[Successful induction therapy for acute myeloid leukemia complicated with brain hemorrhage and hyperleukocytosis].

Adequate management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is essential for the prevention of life-threatening complications related to leukostasis and tumor lysis syndrome, but the optimal therapeutic strategy remains unclear. We report a 15-year-old girl with newly diagnosed AML who had extreme hyperleukocytosis (leukocyte count at diagnosis, 733,000/µl) leading to a brain hemorrhage. She was initially treated with hydroxyurea, but presented with brain hemorrhage due to leukostasis and underwent leukapheresis emergently with intensive care and mechanical ventilation. Full-dose standard induction chemotherapy was initiated after achieving gradual cytoreduction (leukocyte count, 465,000/µl) within five days after the initiation of therapy with hydroxyurea and leukapheresis. These treatments were successful and she experienced no complications. The patient ultimately recovered fully and was discharged with complete remission of AML. Although the effects of hydroxyurea and leukapheresis in the setting of hyperleukocytosis are still controversial, these initial treatments may contribute to successful bridging therapy followed by subsequent induction chemotherapy, especially in AML cases with extreme hyperleukocytosis or life-threatening leukostasis.

Factors related to subjective well-being among community-dwelling older adults living alone: A stratified analysis by sex and marital status from the JAGES.

BACKGROUND: Previous cross-sectional studies suggest that negative health outcomes such as mortality, social isolation, loneliness, and depression among older adults living alone vary by sex and marital status, with men often worse off than women and unmarried people worse off than married people. However, limited evidence exists from longitudinal studies regarding whether positive health outcomes such as subjective well-being (SWB) also vary by sex and marital status. The focus by sex and marital status on the positive health outcomes and diverse profiles of older adults living alone is important for public health in the near future. Therefore, the purpose of this study was to identify changes in SWB over time and its associated factors by sex and marital status among older adults living alone in the community using a longitudinal study in a representative population. METHODS: This was a longitudinal study using data from the Japan Gerontological Evaluation Study. This study is the first to reveal differences in SWB and related factors over 3 years among older adults living alone in the community (n = 8,579) who were stratified by sex and marital status (married men, non-married men, married women, and non-married women). RESULTS: Women moved to higher levels of SWB than did men, and married individuals moved to higher levels of SWB than did unmarried individuals. Independent functioning factors and interpersonal factors were significantly associated with SWB for married men and married women, but for unmarried women, the association by interpersonal factors was more pronounced, and for unmarried men, only limited emotional support and health promotion activities were significant among the interpersonal factors. CONCLUSIONS: This study revealed that among older adults living alone, changes in SWB over time and the independent functioning factors and interpersonal factors associated with this change varied by sex and marital status among older people living alone. These findings are useful for policy-making and guiding intervention activities to promote SWB in a society in which the environment for older adults living alone is changing dramatically.

Mutant gammaPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells.

Missense mutations in protein kinase Cgamma (gammaPKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant gammaPKC found in SCA14 is susceptible to aggregation and induces apoptosis in cultured cell lines. In the present study, we investigated whether mutant gammaPKC formed aggregates and how mutant gammaPKC affects the morphology and survival of cerebellar Purkinje cells (PCs), which are degenerated in SCA14 patients. Adenovirus-transfected primary cultured PCs expressing mutant gammaPKC-GFP also had aggregates and underwent apoptosis. Long-term time-lapse observation revealed that PCs have a potential to eliminate aggregates of mutant gammaPKC-GFP. Mutant gammaPKC-GFP disturbed the development of PC dendrites and reduced synapse formation, regardless of the presence or absence of its aggregates. In PCs without aggregates, mutant gammaPKC-GFP formed soluble oligomers, resulting in reduced mobility and attenuated translocation of mutant gammaPKC-GFP upon stimulation. These molecular properties of mutant gammaPKC might affect the dendritic morphology in PCs, and be involved in the pathogenesis of SCA14.

Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress.

Several causal missense mutations in protein kinase C gamma (gamma PKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant gamma PKC found in SCA14 is susceptible to two types of aggregation, cytoplasmic dot-like and perinuclear massive aggregation, and causes cell death in Chinese hamster ovary cells. Long-term time-lapse imaging revealed that firstly accumulated dot-like aggregation of mutant gamma PKC-green fluorescent protein (GFP) gradually formed perinuclear massive aggregations, followed by cell death. However, it remains unclear how aggregate formation of mutant gamma PKC causes cell death. In the present study, we examined whether these mutant aggregations affect the ubiquitin-proteasome system (UPS) and endoplasmic reticular (ER) stress. Two mutant gamma PKC-GFPs (S119P and G128D) were strongly ubiquitinated, and dot-like aggregations of these mutants were ubiquitin-positive and colocalized with proteasome 20S. Furthermore, proteasome activity in cells with aggregates, especially massive ones, was significantly decreased. Aggregate formation of mutant gamma PKC-GFP induced phosphorylation of PERK (PKR-like ER kinase) and nuclear expression of CHOP (C/EBP homologous protein), hallmarks of ER stress and subsequently activated caspase-3. These results indicate that aggregate formation of mutant gamma PKC found in SCA14 impairs UPS and induces ER stress, leading to apoptotic cell death.