn Injury.

Background: Although an etiology of Kawasaki disease (KD) is unknown, an aberrant innate immune system in predisposed individuals has been proposed to play a key role in the development of KD vasculitis. Various etiological pathogens have been proposed as the trigger of KD and a scaled injury preceding symptom onset has been reported as one of them. Here, we report a 17-month-old Japanese female who was hospitalized due to high fever lasting for 4 days with infection ruled out as a cause. On admission, she displayed severe sunburn all over her body following a prolonged period of outdoor play 5 days ago. On the 5 day of illness, she developed complete KD. Serum levels of high mobility group box 1, a representative for damage-associated molecular patterns (DAMPs), were elevated during acute phase and continued to decrease during subacute phase. This unique course suggested the inflammatory process of KD involving innate immunity via DAMPs.

Efficacy of hypothermia therapy in patients with acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic seizures and impaired consciousness. The efficacy of hypothermia/normothermia therapy in patients with AESD has rarely been reported on. METHODS: We enrolled 15 patients with AESD admitted to Yamaguchi University Hospital and Yamaguchi-ken Saiseikai Shimonoseki General Hospital between 2005 and 2019 and retrospectively evaluated the long-term efficacy of hypothermia therapy compared to that of non-hypothermia therapy. We compared the long-term sequelae of patients with AESD treated with or without hypothermia therapy. We used the Pediatric Cerebral Performance Category (PCPC) scale and intelligence tests including the Wechsler Intelligence Scale for Children, Tanaka-Binet Intelligence Scale, and Enjoji Infantile Developmental Scale to evaluate neurological sequelae and mental disability. The preventive effect of hypothermia therapy was assessed based on the development of post-encephalopathic epilepsy (PEE). RESULTS: There was no significant between-group difference in the PCPC score (p = 0.53). The subjects with severe mental disability in the hypothermia therapy group were 0 (0%), while those in the non-hypothermia group were 2 (29%); however, the difference was not significant. Notably, there were no patients with onset of PEE in the hypothermia therapy group, while there were 4 (57.1%) in the non-hypothermia group (p = 0.03). CONCLUSIONS: Our study suggests that hypothermia therapy may be effective in the long-term sequelae of AESD in terms of preventing the development of PEE. We propose that hypothermia therapy could contribute to improve the quality of life in these patients by preventing the subsequent onset of PEE.

Cysteinyl leukotrienes induce macrophage inflammatory protein-1 in human monocytes/macrophages.

BACKGROUND: Macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta are known for their chemotactic and proinflammatory effects on monocytes/macrophages which have a cysteinyl leukotriene 1 (CysLT(1)) receptor. METHODS: We examined MIP-1alpha and MIP-1beta production stimulated by CysLTs (LTC(4), LTD(4), and LTE(4)) in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood mononuclear cells (PBMCs). Moreover, we examined the inhibitory effect of pranlukast, a CysLT(1) receptor antagonist, and inhibitors of three major mitogen-activated protein kinases (MAPK) on the induction of MIP-1alpha and MIP-1beta production by CysLTs. RESULTS: ELISA demonstrated that CysLTs induced MIP-1alpha and MIP-1beta production in THP-1 cells and PBMCs. PCR demonstrated that LTD(4) increased MIP-1alpha and MIP-1beta mRNA expressions in THP-1 cells. Pranlukast blocked MIP-1alpha and MIP-1beta production promoted by LTD(4) in THP-1 cells and PBMCs. Moreover, an inhibitor of extracellular signal-regulated kinase (ERK) attenuated the induction of MIP-1alpha and MIP-1beta production by LTD(4) in THP-1 cells whereas the inhibitors of c-Jun NH2-terminal kinase or p38 MAPK did not. CONCLUSION: CysLTs induce MIP-1alpha and MIP-1beta production mediated by ERK via binding to the CysLT(1) receptor in human monocytes/macrophages.

Erythema Nodosum Masking Kawasaki Disease with an Initial Manifestation of Skin Lesions.

We report the first case demonstrating an association between Kawasaki disease (KD) and erythema nodosum (EN). A 3-year-old girl presented with EN as an initial manifestation of KD. At the initial visit, she showed high fever of 40°C, injection of the oropharynx, cervical lymphadenopathy, and red-purple cutaneous nodules, particularly on the lower limbs. She complained of severe pain in the neck and cutaneous lesions. Initially, the development of EN was attributed to Salmonella spp infection, which was detected in stool culture. However, the patient did not respond to high-dose ampicillin/sulbactam to which the Salmonella spp is sensitive. Echocardiography performed as screening for fever of unknown origin revealed medium-sized aneurysms of the left anterior descending artery. EN masked the diagnosis of KD, and the patient developed a coronary artery lesion. KD should be considered in the differential diagnosis of refractory EN in pediatric patients.

Successful control of juvenile dermatomyositis-associated macrophage activation syndrome and interstitial pneumonia: distinct kinetics of interleukin-6 and -18 levels.

BACKGROUND: Macrophage activation syndrome (MAS) is the secondary hemophagocytic lymphohistiocytosis associated with rheumatic diseases. Recently, the different cytokine profiles between systemic juvenile idiopathic arthritis (sJIA)-associated MAS (sJIA-MAS) and juvenile systemic lupus erythematosus (JSLE)-associated MAS (JSLE-MAS) were reported. However, there is little information about juvenile dermatomyositis (JDM)-associated MAS (JDM-MAS). CASE PRESENTATION: A 4-year-old girl with JDM was hospitalized because of fever, erythema, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy. Bone marrow aspiration revealed appreciable numbers of activated and hemophagocytosing macrophages. She was diagnosed as having JDM-MAS complicated with interstitial pneumonia (IP) based on the findings of the elevation of serum Krebs von den Lungen-6 (KL-6) levels and chest computed tomography findings. We analyzed circulating levels of interleukin (IL)-2,4,6,10,18, tumor necrosis factor-α and interferon-γ in the patient. Hypercytokinemia occurred at the diagnosis of MAS and IP, showing with the prominent elevations of IL-6 and IL-18 levels. The cytokine profiles were distinct from those reported in patients with sJIA-MAS or JSLE-MAS. High-dose corticosteroid and cyclosporine therapy led to a drastic improvement of MAS with decreased IL-6 levels. Subsequent cyclophosphamide therapy successfully controlled IP, paralleled with the declining pattern of IL-18 and KL-6 levels. CONCLUSION: This is the first report to describe a successful treatment and the cytokine profile of JDM-MAS and IP. Serum IL-6 and IL-18 levels may be useful for predicting the disease activity of JDM-MAS and IP, respectively.

1α,25-Dihydroxyvitamin D(3) inhibits vascular cellular adhesion molecule-1 expression and interleukin-8 production in human coronary arterial endothelial cells.

Kawasaki disease is an acute febrile vasculitis of childhood that is associated with elevated production of inflammatory cytokines, causing damage to the coronary arteries. The production of proinflammatory cytokines and expression of adhesion molecules in human coronary arterial endothelial cells (HCAECs) is regulated by nuclear transcription factor-κB (NF-κB) activation. We have previously reported that the active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25-(OH)(2)D(3)), inhibits tumor necrosis factor-α (TNF-α)-induced NF-κB activation. In this study, we examined the anti-inflammatory effects of 1α,25-(OH)(2)D(3) on TNF-α-induced adhesion molecule expression (vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)) and cytokine production (interleukin-6 (IL-6) and IL-8) in HCAECs. Pretreatment with 1α,25-(OH)(2)D(3) significantly inhibited TNF-α-induced VCAM-1 expression and IL-8 production in HCAECs. Our results suggest that adjunctive 1α,25-(OH)(2)D(3) therapy may modulate the inflammatory response during Kawasaki disease vasculitis.

Molecular epidemiological study of human rhinovirus species A, B and C from patients with acute respiratory illnesses in Japan.

Recent studies suggest that human rhinovirus species A, B and C (HRV-ABCs) may be associated with both the common cold and severe acute respiratory illnesses (ARIs) such as bronchiolitis, wheezy bronchiolitis and pneumonia. However, the state and molecular epidemiology of these viruses in Japan is not fully understood. This study detected the genomes of HRV-ABCs from Japanese patients (92 cases, 0-36 years old, mean±sd 3.5±5.0 years) with various ARIs including upper respiratory infection, bronchiolitis, wheezy bronchiolitis, croup and pneumonia between January and December 2010. HRV-ABCs were provisionally type assigned from the pairwise distances among the strains. On phylogenetic trees based on the nucleotide sequences of the VP4/VP2 coding region, HRV-A, -B and -C were provisionally assigned to 14, 2 and 12 types, respectively. The present HRV-A and -C strains had a wide genetic diversity (>30 % divergence). The interspecies distances were 0.230±0.063 (mean±sd, HRV-A), 0.218±0.048 (HRV-B) and 0.281±0.105 (HRV-C), based on nucleotide sequences, and 0.075±0.036 (HRV-A), 0.049±0.022 (HRV-B) and 0.141±0.064 (HRV-C) at the deduced amino acid level. Furthermore, HRV-A and -C were the predominant species and were detected throughout the seasons. The results suggested that HRV-A and -C strains have a wide genetic divergence and are associated with various ARIs in Japan.