Marked Elevation of Excitatory Amino Acids in Cerebrospinal Fluid Obtained From Patients With Rotavirus-Associated Encephalopathy.

Rotavirus is the most common cause of severe gastroenteritis in young children; however, its pathogenesis and immunity are not completely understood. Even less well recognized is rotavirus-induced central nervous system (CNS) involvement, which has been associated with seizure, encephalopathy and death, among others. To elucidate the host response to rotavirus infection, we retrospectively examined neurotransmitter amino acids in the cerebrospinal fluid (CSF) of 19 children with CNS involvement associated with rotavirus infection. Subjects were classified into two groups: those with encephalopathy followed by prolonged seizure (encephalopathy group) and those who had experienced afebrile, brief cluster of seizures without encephalopathy (cluster group). The levels of glutamate, glycine, and taurine in the encephalopathy group were significantly higher than those in the cluster group. Increased levels of excitatory amino acids in the CSF may induce neurological disorders and be related to disorder severity. To the best of our knowledge, this is the first report regarding amino acids in the CSF obtained from patients with rotavirus-induced CNS involvement. Further study is necessary to elucidate the role of CSF amino acid levels in rotavirus-induced CNS involvement.

Comparison of changes in cerebral and systemic perfusion between appropriate- and small-for-gestational-age infants during the first three days after birth.

PURPOSE: The aims of the current study were to compare changes in cerebral and systemic perfusion in appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) infants immediately after birth. METHODS: Cerebral blood volume (CBV), cerebral Hb oxygen saturation (cSO2) and cerebral fractional tissue oxygen extraction (cFTOE) among 57 AGA infants and 30 SGA infants were monitored using a newly developed time-resolved spectroscopy system during the first 3days of life. The left ventricular ejection fraction (LVEF), left ventricular cardiac output (LVCO) and E/e' values were determined by three-dimensional echocardiography and tissue Doppler imaging performed simultaneously. RESULTS: There were significant differences between the body weights of both the AGA and SGA infants, but not between the gestational age and head circumferences in both groups. Although CBV showed no significant difference between the groups, cSO2 was significantly higher and cFTOE was lower in SGA infants than in AGA infants. Hematocrit (Ht) levels were significantly higher and LVEF and LVCO were lower in SGA infants than in AGA infants. Negative correlation was observed between CBV and Ht levels in AGA infants, but not in SGA infants. CONCLUSIONS: The high Ht levels and vasoreactivity in SGA infants might be a compensatory mechanism in order to maintain oxygen delivery to the brain, which reflects the condition of chronic hypoxia during the fetal period and also reflects the weak contraction and low cardiac output of the left ventricle sustaining the relatively large brain from the fetal period to after birth.

Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients.

OBJECTIVES: Kawasaki disease (KD) is an acute systemic vasculitis. Activation of the immune system is a central feature of KD. Some KD patients are resistant to initial high-dose intravenous immunoglobulin (IVIG) treatment. The study aimed to determine the predictors of IVIG resistance. METHOD: A single-center, retrospective study was conducted using data from 129 patients diagnosed with KD. Two groups of patients emerged within the IVIG-treated population (105 patients): an IVIG responder group (n = 84) and an IVIG-resistant group (n = 21). Laboratory data and patient characteristics were compared between the two groups. RESULTS: The average serum interleukin (IL)-6 level was 102.7 ± 97.4 pg/mL in the IVIG responder group and 207.7 ± 127.1 pg/mL in the IVIG resistant group (P < 0.01). C-reactive protein (CRP) levels and neutrophil percentages were significantly elevated in the IVIG resistant group. Multivariate logistic regression analysis identified that a prediction score could be generated by assigning two points to neutrophil percentages ≥ 75%, and either two points for an IL-6 level ≥ 140 pg/mL or one point for an IL-6 level ≥ 70 pg/mL but < 140 pg/mL. A cut-off score of ≥ three allowed identification of IVIG-resistant patients with an 85% sensitivity and 77% specificity. CONCLUSIONS: Resistance to IVIG therapy is characterized by elevated levels of IL-6, CRP and percentages of circulating neutrophils. Resistance to IVIG treatment can be predicted using a scoring system involving IL-6 and percentages of neutrophils.

Expressions of brain-derived neurotrophic factor (BDNF) in cerebrospinal fluid and plasma of children with meningitis and encephalitis/encephalopathy.

Many reports in the field of childhood brain disorders have documented that brain-derived neurotrophic factor (BDNF) affects central nervous system (CNS) functions. In this clinical study, BDNF levels were evaluated in association with pediatric CNS infections. BDNF levels in the serum and cerebrospinal fluid (CSF) of 42 patients admitted during 5-year period, due to CNS infections, were measured by enzyme-linked immunosorbent assays (ELISAs). Control samples were collected from 108 patients with non-CNS infections (urinary tract infection, acute upper respiratory infection, acute gastroenteritis, etc.). Mean values of BDNF levels, at various ages, were determined and compared. BDNF levels were below the sensitivity of the ELISA in most CSF samples from the control group, but were significantly elevated in the patients with bacterial meningitis. The serum BDNF levels were elevated in all subgroups of patients with CNS infections, and the elevation was particularly notable in those with bacterial meningitis. BDNF expression in the CSF was correlated with CSF interleukin (IL)-6 levels as well as with blood platelet counts and neurological prognoses in those with bacterial meningitis. No correlation was found between BDNF levels and serum leukocyte numbers or C-reactive protein (CRP) levels. BDNF levels were found to be elevated in the serum and CSF of pediatric patients with CNS infections, particularly those with bacterial meningitis. Monitoring the changes in serum and CSF levels of BDNF may facilitate the diagnosis of acute meningitis and acute encephalopathy and allow the differential diagnosis of specific CNS infections.

Effects of indomethacin on patent ductus arteriosus in neonates with genetic disorders and/or congenital anomalies.

OBJECTIVES: The study aimed to evaluate the effectiveness of intravenous indomethacin (IND) therapy for patent ductus arteriosus (PDA) in neonates with genetic disorders and/or congenital anomalies soon after birth. STUDY DESIGN: A total of 301 neonates with a genetic disorder and/or congenital anomalies and with a gestational age of ≥ 35 weeks were admitted during the study period. Eighty-five neonates with 56 genetic disorders (30 cases of trisomy 21, 10 cases of trisomy 18, and 16 others) and 29 congenital anomalies, and with clinical symptoms received intravenous IND therapy. The management methods were similar to those used for PDA in low-birth-weight infants. RESULTS: IND therapy had a clinical benefit at a high rate of 79% in these patients (90% and 70% in neonates with trisomies 21 and 18, respectively), including complete closure of the PDA in 52% of the patients. Although oliguria was observed in 43 infants (51%) and slight gastrointestinal bleeding was observed in 12 (14%), no infants had severe complications such as intracranial bleeding. CONCLUSIONS: IND therapy is an effective treatment option before considering surgery for PDA in neonates with genetic disorders and/or congenital anomalies. This therapy may reduce the difficulty of treatment in the acute stage among these neonates.

High production of interleukin-10 and interferon-γ in influenza-associated MERS in the early phase.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) occurs in various diseases and pathologies, and the clinical symptoms are not consistent with the impaired region. The mechanism of the region specificity is unclear. We investigated the cytokine profiling in cerebrospinal fluid (CSF) and serum obtained from a child with MERS during influenza infection, and compared them with those of serious another serious type of influenza-associated encephalopathy. There was no elevation of Interleukin (IL)-1ß, which induces convulsion. The inhibitory cytokines of IL-10 and IFN-γ were elevated in the early phase in CSF. Comparing them with other patients, the elevation of the cytokine levels were generally mild. Considering that the prognosis of this MERS case was favorable and high levels of inhibitory cytokines including IL-10 and IFN-γ might work to localize the lesion and to prevent sequelae.

Umbilical cord milking stabilizes cerebral oxygenation and perfusion in infants born before 29 weeks of gestation.

OBJECTIVE: To investigate the effects of umbilical cord milking at birth on cerebral perfusion and systemic perfusion in very low birth weight (VLBW) infants. STUDY DESIGN: Cerebral tissue oxygenation index and cerebral fractional tissue oxygen extraction were monitored in 50 stable VLBW infants (gestational age <29 weeks, birth weight <1250 g), with 26 allocated to the milked group and 24 to the control group. We used near-infrared spectroscopy 3-6, 12, 18, 24, 36, 48, and 72 hours after birth. Left ventricular end-diastolic dimension, left ventricular ejection fraction, left ventricle (LV) Tei index (measurement of left ventricular systolic and diastolic function), left ventricular cardiac output, and superior vena cava flow were measured concurrently using echocardiography. RESULTS: There were no significant differences in gestational age and birth weight between the 2 groups. Hematocrit, left ventricular end-diastolic dimension, left ventricular cardiac output, and superior vena cava flow were higher in the milked group than in the control group, with improvement in the LV Tei index despite the absence of left ventricular ejection fraction changes within 24 hours after birth. Tissue oxygenation index increased and cerebral fractional tissue oxygen extraction decreased in the milked group within 24 hours after birth. CONCLUSION: Umbilical cord milking stabilized cerebral oxygenation and perfusion in VLBW infants by improving LV diastolic function by increasing LV preload.

Production of chemokines in respiratory syncytial virus infection with central nervous system manifestations.

Respiratory syncytial virus (RSV) infection in children can be associated with acute encephalopathy. However, the roles of cytokines in the cerebrospinal fluid (CSF) of such patients remain unevaluated. In this study, a profile of 17 cytokines was determined for eight RSV-infected children with neurological complications. In one patient with high levels of 13 cytokines, a cytokine storm was considered to have occurred. Interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1ß levels were also high in other patients. These data suggest that chemokines in CSF play roles in neurological complications in RSV-infected children.

PKC-δ mediates interferon-α-induced apoptosis through c-Jun NH2-terminal kinase activation.

BACKGROUND: Interferon-α (IFN-α) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-α induced a sustained activation of c-Jun NH2-terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-α-initiated activation of JNK1. RESULTS: IFN-α caused activation of PKC-δ in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-δ. The dominant-negative form of mutant PKC-δ (dnPKC-δ) reduced the IFN-α-induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (ΔΨm), and increase in propidium iodide (PI) positive cells. The IFN-α-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-δ inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-δ enhanced the IFN-α-induced TRAIL promoter activity and loss of ΔΨm in Daudi B lymphoma cells. In addition, IFN-α-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-δ. CONCLUSIONS: IFN-α induced JNK1 activation via PKC-δ, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of ΔΨm and increase in PI positive cells. The IFN-α-induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC-δ-mediated signaling component(s).

[Successful treatment of congenital cytomegalovirus infection with valganciclovir].

Congenital cytomegalovirus (CMV) infection occurs frequently in neonates. However, there are no screening tests or definitive treatments for this infection in Japan. We report a case of a 21-day-old Japanese boy with congenital CMV infection. He was referred to our hospital for treatment of congenital bilateral deafness. Brain magnetic resonance imaging (MRI) revealed cortical dysplasia of the temporal poles, enlarged ventricles, and areas of abnormal intensity in the white matter. He was given a diagnosis of congenital CMV infection based on the detection of CMV DNA in his urine and the umbilical cord. After the administration of valganciclovir, no CMV DNA was detected in his serum, and brain MRI and electroencephalogram findings, motor development, and deafness improved. Further investigation is needed to establish a screening test and treatment for congenital CMV infection in Japan.

A boy with non-herpes simplex acute limbic encephalitis and antiglutamate receptor antibodies.

This report concerns a 12-year-old male with intractable seizures over a long period. The case fulfilled the diagnostic criteria for nonherpetic acute limbic encephalitis. He had frequent convulsions starting with a partial seizure at the left angle of the mouth and progressing to secondary generalized seizures. He was treated with several anticonvulsants, combined with methylprednisolone and γ-globulin under mechanical ventilation. However, his convulsions reappeared after tapering of the barbiturate. His magnetic resonance imaging showed a high intensity area in the hippocampus by FLAIR and diffusion. After five months he recovered without serious sequelae. Virological studies, including for herpes simplex virus, were all negative. He was transiently positive for antiglutamate receptor antibodies in cerebrospinal fluid and serum.

A new proposal for a clinical-oriented subclassification of baboon syndrome and a review of baboon syndrome.

OBJECTIVE: To review baboon syndrome (BS). DATA SOURCES: Date sources were obtained from PubMed and Google Scholar: Photographs of baboon syndrome were obtained from our patient. STUDY SELECTIONS: PubMed and Google Scholar were searched up to June 30, 2010. The search terms were "baboon syndrome", "SDRIFE" and "thimerosal allergy". Reverse references from relevant articles and Google Scholar were also used. As BS is a classical disease and cases of offending agents were relatively old, some references were more than five years old. In order to gather as many cases of offending agents as possible, more than 50 references were collected. RESULTS AND CONCLUSION: We divided BS into as 4 groups; classical baboon syndrome, topical drug-induced baboon syndrome, systemic drug-induced baboon syndrome and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). The pathomechanism of BS is still unknown. A delayed type of hypersensitivity reaction, a recall phenomenon, pharmacologic interaction with immune-receptors and anatomical factors may be involved in the causation of BS.

Classification of acute encephalopathy in respiratory syncytial virus infection.

Infection with respiratory syncytial virus (RSV) is known to be associated with central nervous system symptoms such as convulsions. We investigated cytokines, nitrogen oxide (NO)( x ), and the viral genome in cerebrospinal fluid (CSF) obtained from children with RSV infection-related convulsions or central nervous symptoms and compared the data with type of encephalopathy. Of nine patients enrolled (six boys and three girls; aged 10 days-3 years), one metabolic error, five excitotoxicity, one cytokine storm, and two hypoxia cases were found. The patients presented with unilateral convulsions, generalized convulsions, and convulsions following cardiopulmonary arrest, apnea, and nuchal rigidity. In all patients, a rapid check for RSV of nasal fluid was positive. The RSV genome (subgroup A) was detected in the CSF of five of the nine patients; two patients with hypoxic encephalopathy were negative for the RSV genome. The CSF interleukin (IL)-6 levels were high only in patients with the excitotoxicity and cytokine storm type of encephalopathy. NO( x ) levels were high in all the subject cases. In the excitotoxicity type, NO( x ) levels were significantly higher than those in the control and other groups. NO( x ) level may become an important parameter for the diagnosis and classification of acute encephalopathy in RSV. Strategies to treat each type of encephalopathy, targeting cytokines and free radicals, should be established.

Myopathy and neurogenic muscular atrophy in unexpected cardiopulmonary arrest.

BACKGROUND: Neuromuscular disorders can be the cause of sudden death of infants because of their weakness and gastroesophageal reflux (GER). METHODS: Muscle biopsy and genetic studies were performed by usual method. RESULTS: In this report four cases of infants with neuromuscular disorders (two cases of congenital myopathy and two cases of spinal muscular atrophy) who had unexpected cardiopulmonary arrest on arrival (CPAOA) are presented. Two of the cases did not show any symptoms, such as muscle weakness prior to CPAOA. The diagnosis was based on the results of the muscle biopsy and genetic examination. CONCLUSION: These results suggest that sudden infant death caused by neuromuscular disorders should be considered.

Efficacy of prolonged valganciclovir therapy for congenital cytomegalovirus infection.

We report prolonged valganciclovir (VGCV) treatment of a symptomatic cytomegalovirus infection case. Automated auditory brainstem evoked response performed at 5 days of age revealed severe hearing impairment. Cranial magnetic resonance (MR) imaging at 11 days of age showed abnormal findings. At 5 weeks of age, VGCV was started. The viral load in blood cells, plasma, and urine decreased during the 6-week treatment. Because of improvement of hearing level and no adverse effects, VGCV was restarted for an additional 6 weeks. Neither the patient's hearing impairment nor results of cranial MR imaging have become worse in 6 months. It is crucial to gather information from as many cases as possible treated with VGCV to establish a standard protocol for VGCV treatment.

A case of juvenile idiopathic polyarticular arthritis complicated by IgA deficiency in 22q11 deletion syndrome.

Chronic arthritis may occur in association with antibody deficiency and chromosomal aberrations. This report presents the case of a 6-year-old girl with chromosome 22q11 deletion syndrome and chronic arthritis. The onset of arthritis occurred at 4 years of age. The chronic arthritis course has been the polyarticular type. Neither antinuclear antibody nor rheumatoid factor was detected. Serum IgA was extremely low. She was diagnosed with juvenile idiopathic polyarticular arthritis (JIA) complicated by IgA deficiency in the 22q11 deletion syndrome. There is an increased prevalence of chronic arthritis in association with 22q11 deletion syndrome with IgA deficiency, but the reasons for this association are unknown. This study evaluated the possible correlation between cytokines and the susceptibility to chronic arthritis in the 22q11 deletion syndrome with IgA deficiency. The expression of pro-inflammatory cytokines such as IL-8, IL-6, MIP-1ß, and MCP-1 suggests that T and B cells, macrophages and neutrophils modulate joint inflammation by an immune response. And the presence of IL-10 and IL-5 might suggest that the synovitis is associated with JIA and IgA deficiency.

Extreme efficiency of airway pressure release ventilation (APRV) in a patient suffering from acute lung injury with pandemic influenza A (H1N1) 2009 and high cytokines.

The authors report a Japanese boy with severe pandemic influenza A(H1N1) 2009-associated pneumonia and deteriorating oxygenation. He dramatically recovered after the use of Airway Pressure Release Ventilation (APRV) mode. There was no improvement by using any conventional ventilation, however, APRV immediately led to an improvement of his clinical symptoms and laboratory findings.