Shingo Oana

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)-1β levels were also high in other patients. These data suggest that chemokines in CSF play roles in neurological complications in RSV-infected children.

Cerebrospinal Fluid Diacron-Reactive Oxygen Metabolite Levels in Pediatric Patients With Central Nervous System Diseases

This study assessed the validity of cerebrospinal fluid oxidative status of pediatric patients with central nervous system diseases, using the Diacron-Reactive Oxygen Metabolites test (d-Roms; Diacron International s.r.l.; Grosseto, Italy). Eighty-seven pediatric patients (8 with bacterial meningitis, 18 with aseptic meningitis, 23 with febrile seizures, 6 with rotavirus gastroenteritis-induced convulsions, 16 with epilepsy, 2 with adrenoleukodystrophy, 2 with multiple sclerosis, and 12 control subjects) were enrolled. An analysis of the infection-associated group (bacterial meningitis, aseptic meningitis, febrile seizures, and rotavirus gastroenteritis-induced convulsions) indicated that cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in the bacterial meningitis group were significantly higher than in other infection-associated groups. In the bacterial meningitis group, the cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels obtained after improvement were significantly decreased compared with pre-improvement values. In the noninfection-associated group (epilepsy, adrenoleukodystrophy, and multiple sclerosis), the cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in symptomatic epilepsy patients were higher than in cryptogenic epilepsy patients and control subjects, but not significantly. Progressive patients with adrenoleukodystrophy or multiple sclerosis demonstrated high Diacron-Reactive Oxygen Metabolite levels compared with another early-stage adrenoleukodystrophy patient. Oxidative stress may be associated with the pathogenesis of various pediatric central nervous system diseases. Cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels may correlate with clinical status in these diseases.

Increased level of serum interleukin-1 receptor antagonist subsequent to resolution of clinical symptoms in patients with West syndrome

The aim of this study was to evaluate whether proconvulsive interleukin-1β (IL-1β) and anticonvulsive IL-1 receptor antagonist (IL-1Ra) are markers of the effectiveness of treatment in patients with West syndrome (WS). We analyzed serum and cerebrospinal fluid (CSF) levels of IL-1β and IL-1Ra in 13 patients with WS. The serum IL-1Ra levels postimprovement (average, 384.6 pg/ml) in clinical and electroencephalographic (EEG) findings were significantly higher than the preimprovement values (average, 240.6 pg/ml). No significant difference in the preimprovement serum IL-1Ra levels was noted between the anticonvulsant (AED)-response and adrenocorticotropic hormone (ACTH)-response groups (260.0 pg/ml, n=7 vs. 218.0 pg/m, n=6) and the cryptogenic and symptomatic groups (290.1 pg/ml, n=4 vs. 218.3 pg/m, n=9), respectively; as for the preimprovement CSF levels, the AED-response group (114.5 pg/m; n=3) and ACTH-response groups (138.0 pg/m; n=6) and the cryptogenic (59.3 pg/m; n=3) and symptomatic groups (165.6 pg/m; n=6), respectively. Serum and CSF IL-1β levels were detected only in 3 patients preimprovement. Serum IL-1Ra levels were elevated subsequent to resolution of clinical and EEG findings in WS patients. A larger study should be conducted to clarify whether an immunological processes are concerned with the pathophysiology of WS.

Examination of neurological prognostic markers in patients with respiratory syncytial virus-associated encephalopathy

No biomarker has been established as a prognostic indicator of acute encephalopathy associated with various etiological factors. In this study, we examined useful prognostic biomarkers in patients with acute encephalopathy associated with respiratory syncytial virus (RSV) infection. The subjects were 11 children with RSV-associated encephalopathy admitted to our hospital. We measured the levels of interleukin (IL)-6, brain-derived neurotrophic factor (BDNF) and nitrogen oxide (NO)x in cerebrospinal fluid collected on the day of admission. Using the pediatric cerebral performance categories (PCPC) score as a prognostic indicator, we evaluated the association between the biomarkers and neurologic prognosis. Concerning neurologic prognosis, sequelae were noted in more than 50% of the subjects. There was no association between prognosis and age/sex. Increases in the levels of all biomarkers were observed in all subjects. IL-6 and BDNF levels were correlated with PCPC score, but not with NOx. Of the biomarkers investigated, the IL-6 and BDNF levels in cerebrospinal fluid were shown to be correlated with neurologic prognosis. Because many patients with this disease had severe sequelae, assessment should be conducted by early evaluation of the biomarkers examined in this study with respect to the clinical course.

Acute suppurative oligoarthritis and osteomyelitis: A differential diagnosis that overlaps with acute rheumatic fever

BACKGROUND Acute rheumatic fever (ARF) is an illness caused by group A streptococcus (GAS) infection, and remains the leading cause of acquired heart disease in worldwide. Distinguishing between ARF and septic arthritis may be difficult. This report describes a case of suppurative arthritis overlapping with ARF. CASE PRESENTATION A 4-year-old, previously healthy boy presented with fever and left leg pain. The level of anti-streptolysin O (ASO) was elevated. His throat swab cultures grew GAS, but none were detected in his synovial fluid. Magnetic resonance imaging revealed suspected arthritis and osteomyelitis. The patient was treated for septic arthritis, but was subsequently diagnosed with ARF, after the development of carditis. CONCLUSION The clinical and laboratory features of ARF and suppurative arthritis demonstrate substantial overlap. Patients with an elevated ASO should undergo a careful cardiac examination for carditis associated with ARF by an echocardiogram.

Brain-Derived Neurotrophic Factor and Interleukin-6 Levels in the Serum and Cerebrospinal Fluid of Children with Viral Infection-Induced Encephalopathy

We investigated changes in the brain-derived neurotrophic factor (BDNF) and interleukin (IL)-6 levels in pediatric patients with central nervous system (CNS) infections, particularly viral infection-induced encephalopathy. Over a 5-year study period, 24 children hospitalized with encephalopathy were grouped based on their acute encephalopathy type (the excitotoxicity, cytokine storm, and metabolic error types). Children without CNS infections served as controls. In serum and cerebrospinal fluid (CSF) samples, BDNF and IL-6 levels were increased in all encephalopathy groups, and significant increases were noted in the influenza-associated and cytokine storm encephalopathy groups. Children with sequelae showed higher BDNF and IL-6 levels than those without sequelae. In pediatric patients, changes in serum and CSF BDNF and IL-6 levels may serve as a prognostic index of CNS infections, particularly for the diagnosis of encephalopathy and differentiation of encephalopathy types.

A case of recurrent acute encephalopathy with febrile convulsive status epilepticus with carnitine palmitoyltransferase II variation.

Acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) is the most common type of acute encephalopathy in childhood in Japan, which develops with prolonged febrile convulsion, followed by mild unconsciousness. It is generally sporadic and nonrecurrent. In this report, a 1-year-old girl showed signs of AEFCSE triggered by respiratory syncytial virus infection. Two years later, she presented with AEFCSE triggered by influenza virus infection, resulting in severe neurologic sequelae. The patient had a thermolabile genotype of carnitine palmitoyltransferase II (CPT II) variations consisting of three single nucleotide polymorphisms in exons 4 [1055T > G/F352C and 1102G > A/V368I] and 5 [1939A > G/M647V]. The polymorphism has been identified as a genetic predisposition for acute encephalopathy. This report presents the first case of recurrent encephalopathy with CPT II variations that may partially associate with pathogenesis of recurrent AEFCSE.

X‐linked adrenoleukodystrophy with partial deletion of ALD due to fusion with the neighbor gene, PLXNB3

Tadashi Matsumoto,* Noriko Miyake, Yoshiaki Watanabe, Gaku Yamanaka, Shingo Oana, Masaaki Ogiwara, Akinori Hoshika, Noriko Sasaki, Harumi Miyahara, and Norio Niikawa Department of Nursing, Nagasaki University School of Medicine, Nagasaki, Japan Department of Human Genetics, Nagasaki University School of Medicine, Nagasaki, Japan CREST, Japan Science and Technology (JST), Kawaguchi, Japan Department of Pediatrics, Tokyo Medical University, Tokyo, Japan

Novel compound heterozygous DPH1 mutations in a patient with the unique clinical features of airway obstruction and external genital abnormalities

The diphthamide biosynthesis 1 (DPH1) gene encodes one of the essential components of the enzyme catalyzing the first step of diphthamide formation on eukaryotic elongation factor 2 (EEF2). Diphthamide is the posttranslationally modified histidine residue on EEF2 that promotes protein chain elongation in the ribosome. DPH1 defects result in a failure of protein synthesis involving EEF2, leading to growth defects, embryonic lethality, and cell death. In humans, DPH1 mutations cause developmental delay with a short stature, dysmorphic features, and sparse hair, and are inherited in an autosomal recessive manner (MIM#616901). To date, only two homozygous missense mutations in DPH1 (c.17T>A, p.Met6Lys and c.701T>C, p.Leu234Pro) have been reported. We used WES to identify novel compound heterozygous mutations in DPH1 (c.289delG, p.Glu97Lysfs*8 and c.491T>C, p.Leu164Pro) in a patient from a nonconsanguineous family presenting with intellectual disability, a short stature, craniofacial abnormalities, and external genital abnormalities. The clinical phenotype of all patients with DPH1 mutations, including the current patient, revealed core features, although the external genital anomaly was newly recognized in our case.

Pathological analysis of children with childhood central nervous system infection based on changes in chemokines and interleukin‐17 family cytokines in cerebrospinal fluid

In this study, the pathologies of acute meningitis and encephalopathy were investigated, and biomarkers useful as prognostic indices were searched for.