The effect of electroconvulsive seizure on survival, neuronal differentiation, and expression of the maturation marker in the adult mouse hippocampus.

Electroconvulsive seizure (ECS), a model of electroconvulsive therapy in rodents, strongly increases neurogenesis in the adult hippocampus. Neurogenesis is a multi-step process that spans proliferation, survival, neuronal differentiation, and functional maturation. Our previous study demonstrated that ECS stimulates the proliferation of neural stem-like cells. However, the contribution of ECS to survival, neuronal differentiation, and maturation in newborn cells remains unknown. To evaluate the effect of ECS on these processes, we labeled newborn cells with bromodeoxyuridine (BrdU) before ECS treatment to determine the cell age and examined the survival rate and expression of cellular markers in the BrdU-labeled cells. Our results revealed that exposure to ECS (11 repetitions) during the differentiation phase significantly increased survival and promoted neuronal differentiation of newborn cells in the dentate gyrus. Four of ECS repetitions during the early differentiation phase were sufficient to promote dendritic outgrowth in immature neurons and enhance the expression of the immature neuronal marker, calretinin, in newborn cells. In contrast, exposure to ECS (11 repetitions) during the late maturation phase significantly suppressed the expression of the mature neuronal marker, calbindin, in newborn neurons. These results demonstrate that ECS during the differentiation phase promoted survival and neuronal differentiation and, in contrast, suppressed mature marker expression during the late maturation phase, suggesting that ECS has multiple effects on the different stages of adult neurogenesis.

Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia.

Fanconi anemia (FA) is a genetically and clinically heterogeneous disorder that predisposes patients to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). To study which genetic and phenotypic factors predict clinical outcomes for Japanese FA patients, we examined the FA genes, bone marrow karyotype, and aldehyde dehydrogenase-2 (ALDH2) genotype; variants of which are associated with accelerated progression of BMF in FA. In 88 patients, we found morphologic MDS/AML in 33 patients, including refractory cytopenia in 16, refractory anemia with excess blasts (RAEB) in 7, and AML in 10. The major mutated FA genes observed in this study were FANCA (n = 52) and FANCG (n = 23). The distribution of the ALDH2 variant alleles did not differ significantly between patients with mutations in FANCA and FANCG. However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations. In FANCA, patients with the c.2546delC mutation (n = 24) related to poorer MDS/AML-free survival and a younger age at HSCT than those without this mutation. All patients with RAEB/AML had an abnormal karyotype and poorer prognosis after HSCT; specifically, the presence of a structurally complex karyotype with a monosomy (n = 6) was associated with dismal prognosis. In conclusion, the best practice for a clinician may be to integrate the morphological, cytogenetic, and genetic data to optimize HSCT timing in Japanese FA patients.

The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype.

Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients.

IgA nephropathy associated with X-linked thrombocytopenia.

X-Linked thrombocytopenia (XLT) is characterized by congenital thrombocytopenia with small platelets and absence of immunodeficiency; XLT is an allelic variant of Wiskott-Aldrich syndrome (WAS). Both entities are caused by mutations in the same gene. This study presents the case of an 8-year-old boy with XLT. He developed immunoglobulin A (IgA) nephropathy at the age of 4 years. Genetic analysis confirmed the XLT diagnosis. His maternal uncle also had thrombocytopenia from early infancy and developed end-stage renal failure as a result of IgA nephropathy. The maternal uncle was inferred to be affected with XLT because of the carrier status of the patient's mother. Abnormal glycosylation has a role in pathogenesis in IgA nephropathy; moreover, sialophorin glycosylation is defective in WAS. Altered glycosylation may contribute to renal involvement in patients with WAS/XLT despite different defective glycosylation patterns in IgA nephropathy and WAS/XLT.