Long-term outcome in stroke survivors after discharge from a convalescent rehabilitation ward.

AIM: The aim of this study was to investigate the long-term mortality, daily living activities, social activity, and symptoms of depression, in post-stroke patients discharged to their homes from a convalescent rehabilitation ward, and to determine the relationship between demographic variables and long-term outcome. METHODS: This study included 252 consecutive stroke patients (140 men; mean age, 72.4 ± 10.8 years) who had been admitted to a convalescent rehabilitation ward for inpatient rehabilitation. Follow-up assessment was made by postal questionnaire for up to >1 year after discharge, and included the modified Rankin scale, Frenchay activities index (FAI), and Geriatric Depression Scale. RESULTS: Of the 192 respondents (76.2%), 160 (83.3%) were living at home. Eighty-three (51.8%) were independent. Cumulative post-stroke mortality at 1 and 3 years was 3.7% and 19.4%, respectively.Mean total FAI score was 26.5 ± 10.9, suggesting that social inactivity was common. The estimated prevalence of depression was 21.6%. Coronary artery disease and motor functional independence measures were significantly associated with mortality, whereas age, recurrent stroke, severity of paralysis, and motor functional independence measures were significant predictors of independence. In the cross-sectional logistic model, depression symptoms were inversely associated with FAI score. CONCLUSIONS: The mortality rate of patients discharged to their home following inpatient rehabilitation is relatively low. Social inactivity and depression symptoms, however, remain common during the chronic phase, and the severity of depression and restriction of participation were interrelated.

Factors associated with functional recovery and home discharge in stroke patients admitted to a convalescent rehabilitation ward.

AIMS: This study aimed to determine the predictive factors for functional recovery and home discharge in stroke patients receiving in-hospital rehabilitation. METHODS: This study included a consecutive series of 174 stroke patients (average age 73.0 ± 10.8) admitted to the convalescent rehabilitation ward at Azumino Red Cross Hospital in Japan after acute rehabilitation. The main outcome measures were functional recovery (functional independence measure [FIM] at discharge and Montebello rehabilitation factor score [MRFS]) and home discharge. RESULTS: Total FIM improved from 72.6 ± 27.6 to 87.7 ± 29.9 during the hospital stay (P < 0.001). The average MRFS was 0.30 ± 0.28. Of the 174 patients, 151 were discharged home (87%). Age, stroke type, premorbid independence, motor FIM, and cognitive FIM at admission showed a significant association with FIM at discharge, while age, premorbid independence, motor FIM at admission, and cognitive FIM at admission were statistically significant predictors of MRFS. Female sex, not living with family, premorbid independence, and neglect were negatively associated with home discharge. CONCLUSIONS: Premorbid disability and cognitive dysfunction at admission were both negatively associated with functional recovery and home discharge in patients undergoing inpatient stroke rehabilitation.

Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis.

Chicken B lymphocyte precursors and DT40 cells diversify their immunoglobulin-variable (IgV) genes through homologous recombination (HR)-mediated Ig gene conversion. To identify DNA polymerases that are involved in Ig gene conversion, we created DT40 clones deficient in DNA polymerase eta (poleta), which, in humans, is defective in the variant form of xeroderma pigmentosum (XP-V). Poleta is an error-prone translesion DNA synthesis polymerase that can bypass UV damage-induced lesions and is involved in IgV hypermutation. Like XP-V cells, poleta-disrupted (poleta) clones exhibited hypersensitivity to UV. Remarkably, poleta cells showed a significant decrease in the frequency of both Ig gene conversion and double-strand break-induced HR when compared to wild-type cells, and these defects were reversed by complementation with human poleta. Our findings identify a DNA polymerase that carries out DNA synthesis for physiological HR and provides evidence that a single DNA polymerase can play multiple cellular roles.

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas.

OBJECTIVE: Impaired regulation of Aurora-B/AIM-1 expression in human cells causes chromosomal abnormality and instability, and recent observations of high expression but not mutation of Aurora-B/AIM-1 in human cancers imply that Aurora-B/AIM-1 might be a candidate molecule for cancer progression. We analyzed the effects of modification of Aurora-B/AIM-1 expression on the growth of a human glioma cell line and the expression of Aurora-B/AIM-1 in astrocytomas. METHODS: A glioma cell line, U251MG was transfected with wild type (WT) of Aurora-B/AIM-1 or kinase-inactive mutant of Aurora-B/AIM-1 in order to test the effects of overexpression of WT or kinase-inactive Aurora-B/AIM-1 on cell morphology and cell growth. Brain tissue samples were obtained during surgery and processed for reverse transcription-polymerase chain reaction, immunofluorescence in order to analyze the expression of Aurora-B/AIM-1 mRNA and protein. RESULTS: Exogenous overexpression of WT of Aurora-B/AIM-1 in cultured cells of U251MG produced multinuclearity and increased ploidy, and inhibited the growth of tumor cells. Exogenous overexpression of kinase-inactive Aurora-B/AIM-1 in a human glioma cell line also suppressed the tumor cell growth without affecting ploidy. Aurora-B/AIM-1 was highly expressed in astrocytomas and U251MG, and mRNA and protein levels of Aurora-B/AIM-1 in tumor tissues well correlated with their histological malignancy (World Health Organization grading). Survival time also negatively correlated with the levels of Aurora-B/AIM-1 mRNA in tumor samples. CONCLUSION: Aurora-B/AIM-1 was highly expressed in high-grade gliomas and its expression was well correlated with histological malignancy and clinical outcomes. The modification of the level of Aurora-B/AIM-1 expression might be a new target for glioma therapy.

Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates.

Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major postreplicational repair (PRR) pathways. The REV3 gene of Saccharomyces cerevisiae encodes the catalytic subunit of DNA polymerase zeta, which is involved in mutagenic TLS. To investigate the role of REV3 in vertebrates, we disruped the gene in chicken DT40 cells. REV3(-/-) cells are sensitive to various DNA-damaging agents, including UV, methyl methanesulphonate (MMS), cisplatin and ionizing radiation (IR), consistent with its role in TLS. Interestingly, REV3(-/-) cells showed reduced gene targeting efficiencies and significant increase in the level of chromosomal breaks in the subsequent M phase after IR in the G(2) phase, suggesting the involvement of Rev3 in HR-mediated double-strand break repair. REV3(-/-) cells showed significant increase in sister chromatid exchange events and chromosomal breaks even in the absence of exogenous genotoxic stress. Furthermore, double mutants of REV3 and RAD54, genes involved in HR, are synthetic lethal. In conclusion, Rev3 plays critical roles in PRR, which accounts for survival on naturally occurring endogenous as well as induced damages during replication.

RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells.

Translesion DNA synthesis (TLS) and homologous DNA recombination (HR) are two major pathways that account for survival after post-replicational DNA damage. TLS functions by filling gaps on a daughter strand that remain after DNA replication caused by damage on the mother strand, while HR can repair gaps and breaks using the intact sister chromatid as a template. The RAD18 gene, which is conserved from lower eukaryotes to vertebrates, is essential for TLS in Saccharomyces cerevisiae. To investigate the role of RAD18, we disrupted RAD18 by gene targeting in the chicken B-lymphocyte line DT40. RAD18(-/-) cells are sensitive to various DNA-damaging agents including ultraviolet light and the cross-linking agent cisplatin, consistent with its role in TLS. Interestingly, elevated sister chromatid exchange, which reflects HR- mediated post-replicational repair, was observed in RAD18(-/-) cells during the cell cycle. Strikingly, double mutants of RAD18 and RAD54, a gene involved in HR, are synthetic lethal, although the single mutant in either gene can proliferate with nearly normal kinetics. These data suggest that RAD18 plays an essential role in maintaining chromosomal DNA in cooperation with the RAD54-dependent DNA repair pathway.