Functions necessary for gait independence in patients with stroke: A study using decision tree.

BACKGROUND: Little is known about the existence and impact of interactions among multiple impairments to gait independence. The purpose of this study is to reveal the interaction of physical functions and its impact on gait independence in stroke patients. METHODS: This retrospective study included 108 subacute stroke patients. We conducted a decision tree analysis to examine the existence of interactions in relation to gait independence among the gross motor function of lower limb, knee extension strength, sensory function, and trunk function. Further, we confirmed the existence and impact of interaction detected via the decision tree after adjusting for the effects of confounding factors using logistic regression. RESULTS: The knee extension strength and proprioception on the affected side were selected in the first and second level of the decision tree. In addition, the knee extension strength was selected in the third level. The interaction of the knee extension strength and proprioception on the affected side was significantly associated with gait independence, both before and after adjusting for age, visuospatial perception, and cognitive functions. CONCLUSIONS: Our results suggest that the interaction of the knee extension strength and proprioception on the affected side is strongly associated with gait independence in stroke patients.

Prediction of Walking Independence in Older Women with Vertebral Compression Fracture Using Phase Angle: A Preliminary Study Using Propensity Score.

Objectives: This study aimed to clarify whether phase angle can be a predictor of walking independence in older women with vertebral compression fractures (VCFs) and to determine a clinically usable cutoff value. Methods: We retrospectively assessed data of older women (n=59; median age, 83.0 years) with VCFs. Propensity score-matching and logistic regression were performed to examine the association between phase angle at admission and walking independence at discharge. The cutoff value for the phase angle at admission for predicting walking independence was calculated based on the receiver operating characteristic curve. Results: Thirty-one patients (52.5%) could walk independently at discharge. Thirty patients were extracted from the independent and non-independent groups according to the propensity score. After propensity score matching, there was no significant difference between the groups for age, medical history, knee extension strength, skeletal muscle mass index, mini nutritional assessment-short form score, or revised Hasegawa's dementia scale score. However, the phase angle of the independent group was significantly higher than that of the non-independent group (P<0.05). Logistic regression revealed that phase angle at admission was significantly associated with walking independence at discharge (odds ratio, 12.2; 95% confidence interval, 2.1-72.0; P<0.01). The area under the receiver operating characteristic curve was 0.868, and the calculated phase angle cutoff value was 3.55°. Conclusions: This study revealed that the phase angle can predict walking independence in older women with VCFs. The cutoff values for women calculated in this study can be used as a simple and objective predictive index of walking independence.

Balance Function Required for Bathing Independence in Patients with Stroke and Hip Fracture.

Objectives: Little attention has been paid to the relationship between balance function and bathing independence. This research aimed to determine the degree of balance function needed by patients with stroke and patients with hip fracture (hereinafter referred to as patients with stroke and hip fracture) to bathe independently. Methods: Retrospective data analysis was performed on 59 patients with hip fracture and 201 patients with stroke. Logistic regression was performed to determine whether bathing independence was associated with the Berg Balance Scale (BBS) in patients with stroke and hip fracture. A receiver operating characteristic curve was generated to calculate cutoff values. Results: The BBS was significantly associated with bathing independence in patients with stroke and hip fracture. The calculated BBS cutoff value was 48 points for those with stroke (sensitivity, 84.7%; specificity, 79.1%) and 43 points for those with hip fracture (sensitivity, 81.3%; specificity, 77.8%). Conclusions: Balance function was independently associated with bathing independence. The level of balance function required for bathing independence may be lower for patients with hip fracture than for those with stroke. This could be a simple and useful indicator for rehabilitation professionals to interpret BBS results when conducting bathing interventions.

VSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin.

Humanin (HN) is a 24-residue peptide displaying a protective activity in vitro against a range of cytotoxic and neurotoxic insults, as well as mediating in vivo amelioration of Alzheimer disease (AD)-related memory impairment in experimental models. Published evidence suggests that the mechanisms through which HN exerts its cyto- and neuroprotective activity may include its secretion and binding to membrane-associated receptors. Here, we describe the identification of a new modulator of HN neuroprotective activity, V-set and transmembrane domain containing 2 like (VSTM2L), previously known as C20orf102. VSTM2L interacts with HN in both yeast and mammalian cells, is secreted in cultured cells, is present in serum, and is selectively expressed in the central nervous system. VSTM2L colocalizes with HN in distinct brain areas as well as in primary cultured neurons, where it plays a role in the modulation of neuronal viability. When tested in HN neuroprotection bioassays, VSTM2L acts as a strong antagonist of HN neuroprotective activity. In summary, VSTM2L is the first example of a secreted antagonist of HN and may play a role in the modulation of HN biological functions.

Cutoff Value for a Nutritional Indicator Related to Gait Independence in Elderly Fracture Patients: A Preliminary Study.

OBJECTIVE: Previous studies have reported the relationship between nutritional status and gait independence in elderly fracture patients. However, the degree to which nutritional indicators are related to gait independence is unclear. The purpose of this study is to calculate a cutoff value for a nutritional indicator related to gait independence in patients with hip and vertebral compression fractures. METHOD: This study included 69 patients (33 hip fracture, 36 vertebral compression fracture) who underwent rehabilitation at a convalescent rehabilitation ward. The relationships between nutritional indexes (Mini-Nutritional Assessment-Short Form [MNAⓇ-SF] and skeletal muscle mass index [SMI] ) at admission and gait independence at discharge were analyzed using logistic regression. In addition, receiver operating characteristic analysis was performed to calculate a cutoff value that predicts gait independence. RESULTS: Among the nutritional indicators used in this study, only MNAⓇ-SF was significantly able to predict gait independence at discharge, and this association was maintained, even after adjustment for confounders. The calculated MNAⓇ-SF cutoff values were 5.5 (sensitivity 100%, specificity 46.3%) and 7.5 points (sensitivity 67.9%, specificity 78.0%). CONCLUSION: This study suggests that MNAⓇ-SF may be an index for predicting gait independence in patients with hip or vertebral compression fractures in the convalescent rehabilitation ward. The cutoff values calculated in this study were simple and useful index for physical therapists to interpret the results of MNAⓇ-SF.

Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a receptor for an anti-Alzheimer's disease rescue factor Humanin.

Humanin (HN) inhibits Alzheimer's disease (AD)-relevant neuronal death and dysfunction, by interacting with a receptor (s) involving ciliary neurotrophic factor receptor alpha (CNTFR), WSX-1, and gp130. It remains unknown whether this complex is the sole HN receptor that mediates HN-induced anti-AD activity. We here report that an alternatively spliced WSX-1 isoform, encoding an extracellular 270-amino-acid region of WSX-1 with cytokine-binding regions (named soluble WSX-1; sWSX-1), is expressed in neuronal cells lacking function of full-length WSX-1 and enables HN to rescue AD-relevant death. This result suggests that CNTFR/soluble WSX-1/gp130 behaves as an alternative functional HN receptor.

CR/periphilin is a transcriptional co-repressor involved in cell cycle progression.

CR/periphilin (CR) retards cell cycle progression mainly at the S-phase in part by transcriptionally repressing expression of Cdc7, the key regulator of DNA replication, and in part by unknown mechanisms. In this study, we show that enforced expression of CR inhibits Cdc7 promoter activity. The attachment of the DNA-binding domain of the yeast GAL4 transcription factor to CR that appears without DNA-binding sequences, enables CR to repress GAL4 promoter-mediated transcription in a histone deacetylase (HDAC) activity-dependent manner. CR forms a complex with mSin3A, a common component in transcriptional repressor complexes, as well as with HDAC1, suggesting that CR may behave as a co-repressor by functional interaction with the Sin3/HDAC co-repressor complex. We also demonstrate that an alternatively spliced variant of CR, CR-S, which is without a region encoded by exon 4 of the CR gene and is a weak interactor with HDAC1, shows a suppressing effect on CR activity.

[Increased body mass index in young adults is associated with metabolic syndrome].

OBJECTIVES: Specific Health Examinations and Guidance (Tokutei kenko shinsa/Tokutei hoken shido) are provided for people over 40 years of age to reduce the incidence of metabolic syndrome (MetS). In the present study, we evaluated the importance of weight control in people below 40 years of age. METHODS: Male subjects (n = 877), aged 30 years, without MetS, were examined. Subjects were classified into 3 groups based on body mass index (BMI): non-obese (BMI < 22), pre-obese (22 ≤ BMI < 25), and obese (BMI ≥ 25). Cox proportional hazards regression analysis was performed for each group to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of MetS in individuals in their 40s on the basis of changes in their BMI, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, high-density lipoprotein, and triglyceride levels between 30 and 35 years of age. In addition, subjects were classified into 3 sub-groups based on changes in BMI: stable-decrease (BMI change < 1), slight increase (1 ≤ BMI increase<2), and increase (2 ≤ BMI increase). HRs for the 3 BMI change sub-groups for MetS were calculated for non-obese and pre-obese subjects. RESULTS: There was a significant association between changes in BMI and the incidence of MetS for non-obese individuals in their 40s (HR: 2.80, 95% CI: 1.61-4.88) and pre-obese subjects (HR: 2.00, 95% CI: 1.44-2.77). There were also significant associations between the stable/decrease and increase (HR: 9.39, 95% CI: 1.52-57.70) sub-groups and MetS in the non-obese group, as well as for the slight increase (HR: 2.30, 95% CI: 1.03-5.11) and increase (HR: 10.13, 95% CI: 4.30-23.80) sub-groups in the pre-obese group. CONCLUSIONS: BMI change in young adults is an important risk factor for MetS among individuals in their 40s. Even subjects with a BMI lower than 25 had differences in the risk of developing MetS based on their BMI change sub-group. In the field of occupational health, it will be necessary to promote stable weight control in young adults to reduce the incidence of MetS.

Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130.

Humanin (HN) inhibits neuronal death induced by various Alzheimer's disease (AD)-related insults via an unknown receptor on cell membranes. Our earlier study indicated that the activation of STAT3 was essential for HN-induced neuroprotection, suggesting that the HN receptor may belong to the cytokine receptor family. In this study, a series of loss-of-function tests indicated that gp130, the common subunit of receptors belonging to the IL-6 receptor family, was essential for HN-induced neuroprotection. Overexpression of ciliary neurotrophic factor receptor alpha (CNTFR) and/or the IL-27 receptor subunit, WSX-1, but not that of any other tested gp130-related receptor subunit, up-regulated HN binding to neuronal cells, whereas siRNA-mediated knockdown of endogenous CNTFR and/or WSX-1 reduced it. These results suggest that both CNTFR and WSX-1 may be also involved in HN binding to cells. Consistent with these results, loss-of-functions of CNTFR or WSX-1 in neuronal cells nullified their responsiveness to HN-mediated protection. In vitro-reconstituted binding assays showed that HN, but not the other control peptide, induced the hetero-oligomerization of CNTFR, WSX-1, and gp130. Together, these results indicate that HN protects neurons by binding to a complex or complexes involving CNTFR/WSX-1/gp130.

The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression.

The ARF tumor suppressor gene antagonizes generation of various tumors. ARF-mediated tumor suppression occurs in a p53-independent manner as well as in a p53-dependent manner. We here demonstrate that BCL6 is a target of the ARF tumor suppressor. Either mouse p19(ARF) or human p14(ARF) binds to BCL6 and downregulates BCL6-induced transcriptional repression. ARF-mediated downregulation of the BCL6 activity may account in part for ARF-mediated tumor suppression.

p19ARF-induced p53-independent apoptosis largely occurs through BAX.

Combined disruption of the ARF gene and the p53 gene causes mouse predisposition to tumors of a wider variety and at a higher frequency than disruption of the p53 gene, indicating that the ARF gene has p53-independent anti-tumor function in addition to p53-dependent function. Coincidentally with this notion, ectopic expression of the p19(ARF) induces apoptosis for wild-type mouse embryo fibroblasts which have been immortalized by introduction of the SV40 virus genome (SV40-MEFs). The protein expression levels of p53, p21(Cip1), and Bax were not upregulated by ectopic expression of p19(ARF) in SV40-MEFs, indicating that expression of p19(ARF) induced apoptosis through p53-independent pathways in this system. Ectopic expression of p19(ARF) induced prominent apoptosis even in SV40-Bak-/-MEFs. In contrast, expression of p19(ARF) induced only a very low grade of apoptosis in Bax-/- or Bax-/-/Bak-/-SV40-MEFs. Remarkable attenuation of p19(ARF)-induced apoptosis by disruption of the Bax gene thus leads to the conclusion that Bax plays a major role in p53-independent apoptosis induced by p19(ARF).

Multiple domains of the mouse p19ARF tumor suppressor are involved in p53-independent apoptosis.

The ARF (p19ARF for the mouse ARF consisting of 169 amino acids and p14ARF for the human ARF consisting of 132 amino acids) genes upregulate p53 activities to induce cell cycle arrest and sensitize cells to apoptosis by inhibiting Mdm2 activity. p53-independent apoptosis also is induced by ectopic expression of p19ARF. We constructed various deletion mutants of p19ARF with a cre/loxP-regulated adenoviral vector to determine the regions of p19ARF which are responsible for p53-independent apoptosis. Ectopic expression of the C-terminal region (named C40) of p19ARF whose primary sequence is unique to the rodent ARF induced prominent apoptosis in p53-deficient mouse embryo fibroblasts. Relatively low-grade but significant apoptosis also was induced in p53-deficient mouse embryo fibroblasts by ectopic expression of p19ARF1-129, a p19ARF deletion mutant deficient in the C40 region. In contrast, ectopic expression of the wild-type p14ARF did not induce significant apoptosis in human cells. Taken together, we concluded that p53-independent apoptosis was mediated through multiple regions of the mouse ARF including C40, and the ability of the ARF gene to mediate p53-independent apoptosis has been not well conserved during mammalian evolution.

ik3-2, a relative to ik3-1/Cables, is involved in both p53-mediated and p53-independent apoptotic pathways.

ik3-2 is a close relative to ik3-1/Cables, an associator with cdk3 and cdk5. ik3-1/Cables has been identified to be a candidate tumor suppressor for colon and head/neck cancers. In agreement, it has been pointed out that ik3-1/Cables is a regulator for both p53- and p73-induced apoptosis [J. Biol. Chem. 277 (2002) 2951] although ectopic expression of ik3-1/Cables does not induce apoptosis. Here we show that adenovirus-mediated overexpression of ik3-2 results in apoptosis of p53-intact U2OS cells. ik3-2 binds to p53 in vivo and ectopic coexpression of ik3-2 enhances apoptosis induced by adenovirus-mediated expression of p53. Furthermore, ectopic expression of ik3-2 results in apoptosis of primary p53/Mdm2- and p53/ARF-null mouse embryo fibroblasts, indicating that ik3-2-induced apoptosis is partially p53-independent. Both the highly conserved C-terminal cyclin box-homologous domain (ik3-2-C) and the N-terminal region consisting of 70 amino acids (ik3-2-N) are responsible for ik3-2-mediated enhancement of p53-induced apoptosis. In contrast, ik3-2-induced p53-independent apoptosis is mediated through ik3-2-N. We thus identified ik3-2 as a proapoptotic factor involved in both p53-mediated and p53-independent apoptotic pathways.

Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest.

Cdc7 expression repressor (CR)/periphilin has been originally cloned as an interactor with periplakin, a precursor of the cornified cell envelope, and suggested to constitute a new type of nuclear matrix. We here show that CR/periphilin is a ubiquitously expressed nuclear protein with speckled distribution. Overexpression of CR/periphilin induces S-phase arrest. Analysis of expression of regulators involved in DNA replication has revealed that both mRNA and protein expression of Cdc7, a regulator of the initiation and continuation of DNA replication, are markedly downregulated by overexpression of CR/periphilin. However, co-expression of Cdc7 only marginally rescues S-phase arrest induced by CR, indicating that CR retards S-phase progression by modifying expression of some genes including Cdc7, which are involved in progression of DNA replication or coordination of DNA replication and S-phase progression.