Identification of a novel biomarker candidate, a 4.8-kDa peptide fragment from a neurosecretory protein VGF precursor, by proteomic analysis of cerebrospinal fluid from children with acute encephalopathy using SELDI-TOF-MS.

BACKGROUND: Acute encephalopathy includes rapid deterioration and has a poor prognosis. Early intervention is essential to prevent progression of the disease and subsequent neurologic complications. However, in the acute period, true encephalopathy cannot easily be differentiated from febrile seizures, especially febrile seizures of the complex type. Thus, an early diagnostic marker has been sought in order to enable early intervention. The purpose of this study was to identify a novel marker candidate protein differentially expressed in the cerebrospinal fluid (CSF) of children with encephalopathy using proteomic analysis. METHODS: For detection of biomarkers, CSF samples were obtained from 13 children with acute encephalopathy and 42 children with febrile seizure. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology, which is currently applied in many fields of biological and medical sciences. Diagnosis was made by at least two pediatric neurologists based on the clinical findings and routine examinations. All specimens were collected for diagnostic tests and the remaining portion of the specimens were used for the SELDI-TOF MS investigations. RESULTS: In experiment 1, CSF from patients with febrile seizures (n = 28), patients with encephalopathy (n = 8) (including influenza encephalopathy (n = 3), encephalopathy due to rotavirus (n = 1), human herpes virus 6 (n = 1)) were used for the SELDI analysis. In experiment 2, SELDI analysis was performed on CSF from a second set of febrile seizure patients (n = 14) and encephalopathy patients (n = 5). We found that the peak with an m/z of 4810 contributed the most to the separation of the two groups. After purification and identification of the 4.8-kDa protein, a 4.8-kDa proteolytic peptide fragment from the neurosecretory protein VGF precursor (VGF4.8) was identified as a novel biomarker for encephalopathy. CONCLUSIONS: Expression of VGF4.8 has been reported to be decreased in pathologically degenerative changes such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and encephalopathy. Thus, the VGF4.8 peptide might be a novel marker for degenerative brain conditions.

Enhanced expression of cytokines/chemokines in cerebrospinal fluids in mumps meningitis in children.

BACKGROUND: The mumps virus is frequently the causative agent in aseptic meningitis and mumps has still prevailed in Japan. We compared data obtained from patients with mumps meningitis and patients with aseptic meningitis caused by other viruses in order to identify mumps meningitis-specific cytokine/chemokine alterations in cerebrospinal fluid (CSF). METHODS: We elucidated the cytokine/chemokine network based on the cytokine/chemokine profiles in CSF from children with mumps meningitis and meningitis due to other viral infections using multiplex cytokine measurement. Seventeen cytokines/chemokines, namely interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1ß (MIP-1ß), were measured simultaneously in CSF supernatants from eight children with mumps meningitis, 11 children with other types of viral meningitis and eight children with fever without neurological complications such as convulsion. RESULTS: We found that IL-8, IL-10, IL-12, IL-13 and IFN-γ showed a statistically significant increase in CSF from mumps meningitis when compared to other types of viral meningitis and fever without neurological complications. CONCLUSION: Mumps meningitis may induce a distinct immunological response when compared with other types of viral meningitis.

High mobility group box 1 in cerebrospinal fluid from several neurological diseases at early time points.

The present study aimed to elucidate the possible role of High Mobility Group Box 1 (HMGB1), which is a candidate prognostic marker in diseases that combine inflammation and tissue injury, in acute encephalopathy. HMGB1 in cerebrospinal fluid (CSF) obtained on admission from eight children with acute encephalopathy, and 16 children with febrile seizure, eight children with bacterial/aseptic meningitis, and eight children with fever without neurological symptoms were analyzed using enzyme-linked immunosorbent assay (ELISA). We found no increase in HMGB1 in CSF from acute encephalopathy or in CSF from febrile seizure or fever without neurological complications at early time points, while marked elevation of HMGB1 was seen in CSF from bacterial and aseptic meningitis. In conclusion, HMGB1 is a poor disease marker for acute encephalopathy.

IL-17 is elevated in cerebrospinal fluids in bacterial meningitis in children.

Bacterial meningitis has a poor prognosis and neurologic complications. The present study aimed to investigate the cytokine/chemokine network in cerebrospinal fluid (CSF) from children with bacterial meningitis and aseptic meningitis. Interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta, were measured simultaneously in CSF supernatants. We found that, IL-17 was significantly elevated in CSF with bacterial meningitis. We believe that IL-17 plays a key role in neutrophil infiltration into CSF and neuronal protection in bacterial meningitis.

High prevalence of antibodies against Bartonella henselae with cervical lymphadenopathy in children.

BACKGROUND: Cat-scratch disease is the most common form of Bartonella henselae infection. Although reports have shown that CSD is relatively common, they have not shown the prevalence of seropositivity for Bartonella henselae in cases of cervical lymphadenitis and Kawasaki disease, which are relatively common diseases in children. METHODS: We evaluated the presence of immunoglobulin (Ig) G- and IgM-class antibodies against Bartonella henselae in children with cervical lymphadenitis, Kawasaki disease, and infectious diseases without lymphadenopathy in a semi-rural area in Japan. RESULTS: We found that the positivity rate for the IgG antibody against Bartonella henselae in patients with cervical lymphadenitis who owned cats or dogs was significantly higher than that in patients with Kawasaki disease and infectious diseases without lymphadenopathy. However, the average age of children with cervical lymphadenitis did not significantly differ when compared to those with other infectious diseases. CONCLUSION: Our serological study showed that Bartonella henselae infection may contribute to the etiology of cervical lymphadenitis in children.

Fungal thoracic Spondylodiskitis in an immunocompetent 14-year-old girl.

Fungal spondylodiskitis (inflammation of intervertebral disk tissue and adjacent vertebrae) is rare, particularly in immunocompetent patients. Here, we report a case of fungal and bacterial thoracic spondylodiskitis in a 14-year-old girl with abdominal and back pain. The spondylodiskitis was diagnosed on the basis of the presence of beta-D glucan and the unusual clinical course, although cultures for fungus were negative. We conclude spondylodiskitis must be considered in cases of abdominal pain without clear etiology and in cases of fungal infection with unexplainable findings after standard treatment for bacterial infection, even when fungal cultures are negative.

Vigabatrin Therapy for Infantile Spasms in a Case of Cardiofaciocutaneous Syndrome with Cardiac Hypertrophy Developing during Adrenocorticotropic Hormone Treatment.

In a patient with cardiofaciocutaneous syndrome complicated by intractable infantile spasms (West syndrome), cardiac hypertrophy developed during adrenocorticotropic hormone treatment. Various types of antiepileptic drugs, intravenous immunoglobulin, thyrotropin releasing hormone, and a ketogenic diet were ineffective in this case. However, vigabatrin both decreased clinical seizures and improved electroencephalogram findings. Although vigabatrin has not been approved for use in Japan, the results in the present case suggest that this drug should be considered as an alternative therapy for cases of infantile spasms associated with syndromes involving cardiomyopathy or its potential risk factors, such as cardiofaciocutaneous syndrome.

[Clinical neurophysiological study of verbal and non-verbal sound perception: normal development of P300 event-related potential to different sound stimuli].

Developmental changes of P300 event related potential were evaluated in healthy children and adults aged from 7 to 29 years old, adopting 2 pairs of oddball stimuli: a non-verbal sound (tone burst: TB) pair and a verbal sound (VS) pair. P300 was evident for the target stimuli. In adult subjects, P300 was dominant at Pz for both stimuli. Peak latency of P300 was significantly longer for VS than for TB in both groups. P300 amplitude of the child group was higher than that of the adult group, however, there was no difference in P300 amplitude between stimuli conditions. Developmental changes of P300 from each stimuli condition were simulated by a quadratic equation. The age showing the shortest P300 peak latency was younger for TB (20.3 years) than for VS (23.6 years). The P300 peak latency reduced around 10 years old more rapidly for VS than for TB. In conclusion, there was no difference of the dominancy of P300 between the stimuli. The developmental changes of P300 were regulated by several components of the sound stimuli, such as their frequency.

Hydrocephalus with spontaneous regression in a 14-year-old girl.

We report on a 14-year-old girl with hydrocephalus that underwent spontaneous regression without any specific treatment, such as ventriculoperitoneal shunt surgery. A 14-year-old girl was referred to our hospital with severe headache, dizziness, nausea, and vomiting. Computed tomography and FLAIR-MRI findings on admission showed markedly dilated lateral, third and fourth ventricles with periventricular hyperintensity and downward displacement of the tonsils induced by dilatation of the fourth ventricle. We diagnosed hydrocephalus of unknown etiology. Although no specific treatment for hydrocephalus was performed, the symptoms gradually improved. One year after onset, the patient was completely free of neurological symptoms, and findings of physical examination and magnetic resonance imaging of the brain had returned to normal. The etiology of the spontaneous regression is unclear, but the following mechanisms are discussed: 1) rupture of ventricular diverticulum, 2) head injury causing skull-base fracture with leakage of cerebrospinal fluid, 3) extremely radiosensitive neoplasms diminished by X-p exploration, and 4) cerebrospinal fluid leakage due to lumbar puncture.

Acute pancreatitis complicating typhoid fever in a 4-year-old girl.

Pancreatitis represents an extremely rare complication of typhoid fever. Herein we report the case of a 4-year-old Bangladeshi girl with acute pancreatitis caused by Salmonella typhi.