A Sporadic Neonatal Case of Epidermolysis Bullosa Simplex Generalized Intermediate with KRT5 and KRT14 Gene Mutations.

Background Epidermolysis bullosa simplex (EBS) is a rare genodermatosis resulting from multiple gene mutations, including KRT5 and KRT14. The clinical expression of the mechanobullous skin fragility disease has not been fully explained by the genotype. Case Description An 11-day-old Japanese newborn infant was hospitalized because of herpetiform skin blistering on the feet, which expanded systemically after birth. There was no evidence of virus infection. The biopsied skin lesion showed a blister on the lamina densa without keratin clumps, indicating a diagnosis of EBS-generalized intermediate. We punctured the blisters to remove the contents daily, which led to no exacerbation or infection. The genetic study determined that the patient carried double substitutions of KRT5 c.1424A > G (p.E475G) and KRT14 c.1237G > A (p.A413T). The asymptomatic mother and sister carried the KRT14 substitution, but the healthy father had no substitution of the KRT gene. Conclusion This is the first report of EBS-generalized intermediate in a newborn with de novo KRT5 gene mutation and KRT14 gene polymorphism, and no familial history of epidermolysis. Neonatal blistering due to EBS requires optimal skin management after excluding infectious and immunobullous diseases.

Successful Treatment of Corticosteroid with Antiviral Therapy for a Neonatal Liver Failure with Disseminated Herpes Simplex Virus Infection.

Background Herpes simplex virus (HSV) infection carries one of the poorest outcomes of neonatal liver failure (NLF). Neonates with disseminated HSV infection can develop hemophagocytic lymphohistiocytosis (HLH), and occasionally need orthotopic liver transplantation. Early interventions may be critical for the cure of NLF. Case Report We describe herewith a 6-day-old neonate with fulminant hepatic failure due to disseminated HSV-1 infection, who successfully responded to high-dose corticosteroid therapy 72 hours after the onset of disease. Preceding acyclovir, gamma globulin, and exchange blood transfusion therapies failed to control the disease. Methylprednisolone pulse therapy led to a drastic improvement of liver function and cytokine storms, and prevented the disease progression to HLH. Sustained levels of plasma and cerebrospinal fluid HSV DNA declined after prolonged acyclovir therapy. Bilateral lesions of the periventricular white matter areas, assessed by magnetic resonance imaging, disappeared at 3 months of age. The infant showed normal growth and development at 4 years of age. Conclusion Early anti-hypercytokinemia therapy using corticosteroid, and prolonged antiviral therapy might only provide the transplantation-free cure of NLF with HSV dissemination.

Serum tau protein level serves as a predictive factor for neurological prognosis in neonatal asphyxia.

BACKGROUND: Tau protein is a microtubule-associated protein that is present in axons. Elevated tau protein levels in cerebrospinal fluid or serum are associated with several central nervous system diseases and can indicate neuronal injury. OBJECTIVE: In the present study, we measured and then compared serum tau protein levels between infants with neonatal asphyxia and control subjects. We examined these data to investigate the correlation between serum tau protein levels and neurological outcomes after neonatal asphyxia. PATIENTS AND METHODS: Serum tau protein levels were determined by an enzyme-linked immunosorbent assay in 19 neonates with neonatal asphyxia. Of these 19 neonates, 3 had severe spastic tetraplegia, and 1 had west syndrome. A group of 19 unaffected neonates was included in the study as a control group. RESULTS: Serum tau protein levels on postnatal day 3 were significantly higher in the poor outcome group than those in the good outcome (p=0.010) and control groups (p=0.006). On postnatal day 7, serum tau protein levels again were significantly higher in the poor outcome group than those in the good outcome (p=0.007) and control groups (p=0.006). CONCLUSIONS: The present findings indicate serum tau protein levels measured on postnatal days 3 and 7 can predict neurological prognosis following neonatal asphyxia.

MMP-9 and TIMP-1 in the cord blood of premature infants developing BPD.

We investigated matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in the cord blood of 29 premature infants who were <30 weeks gestation. One, 8, and 14 infants developed severe, moderate and mild bronchopulmonary dysplasia (BPD), respectively, and 6 did not. MMP-9 and TIMP-1 levels in the cord blood were determined by ELISA. MMP-9/TIMP-1 ratios in the cord blood of infants who developed severe or moderate BPD (n = 9) were significantly higher than those who developed mild BPD or did not develop BPD (n = 20; P = 0.015). Multivariate linear regressions demonstrated that MMP-9 levels and MMP-9/TIMP-1 ratios in the cord blood of the premature infants correlated with the oxygen supplementation period (r = 0.58, P = 0.003 and r = 0.41, P = 0.030, respectively). The MMP-9 levels and MMP-9/TIMP-1 ratios correlated with the severity of maternal chorioamnionitis (both trend P = 0.006). The MMP-9 levels and MMP-9/TIMP-1 ratios in the cord blood may be related to the pathogenesis and severity of BPD and maternal chorioamnionitis.

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in perinatal asphyxia.

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) play important roles in the function of the blood-brain-barrier (BBB). We investigated the roles of MMP-9 and TIMP-1 in the pathogenesis of hypoxic-ischemic encephalopathy following perinatal asphyxia. Serum concentrations of MMP-9 and TIMP-1 were determined by ELISA in 12 neonates with perinatal asphyxia and 15 controls on the birth day and the next day. Serum MMP-9 concentrations in asphyxiated neonates with neurological sequelae (n=5) were significantly higher than concentration in asphyxiated neonates without sequelae (n=7) and controls on birth day (p=0.003 and p<0.001, respectively). The ratios of serum MMP-9/TIMP-1 on birth day in asphyxiated neonates with neurological sequelae were significantly higher than those in asphyxiated neonates without sequelae (p=0.048). There were no significant differences in the serum MMP-9 concentrations or the ratios of MMP-9/TIMP-1 between asphyxiated neonates with and without neurological sequelae on the day after birth. Our preliminary study suggests that serum MMP-9 levels on birth day are important for predicting neurological prognosis of neonates with asphyxia.

Inhaled corticosteroid therapy reduces cytokine levels in sputum from very preterm infants with chronic lung disease.

AIM: To evaluate the effects of inhaled corticosteroid therapy and high-frequency oscillatory ventilation (oscillation) on preterm infants with chronic lung disease (CLD). METHODS: Ten infants with CLD who received inhaled corticosteroid therapy were enrolled. Week 1 was defined as the first week of therapy. The concentrations of interleukin (IL)-8, tumour necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-10 and IL-12p70 in serial sputum specimens from the infants were determined using a cytometric bead array. RESULTS: The sputum concentrations of IL-8 obtained from the infants during week 3-4 were significantly lower than those obtained before therapy and during week 1-2. The sputum concentrations of TNF-alpha, IL-6 and IL-10 during week 3-4 were significantly lower than the concentrations during week 1-2. The ratio of IL-8 levels during week 1-2 to those before therapy in infants who received oscillation (n = 4) was significantly lower than in those who received intermittent mandatory ventilation (n = 6). CONCLUSION: Inhaled corticosteroids may be associated with a decrease in pro-inflammatory cytokine levels in sputum from infants with CLD from 2 weeks after the start of therapy. Our further investigations suggest that therapy with oscillation modulated airway inflammation earlier than therapy with intermittent mandatory ventilation.

Male siblings with tibia-metacarpal type of chondrodysplasia punctata without maternal factors.

We report male siblings with tibia-metacarpal type of chondrodysplasia punctata, which was diagnosed by radiographic findings and clinical appearances. This is the first report of siblings without maternal systemic lupus erythematosus or medications during both pregnancies.

Analysis of serum and cerebrospinal fluid cytokine levels in subacute sclerosing panencephalitis in Papua New Guinea.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare progressive inflammatory disease characterized by the persistent infection of the brain by the measles virus. However, the immunological pathophysiology of SSPE is still unclear. METHODS: We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in the serum and cerebrospinal fluid (CSF) of 23 patients with SSPE in Papua New Guinea (PNG), a country with a high incidence of SSPE, and Japanese controls by cytometric bead array or ELISA. RESULTS: The serum IL-6 and IL-10 levels of SSPE patients were significantly higher than those of controls (p=0.0075, and p=0.0019, respectively). The serum IL-6 and IL-10 levels of SSPE patients with fever were significantly higher than those without fever (p=0.0107, and p=0.0006, respectively). The CSF IL-6 levels of SSPE patients were significantly higher than those of controls (p=0.0218). The CSF IL-6 levels of SSPE patients with myoclonic jerks were significantly higher than those without myoclonic jerks (p=0.0189). There were no differences in serum IFN-gamma, TNF-alpha, IL-2, IL-4, and sTNFR1, or CSF IFN-gamma, TNF-alpha, IL-2, IL-4, IL-10, and sTNFR1 levels between the affected patients and controls. CONCLUSION: Our present study suggests that serum IL-6 and IL-10 levels are related to fever, and the CSF IL-6 level, myoclonic jerks, in SSPE patients in PNG.

Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis.

In multiple sclerosis, there have been many reports on matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). However, MMPs and TIMPs have not been reported in acute disseminated encephalomyelitis (ADEM). We determined the relationship between the serum concentrations of MMP-9 and TIMP-1 and activity of lesions on MRI in 14 patients with ADEM to investigate the roles of MMP-9 and TIMP-1 in the pathogenesis of ADEM. Serum MMP-9 and TIMP-1 levels, measured by ELISA and gadolinium-enhanced (Gd+) brain MRI, were analyzed. Serum MMP-9 and TIMP-1 levels at the acute stage were higher than controls, and the serum MMP-9 levels at the acute stage were higher than those at the convalescent stage in ADEM. In seven patients with Gd+ lesions on brain MRI, serum MMP-9 levels and the MMP-9/TIMP-1 ratio at the acute stage were higher than those at the convalescent stage, and serum TIMP1 levels at the acute stage were lower than those at the convalescent stage. In seven patients without Gd+ lesions on brain MRI, serum TIMP-1 levels at the acute stage were higher than those at the convalescent stage. We speculated that MMP-9 is related to lesion formation at the early stage in ADEM and that TIMP-1 is induced to modulate MMP-9 activity. These findings suggest that MMP-9 and TIMP-1 secondarily play some roles in the inflammatory cascade of ADEM.

Analysis of cytokine levels in cerebrospinal fluid in mumps meningitis: comparison with echovirus type 30 meningitis.

BACKGROUND: It is unclear whether or not the CSF cytokine profiles in viral meningitis differ with the kind of causative virus. METHODS: We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-10 in CSF during the acute stage in 15 children with mumps meningitis (MM), and 34 with echovirus type 30 meningitis (EM). RESULTS: The CSF IFN-gamma, IL-2, IL-6, and IL-10 levels were elevated in MM, and the CSF IFN-gamma, IL-2, and IL-6 levels were elevated in EM. The CSF IFN-gamma, IL-2, and IL-10 levels in MM were significantly higher than those in EM (p<0.0001, p<0.0001, and p<0.0001, respectively). The CSF IL-6 levels in EM were significantly higher than those in MM (p=0.0255). The CSF TNF-alpha and IL-4 levels were not elevated in MM or EM. In MM, the IL-6 level was correlated with the IL-2 and IL-10 levels in CSF (p=0.0347 and p=0.0120, respectively). In EM, the IFN-gamma level was correlated with the IL-10 level in CSF (p=0.0002). CONCLUSION: CSF cytokine profiles in MM were different from those in EM. Therefore, it is likely that the pathogenesis of MM is different from that of EM.

Effect of montelukast on nuclear factor kappaB activation and proinflammatory molecules.

BACKGROUND: Montelukast is known as a cysteinyl leukotriene 1 receptor antagonist. However, the action of montelukast in terms of nuclear factor KB (NF-kappaB) activation and the production of proinflammatory molecules is unknown. OBJECTIVE: To demonstrate the potential anti-inflammatory effect of montelukast. METHODS: We examined whether montelukast inhibits the activation of NF-kappaB, a transcription factor that regulates the expression of proinflammatory molecules. The inhibitory effects of montelukast on tumor necrosis factor kappa (TNF-kappa)--induced NF-kappaB activation on THP-1 cells, a human monocytic leukemia cell line, were evaluated by flow cytometry, and those on lipopolysaccharide-induced interleukin 1beta (IL-1beta), IL-6, TNF-alpha, and monocyte chemoattractant protein 1 (MCP-1) production in peripheral blood mononuclear cells were evaluated by enzyme-linked immunosorbent assay. RESULTS: Flow cytometry demonstrated that montelukast inhibited NF-kappaB activation in THP-1 cells in a dose-related manner. Furthermore, 10(-5)M montelukast significantly inhibited lipopolysaccharide-induced IL-6, TNF-alpha, and MCP-1 production in the peripheral blood mononuclear cells of controls and patients with asthma. Lipopolysaccharide-induced IL-1beta production was not inhibited by montelukast. CONCLUSIONS: These findings suggest that high doses of montelukast modulate the production of IL-6, TNF-alpha, and MCP-1 through the inhibition of NF-kappaB activation. However, the anti-inflammatory effect of montelukast at therapeutic doses in patients with asthma needs to be further investigated.