Kazuhiro Shiraishi

Protective effect of aminoguanidine on hypoxic-ischemic brain damage and temporal profile of brain nitric oxide in neonatal rat

Nitric oxide (NO) produced by inducible NO synthase contributes to ischemic brain damage. However, the role of inducible NO synthase-derived NO on neonatal hypoxic-ischemic encephalopathy has not been clarified. We demonstrate here that aminoguanidine, a relatively selective inhibitor of inducible NO synthase, ameliorated neonatal hypoxic-ischemic brain damage and that temporal profiles of NO correlated with the neuroprotective effect of aminoguanidine. Seven-day-old Wister rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure (8% oxygen). Infarct volumes (cortical and striatal) were assessed 72 h after the onset of hypoxia-ischemia by planimetric analysis of coronal brain slices stained with hematoxylin-eosin. Aminoguanidine (300 mg/kg i.p.), administered once before the onset of hypoxia-ischemia and then three times daily, significantly ameliorated infarct volume (89% reduction in the cerebral cortex and 90% in the striatum;p < 0.001). NO metabolites were measured by means of chemiluminescence using an NO analyzer. In controls, there was a significant biphasic increase in NO metabolites in the ligated side at 1 h (during hypoxia) and at 72 h after the onset of hypoxia (p < 0.05). Aminoguanidine did not suppress the first peak but significantly reduced the second one (p < 0.05), and markedly reduced infarct size in a neonatal ischemic rat model. Suppression of NO production after reperfusion is a likely mechanism of this neuroprotection.

Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality

Borealin/DasraB is a member of the chromosomal passenger protein complex (CPC) required for proper segregation of chromosomes during mitosis. In Drosophila melanogaster, inactivation of Borealin/DasraB results in polyploidy, delayed mitosis and abnormal tissue development, indicating its critical role for cell proliferation. However, the in vivo role of mammalian Borealin/DasraB remains unclear. Here, we analyzed the expression of Borealin/DasraB and found that borealin is widely expressed in embryonic tissues and later restricted to adult tissues which relies on rapid cell proliferation. To determine the role of borealin during mouse development, we generated borealin-null mice through targeted disruption. While heterozygous mice developed normally, disruption of both borealin alleles resulted in early embryonic lethality by 5.5 dpc (days postcoitus) due to mitotic defects and apoptosis in blastocyst cells that showed microtubule disorganization and no CPC enrichment. At 5.5 dpc, borealin-null embryos exhibited excessive apoptosis and elevated expression of p53. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that Borealin/DasraB inactivation triggered impaired mitosis and apoptosis though p53-independent mechanisms. Our data show that Borealin/DasraB is essential for cell proliferation during early embryonic development, and its early embryonic lethality cannot be rescued by the loss of p53.

Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a Japanese boy with recurrent optic neuritis

BACKGROUND Myelin oligodendrocyte glycoprotein (MOG) localizes on the outermost surface of the myelin sheath and oligodendrocytes in the central nervous system (CNS). Autoantibodies against MOG are reportedly found in patients with spectrum of inflammatory demyelinating diseases of the CNS, including acute disseminated encephalomyelitis, multiple sclerosis, and neuromyelitis optica. In addition, recent studies have emphasized an association between anti-MOG antibodies and optic neuritis. PATIENT We present the first case report of a 7-year-old Japanese boy who was positive for anti-MOG antibodies. He experienced four episodes of unilateral optic neuritis and one seizure event. Magnetic resonance imaging revealed T2-hyperintense lesions in the subcortical white matter and midbrain. Although he fulfilled the diagnostic criteria for multiple sclerosis, recombinant interferon beta did not prevent recurrence. Established cell-based immunoassays revealed that he was positive for anti-MOG antibodies and negative for anti-aquaporin 4 antibodies. CONCLUSIONS Our case report supports the relationship between anti-MOG antibodies and recurrent optic neuritis. Additional studies are needed to establish the clinical significance of anti-MOG antibodies for diagnosis, treatment, and prognosis.

Cyclosporin A Treatment for Membranoproliferative Glomerulonephritis Type II

A nephrotic patient with membranoproliferative glomerulonephritis type II (MPGN II) was treated with cyclosporin A (CSA) and alternate-day low-dose prednisolone. This patient developed the nephrotic syndrome twice. The second episode of the nephrotic syndrome was steroid resistant, and therefore this patient was treated with a CSA regimen. During treatments with alternate-day low-dose prednisolone and CSA, this patient recovered from the nephrotic syndrome. We conclude that CSA therapy may be effective for patients with the steroid-resistant nephrotic syndrome caused by MPGN II.

Congenital fiber type disproportion : Severe form with marked improvement

A 30-month-old male exhibited marked hypotonia at birth accompanied by respiratory distress necessitating ventilator support. He subsequently demonstrated marked improvement in muscle power. He became independent of the respirator at 21 days of age and was able to sit without support at 11 months and walked alone at 24 months. Histopathologic analysis of the quadriceps femoris muscle confirmed the diagnosis of congenital fiber type of disproportion at 11 months of age. No other studies have described a patient with a severe neonatal form of congenital fiber type of disproportion who demonstrated such clear improvement. Physicians should be aware of this possibility when they interact with such patients and their families.

Dystonia in a 13-year-old boy with secondary progressive multiple sclerosis

We report a patient who developed relapsing-remitting multiple sclerosis (MS) at 8 years old, and then had a progressive clinical course and dystonia. Dystonia of the patient is probably due to a lesion of the basal ganglia. Abnormal posture or movement disorder is very rarely found in MS, and progressive clinical course is also rare in childhood. The patient is worthy of attention because of his childhood onset, progressive clinical course and dystonia.

Clinical features in very early-onset demyelinating disease with anti-MOG antibody

BACKGROUND The clinical features of patients with very early-onset acquired demyelinating syndrome (ADS) with the anti-myelin oligodendrocyte glycoprotein (MOG) antibody are unknown. We investigated the clinical characteristics and described detailed treatment of weekly intramuscular interferon β-1a (IFNβ-1a) in children aged <4years with ADS and the anti-MOG antibody. METHODS We conducted a retrospective chart review of patients with anti-MOG positivity who were diagnosed as having multiple sclerosis (MS) at <4years of age. RESULTS Subjects comprised 2 boys and 2 girls. Initial symptoms included ataxia, facial paresis, status epilepticus, and encephalopathy. Abnormal lesions on magnetic resonance imaging scans were often detected in the brainstem and cerebellum as well as the cerebrum. All patients started receiving IFNβ-1a at age 3.1-3.5years. The initial doses ranged from 3 to 6μg, which were 1/10-1/5 doses, respectively, for adults. During 0.6-4.3years of IFNβ-1a administration, all patients had flu-like symptoms, and 1 patient had an increased liver enzyme level. Although 1 patient discontinued IFNβ-1a therapy because of frequent relapses, no patient discontinued therapy due to severe adverse events. CONCLUSIONS This case series adds novel information regarding the clinical features of children <4years old with ADS and the anti-MOG antibody.