Publications by authors named "Huaxin Si"

25 Publications

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The protective effect of small peptides from Periplaneta americana on hydrogen peroxide-induced apoptosis of granular cells.

In Vitro Cell Dev Biol Anim 2021 Jun 21. Epub 2021 Jun 21.

School of Public Health, Dali University, Dali, Yunnan Province, 671000, People's Republic of China.

This study investigates the protective effect of small peptides from Periplaneta americana (SPPA) on hydrogen peroxide (HO)-induced apoptosis of ovarian granular cells. HO was applied to human ovarian granular cells (KGN cell strains). Cell viability was tested by cell counting Kit-8 (CCK-8). Cell apoptosis was tested by flow cytometry, and a cell apoptosis model was established. The model cells were treated with SPPA, and the cell survival rate was monitored using the CCK-8 method. The oxidative stress state of cells was examined using SOD, ROS, MDA, and NO kits. The protein expression levels of SIRT1, p53, and the apoptosis-related gene Caspase3 were measured using Western Blot methodology. Relative to the control group, cell viability declined significantly after the HO treatment only (P < 0.01), while the apoptosis rate increased significantly (P < 0.01). The activity of SOD was weakened significantly (P < 0.01), while the cell levels of ROS, MDA, and NO increased dramatically (P < 0.01). Cell viability dramatically recovered (P < 0.01), and the SOD activity is hugely increased (P < 0.01) after SPPA treatment. In contrast, contents of ROS, MDA, and NO decreased sharply (P < 0.01), and significant dose-response relationships are characterized. Moreover, the HO treatment group showed significantly downregulated expression of SIRT1 (P < 0.01) but significantly upregulated expressions of p53 and Caspase3 (P < 0.01) compared to the control group. Following the SPPA treatment of apoptosis cells, expression of SIRT1 increased significantly, while expressions of p53 and Caspase3 declined significantly (P < 0.01). This study suggests that SPPA inhibits HO-induced human KGN cell apoptosis through antioxidation, and the SIRT1/p53 signal pathway mediates the antioxidation.
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http://dx.doi.org/10.1007/s11626-021-00586-2DOI Listing
June 2021

Sleep quality, depression and frailty among Chinese community-dwelling older adults.

Geriatr Nurs 2021 May-Jun;42(3):714-720. Epub 2021 Apr 6.

School of Nursing, Peking University, 100191 Beijing, China.

We aimed to explore the relationship between sleep quality and frailty, and depression as a mediator and its interaction with sleep quality on frailty. This was a cross-sectional study among 936 Chinese community-dwelling adults aged≥60 years. Sleep quality, frailty and depression were measured by the Pittsburgh Sleep Quality Index (PSQI), the Frailty Phenotype and the 5-item Geriatric Depression Scale (GDS-5), respectively. We found that depression mediated the association between poor sleep quality and physical frailty, attenuating the association between poor sleep and physical frailty by 51.9%. Older adults with both poor sleep quality and depression had higher risk of frailty than those with poor sleep quality or depression alone. These results implicate multidisciplinary care for frail older adults with poor sleep quality.
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http://dx.doi.org/10.1016/j.gerinurse.2021.02.020DOI Listing
April 2021

Age-Related Positivity Effect" in the Relationship Between Pain and Depression Among Chinese Community-Dwelling Older Adults: Sex Differences.

Pain Manag Nurs 2021 Apr 1. Epub 2021 Apr 1.

School of Nursing, Peking University, Beijing, China. Electronic address:

Purpose: To examine the "age-related positivity effect" and its sex differences in the pain-depression relationship among Chinese community-dwelling older adults.

Design: Cross-sectional design.

Methods: The study was conducted with a sample of 1,913 older adults in Jinan, China. Data were collected on pain intensity, age, sex, depressive symptoms, and potential covariates.

Results: The hierarchical linear regression analyses revealed that pain intensity was significantly related to depressive symptoms, there was a significant two-way interaction between age and pain intensity, and there was a significant three-way interaction between sex, age, and pain intensity. The Johnson-Neyman plot revealed that the relationship between pain and depressive symptoms decreased with advancing age, indicating an "age-related positivity effect." And the age-related positivity effect in the pain-depression relationship was significant only in men, but not in women.

Conclusions: The study suggests that all older women and "young-old" men (younger senior citizens aged 60-79) in China are more likely to experience depressive symptoms from pain. Interventions on cognitive psychology should particularly target all older women and young-old men to reduce the detrimental effect of pain on emotional well-being.
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http://dx.doi.org/10.1016/j.pmn.2021.02.010DOI Listing
April 2021

Development and validation of an instrument to measure beliefs in physical activity among (pre)frail older adults: An integration of the Health Belief Model and the Theory of Planned Behavior.

Patient Educ Couns 2021 Mar 9. Epub 2021 Mar 9.

School of Nursing, Peking University, Beijing 100191, China. Electronic address:

Objective: To develop and evaluate the psychometric properties of an instrument assessing beliefs in physical activity based on the integration of the Health Belief Model (HBM) and the Theory of Planned Behavior (TPB) among (pre)frail older adults.

Methods: A literature review and semi-structured interviews were conducted to generate the initial item pool of the instrument. A rural sample of 611 (pre)frail older adults was enrolled to examine the validity and reliability of the instrument.

Results: The exploratory factor analysis extracted eight factors for this instrument, explaining 71.3% of the variance in beliefs in physical activity. The confirmatory factor analysis confirmed the eight-factor structure. Linear regression models found that the integrated HBM-TPB constructs explained 65.9% of the variance in physical activity intention and 13.6% in physical activity. The Cronbach's alpha coefficients for the factors ranged from 0.80 to 0.98, and ICCs ranged from 0.71 to 0.85.

Conclusion: This instrument has satisfactory construct validity, predictive validity, internal consistency reliability and test-retest reliability, and it can be used in (pre)frail older adults to measure beliefs in physical activity.

Practice Implications: This instrument may help health care providers understand beliefs in physical activity and facilitate targeted interventions among (pre)frail older adults.
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http://dx.doi.org/10.1016/j.pec.2021.03.009DOI Listing
March 2021

Predictive performance of 7 frailty instruments for short-term disability, falls and hospitalization among Chinese community-dwelling older adults: A prospective cohort study.

Int J Nurs Stud 2021 May 1;117:103875. Epub 2021 Feb 1.

School of Nursing, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China. Electronic address:

Background: Frailty becomes a great challenge with population aging. The proactive identification of frailty is considered as a rational solution in the community. Previous studies found that frailty instruments had insufficient predictive accuracy for adverse outcomes, but they mainly focused on long-term outcomes and constructed frailty instruments based on available data not original forms. The predictive performance of original frailty instruments for short-term outcomes in community-dwelling older adults remains unknown.

Objective: To examine the predictive performance of seven frailty instruments in their original forms for 1-year incident outcomes among community-dwelling older adults.

Design: A prospective cohort study.

Settings: A total of 22 communities were selected by a stratified sampling method from one Chinese city.

Participants: A total of 749 older adults aged ≥ 60 years (mean age of 69.2 years, 69.8% female) were followed up after 1 year.

Methods: Baseline frailty was assessed by three purely physical dimensional instruments (i.e. Frailty Phenotype, the Study of Osteoporotic Fracture and FRAIL Scale) and four multidimensional instruments (i.e. Frailty Index, Groningen Frailty Indicator, Tilburg Frailty Indicator and Comprehensive Frailty Assessment Instrument), respectively. Outcomes included incident disability, falls, hospitalization and the combined outcome at 1-year follow-up. The receiver operating characteristic curves were plotted to assess the predictive performance of frailty instruments.

Results: The areas under the curves of seven frailty instruments in predicting incident outcomes ranged from 0.55 [95% confidence interval (CI): 0.51-0.60] to 0.67 (95% CI: 0.61-0.72), with high specificity (72.3-99.2%) and low sensitivity (4.0-49.6%). Four multidimensional instruments had much higher sensitivity (20.9-49.6% versus 4.0-11.7%) than three purely physical dimensional instruments. Overall, the Frailty Index was more accurate than some instruments in predicting incident outcomes, while several self-report instruments had comparable predictive accuracy to the Frailty Index for all (FRAIL Scale) or some (Groningen Frailty Indicator and Tilburg Frailty Indicator) of the incident outcomes.

Conclusions: All frailty instruments have inadequate predictive accuracy for short-term outcomes among community-dwelling older adults. The Frailty Index roughly performs better but self-report instruments are comparable to the Frailty Index for all or some of the outcomes. An accurate frailty instrument needs to be developed, and the simple self-report instruments could be used temporarily as practical and efficient tools in primary care.
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http://dx.doi.org/10.1016/j.ijnurstu.2021.103875DOI Listing
May 2021

Functional disability mediates the relationship between pain and depression among community-dwelling older adults: Age and sex as moderators.

Geriatr Nurs 2021 Jan-Feb;42(1):137-144. Epub 2021 Jan 2.

School of Nursing, Peking University, Beijing 100191, China. Electronic address:

Objective: To examine the moderating effects of age and sex in the role of functional disability as a mediator between pain and depression.

Methods: Participants were 1917 community-dwelling older adults from Jinan, China. Data were collected on pain intensity, functional disability in activities of daily living and instrumental activities of daily living, depressive symptoms and covariates.

Results: Functional disability partially mediated the relationship between pain intensity and depressive symptoms (estimate = 0.015, SE = 0.007, 95% CI [0.004, 0.030]). Age and sex moderated both the direct and indirect effect of the mediation model. The mediating effect of functional disability was significant in the old-old men, young-old men, and young-old women, but not in the old-old women.

Conclusions: Interventions should target both pain and pain-related functional disability to improve their emotional well-being among community-dwelling older adults. Importantly, strategies should be tailored across different age and sex groups to improve their effectiveness.
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http://dx.doi.org/10.1016/j.gerinurse.2020.12.010DOI Listing
January 2021

Comparison of 6 frailty screening tools in diagnostic properties among Chinese community-dwelling older people.

Geriatr Nurs 2021 Jan-Feb;42(1):276-282. Epub 2020 Sep 16.

School of Nursing, Peking University, 38 Xueyuan Road, PO BOX: 100191, 100191 Beijing, Haidian District, China. Electronic address:

We aimed to compare the diagnostic test accuracy (DTA) of six frailty screening tools against comprehensive geriatric assessment (CGA) in the community. A total of 1177 community-dwelling older people were recruited. Frailty was assessed by purely physical tools including Physical Frailty Phenotype (PFP), FRAIL (fatigue, resistance, ambulation, illness and loss of weight), Study of Osteoporotic Fracture (SOF), and multidimensional tools including Tilburg Frailty Indicator (TFI), Groningen Frailty Indicator (GFI) and Comprehensive Frailty Assessment Instrument (CFAI). The receiver operating characteristic curve analyses were performed. The GFI, TFI and CFAI [areas under the curve (AUCs): 0.78-0.80] had better diagnostic accuracy than SOF, PFP and FRAIL (AUCs: 0.69-0.72) (χ: 6.37-26.76, P<.05). The optimal cut-offs for the PFP, FRAIL and SOF were identical to their original prefrail cut-offs. These results implicate that the multidimensional tools are more effective to identify frailty in the whole community setting, while the self-report FRAIL may be used to identify the prefrail and facilitate early interventions particularly in the community setting with adequate healthcare resources.
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http://dx.doi.org/10.1016/j.gerinurse.2020.08.017DOI Listing
September 2020

Relationship Between Frailty and Depression Among Community-Dwelling Older Adults: The Mediating and Moderating Role of Social Support.

Gerontologist 2020 11;60(8):1466-1475

School of Nursing, Peking University, Beijing, China.

Background And Objectives: Frailty is associated with depression in older adults and reduces their social support. However, the mechanism underlying such relationship remains unclear. We aim to examine whether social support acts as a mediator or moderator in the relationship between frailty and depression.

Research Design And Methods: This cross-sectional study was conducted among 1,779 community-dwelling older adults aged 60 and older. Frailty, social support, and depressive symptoms were measured by the Physical Frailty Phenotype, Social Support Rating Scale, and five-item Geriatric Depression Scale, respectively. Data were also collected on age, gender, years of schooling, monthly income, cognitive function, number of chronic diseases, physical function, and pain.

Results: Linear regression models showed that subjective support and support utilization, but not objective support, mediated and moderated the relationship between frailty and depressive symptoms. The Johnson-Neyman technique determined a threshold of 30 for subjective support, but not for support utilization, beyond which the detrimental effect of frailty on depressive symptoms was offset.

Discussion And Implications: Social support underlies the association of frailty with depression, and its protective role varies by type. Interventions on depression should address improving perceptions and utilization of social support among frail older adults rather than simply providing them with objective support.
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http://dx.doi.org/10.1093/geront/gnaa072DOI Listing
November 2020

The association between frailty and medication adherence among community-dwelling older adults with chronic diseases: Medication beliefs acting as mediators.

Patient Educ Couns 2020 May 15. Epub 2020 May 15.

School of Nursing, Peking University, 100191, Beijing, China. Electronic address:

Objective: To explore the association between frailty and medication adherence by modeling medication beliefs (i.e., necessity and concerns) as mediators among community-dwelling older patients.

Methods: This cross-sectional study was conducted among 780 Chinese older patients. Frailty, medication adherence and medication beliefs were assessed using the Comprehensive Frailty Assessment Instrument (CFAI), the 4-item Morisky Medication Adherence Scale (MMAS-4) and the Beliefs about Medicines Questionnaire-Specific (BMQ-Specific), respectively. The PROCESS SPSS Macro version 2.16.3, model 4 was used to test the significance of the indirect effects.

Results: Frailty was associated with high medication necessity (β = 0.091, p = 0.011) and high medication concerns (β = 0.297, p < 0.001). Medication adherence was positively associated with medication necessity (β = 0.129, p = 0.001), and negatively associated with medication concerns (β = -0.203, p < 0.001). Medication necessity and medication concerns attenuated the total effect of frailty on medication adherence by -13.6% and 70.3%, respectively CONCLUSION: High medication concerns among frail older patients inhibit their medication adherence, which cannot be offset by the positive effect of their high medication necessity on medication adherence.

Practice Implications: Interventions should target medication beliefs among frail older patients, particularly medication concerns, to efficiently improve their medication adherence.
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http://dx.doi.org/10.1016/j.pec.2020.05.013DOI Listing
May 2020

Age differences in the relationship between frailty and depression among community-dwelling older adults.

Geriatr Nurs 2020 Jul - Aug;41(4):485-489. Epub 2020 Feb 20.

School of Nursing, Peking University, 100191 Beijing, China. Electronic address:

Objective: This study aims to examine age differences in the relationship between frailty and depression among older adults METHODS: A total of 1789 community-dwelling older adults were recruited from eastern China. Physical frailty and depressive symptoms were assessed using the Frailty Phenotype and the 5-item Geriatric Depression Scale, respectively.

Results: The hierarchical multiple linear regression analysis revealed that frailty was significantly related to depressive symptoms (β = 0.272, P < 0.001) and there was a significant interaction between age and frailty (β = -0.703, P < 0.001). The Johnson-Neyman plot revealed that the relationship between frailty and depressive symptoms became weaker as people aged.

Conclusions: Frailty is more likely to cause depressive symptoms among the young-old than among the old-old, reflecting the age-related positivity effect. This highlights that interventions on emotional regulation should particularly target the young-old to reduce the effect of frailty on depression.
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http://dx.doi.org/10.1016/j.gerinurse.2020.01.021DOI Listing
March 2021

Cross-cultural adaptation and psychometric properties of the Groningen Frailty Indicator (GFI) among Chinese community-dwelling older adults.

Geriatr Nurs 2020 May - Jun;41(3):236-241. Epub 2019 Oct 24.

School of Nursing, Peking University, 100191 Beijing, China. Electronic address:

The objective was to examine the feasibility, reliability and validity of the Groningen Frailty Indicator (GFI) among Chinese community-dwelling older adults. Of the 1230 participants, 1202 (97.7%) completed all items on the GFI. The internal consistency was acceptable (Cronbach's α = 0.64), and the test-retest reliability within a 7-15-day interval was good (ICC = 0.87). The GFI showed good diagnostic accuracy in the identification of frailty with reference to the frailty index (AUC = 0.84), and the optimal frailty cut-point was 3. Convergent validity was supported by significant correlations between each domain of the GFI and the corresponding alternative measurement(s). Higher proportions of frailty (GFI ≥ 3) were found in those who were older, female, less-educated, lived alone, and had 2 or more chronic diseases than in their counterparts, supporting its known-group discriminant validity. The Chinese GFI has good feasibility, acceptable reliability and satisfactory validity among community-dwelling older adults.
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http://dx.doi.org/10.1016/j.gerinurse.2019.10.002DOI Listing
March 2021

Prevalence, Factors, and Health Impacts of Chronic Pain Among Community-Dwelling Older Adults in China.

Pain Manag Nurs 2019 08 15;20(4):365-372. Epub 2019 May 15.

School of Nursing, Shandong University, Jinan, China.

Background: Chronic pain (CP) is prevalent among older adults in many Western countries and its prevalence, factors, and self-reported or objective measured health impacts have been well documented. However, there is limited information on these aspects among Chinese community-dwelling older adults.

Aims: Our aim was to assess the prevalence of CP and identify its associated factors as well as health impacts among older adults in China.

Design: Cross-sectional design.

Settings: Community settings.

Participants/subjects: A total of 1219 community-dwelling adults aged 60 years or older.

Methods: Data on CP, sociodemographic characteristics, comorbidity, cognitive function, and physical activity, as well as self-reported outcomes (functional disability, depression, quality of sleep, and undernutrition) and objective measured physical function, were obtained.

Results: Among 1,219 participants, 41.1% reported CP, of whom 16.6% experienced moderate to severe pain. The risk of CP was higher among older women with comorbidity and with depression and lower among older adults with higher educational level as well as with adequate physical activity. CP had significant associations with inadequate physical activity, functional disability, depression, poorer quality of sleep, and undernutrition, as well as worsening physical performance, poorer standing balance, and chair stands.

Conclusions: CP is a common problem among Chinese community-dwelling older adults, particularly among the most vulnerable subgroups, and has substantial impacts on self-reported functional disability, depression, poor quality of sleep, and undernutrition, as well as objective measured physical function. Therefore it is relevant for older adults to develop effective CP management programs.
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http://dx.doi.org/10.1016/j.pmn.2019.01.006DOI Listing
August 2019

Plant-Produced Subunit Vaccine Candidates against Yellow Fever Induce Virus Neutralizing Antibodies and Confer Protection against Viral Challenge in Animal Models.

Am J Trop Med Hyg 2018 02 30;98(2):420-431. Epub 2017 Nov 30.

Fraunhofer USA Center for Molecular Biotechnology, Newark, Delaware.

Yellow fever (YF) is a viral disease transmitted by mosquitoes and endemic mostly in South America and Africa with 20-50% fatality. All current licensed YF vaccines, including YF-Vax (Sanofi-Pasteur, Lyon, France) and 17DD-YFV (Bio-Manguinhos, Rio de Janeiro, Brazil), are based on live attenuated virus produced in hens' eggs and have been widely used. The YF vaccines are considered safe and highly effective. However, a recent increase in demand for YF vaccines and reports of rare cases of YF vaccine-associated fatal adverse events have provoked interest in developing a safer YF vaccine that can be easily scaled up to meet this increased global demand. To this point, we have engineered the YF virus envelope protein (YFE) and transiently expressed it in as a stand-alone protein (YFE) or as fusion to the bacterial enzyme lichenase (YFE-LicKM). Immunogenicity and challenge studies in mice demonstrated that both YFE and YFE-LicKM elicited virus neutralizing (VN) antibodies and protected over 70% of mice from lethal challenge infection. Furthermore, these two YFE-based vaccine candidates induced VN antibody responses with high serum avidity in nonhuman primates and these VN antibody responses were further enhanced after challenge infection with the 17DD strain of YF virus. These results demonstrate partial protective efficacy in mice of YFE-based subunit vaccines expressed in . However, their efficacy is inferior to that of the live attenuated 17DD vaccine, indicating that formulation development, such as incorporating a more suitable adjuvant, may be required for product development.
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http://dx.doi.org/10.4269/ajtmh.16-0293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929170PMC
February 2018

Association between pain and frailty among Chinese community-dwelling older adults: depression as a mediator and its interaction with pain.

Pain 2018 02;159(2):306-313

School of Nursing, Shandong University, Jinan, China.

Pain and frailty are both prevalent and have severe health impacts among older adults. We conducted a cross-sectional observational study to examine the association between pain and frailty, and depression as a mediator and its interaction with pain on frailty among 1788 Chinese community-dwelling older adults. Physical frailty, pain intensity, and depressive symptoms were assessed using the Frailty Phenotype, the Faces Pain Scale-revised, and the 5-item Geriatric Depression Scale, respectively. We found that both pain (odds ratio [OR] = 1.61; 95% confidence interval [CI]: 1.32-1.97) and depressive symptoms (OR = 4.67; 95% CI: 3.36-6.50) were positively associated with physical frailty (OR = 1.61; 95% CI: 1.32-1.97), and depressive symptoms were associated with pain (OR = 1.94; 95% CI: 1.15-3.39), attenuating the association between pain and physical frailty by 56.1%. Furthermore, older adults with both pain and depressive symptoms (OR = 8.13; 95% CI: 5.27-12.53) had a higher risk of physical frailty than those with pain (OR = 1.41; 95% CI: 1.14-1.76) or depressive symptoms (OR = 3.63; 95% CI: 2.25-5.85) alone. The relative excess risk of interaction, the attributable proportion due to interaction, and the synergy index (S) were 4.08, 0.50, and 2.34, respectively. These findings suggest that the positive association of pain with frailty is persistent and partially mediated by depression, and comorbid depression and pain have an additive interaction on physical frailty. It has an implication of multidisciplinary care for frail older adults with pain.
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http://dx.doi.org/10.1097/j.pain.0000000000001105DOI Listing
February 2018

Cross-cultural adaptation and validation of the Comprehensive Frailty Assessment Instrument in Chinese community-dwelling older adults.

Geriatr Gerontol Int 2018 Feb 20;18(2):301-307. Epub 2017 Oct 20.

Department of Nursing Fundamental, School of Nursing, Shandong University, Jinan, China.

Aim: To cross-culturally adapt and validate the Comprehensive Frailty Assessment Instrument (CFAI) among Chinese community-dwelling older adults.

Methods: The Chinese CFAI was developed through forward-backward translations. An urban sample of 1235 community-dwelling older adults received face-to-face interviews to examine the validity (construct validity and criterion validity) and reliability (internal consistency and test-retest reliability).

Results: The Chinese CFAI achieved semantic and idiomatic equivalence, and showed acceptable reliability and an expected factor structure, except for the social support domain. The exploratory factor analysis extracted five factors explaining 53.8% of the total variance of frailty. The confirmatory factor analysis showed that the data fit well to the second-order factor theoretical model, with a root mean square error of approximation of 0.05, Tucker-Lewis Index of 0.93 and Comparative Fit Index of 0.95. The receiver operating characteristic analysis presented an acceptable criterion validity using the Rockwood Frailty Index as an external criterion (area under the curve 0.80), with balanced sensitivity (65.31%) and specificity (81.19%) at the optimal 39-point frailty cut-off of the CFAI.

Conclusions: The Chinese CFAI has good validity and reliability as a practical frailty measure in Chinese community-dwelling older adults. Geriatr Gerontol Int 2018; 18: 301-307.
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http://dx.doi.org/10.1111/ggi.13183DOI Listing
February 2018

Cross-Cultural Adaptation and Validation of the FRAIL Scale in Chinese Community-Dwelling Older Adults.

J Am Med Dir Assoc 2018 01 27;19(1):12-17. Epub 2017 Jul 27.

School of Nursing, Shandong University, Jinan, China. Electronic address:

Objective: To cross-culturally adapt and test the FRAIL scale in Chinese community-dwelling older adults.

Design: Cross-sectional study.

Methods: The Chinese FRAIL scale was generated by translation and back-translation. An urban sample of 1235 Chinese community-dwelling older adults was enrolled to test its psychometric properties, including convergent validity, criterion validity, known-group divergent validity, internal consistency and test-retest reliability.

Results: The Chinese FRAIL scale achieved semantic, idiomatic, and experiential equivalence. The convergent validity was confirmed by statistically significant kappa coefficients (0.209-0.401, P < .001) of each item with its corresponding alternative measurement, including the 7th item of the Center for Epidemiologic Studies-Depression Scale, the Timed Up and Go test, 4-m walking speed, polypharmacy, and the Short-Form Mini Nutritional Assessment. Using the Fried frailty phenotype as an external criterion, the Chinese FRAIL scale showed satisfactory diagnostic accuracy for frailty (area under the curve = 0.91). The optimal cut-point for frailty was 2 (sensitivity: 86.96%, specificity: 85.64%). The Chinese FRAIL scale had fair agreement with the Fried frailty phenotype (kappa = 0.274, P < .001), and classified more participants into frailty (17.2%) than the Fried frailty phenotype (3.9%). More frail individuals were recognized by the Chinese FRAIL scale among older and female participants than their counterparts (P < .001), respectively. It had low internal consistency (Kuder-Richardson formula 20 = 0.485) and good test-retest reliability within a 7- to 15-day interval (intraclass correlation coefficient = 0.708).

Conclusions: The Chinese FRAIL scale presents acceptable validity and reliability and can apply to Chinese community-dwelling older adults.
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http://dx.doi.org/10.1016/j.jamda.2017.06.011DOI Listing
January 2018

Kaposi's sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation.

PLoS Pathog 2012 1;8(3):e1002566. Epub 2012 Mar 1.

Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.

Aberrant expression of Aurora A kinase has been frequently implicated in many cancers and contributes to chromosome instability and phosphorylation-mediated ubiquitylation and degradation of p53 for tumorigenesis. Previous studies showed that p53 is degraded by Kaposi's sarcoma herpesvirus (KSHV) encoded latency-associated nuclear antigen (LANA) through its SOCS-box (suppressor of cytokine signaling, LANA(SOCS)) motif-mediated recruitment of the EC(5)S ubiquitin complex. Here we demonstrate that Aurora A transcriptional expression is upregulated by LANA and markedly elevated in both Kaposi's sarcoma tissue and human primary cells infected with KSHV. Moreover, reintroduction of Aurora A dramatically enhances the binding affinity of p53 with LANA and LANA(SOCS)-mediated ubiquitylation of p53 which requires phosphorylation on Ser215 and Ser315. Small hairpin RNA or a dominant negative mutant of Aurora A kinase efficiently disrupts LANA-induced p53 ubiquitylation and degradation, and leads to induction of p53 transcriptional and apoptotic activities. These studies provide new insights into the mechanisms by which LANA can upregulate expression of a cellular oncogene and simultaneously destabilize the activities of the p53 tumor suppressor in KSHV-associated human cancers.
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http://dx.doi.org/10.1371/journal.ppat.1002566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291660PMC
July 2012

Live attenuated herpes simplex virus 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread.

J Virol 2012 Apr 8;86(8):4586-98. Epub 2012 Feb 8.

Infectious Disease Division, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

A herpes simplex virus 2 (HSV-2) glycoprotein E deletion mutant (gE2-del virus) was evaluated as a replication-competent, attenuated live virus vaccine candidate. The gE2-del virus is defective in epithelial cell-to-axon spread and in anterograde transport from the neuron cell body to the axon terminus. In BALB/c and SCID mice, the gE2-del virus caused no death or disease after vaginal, intravascular, or intramuscular inoculation and was 5 orders of magnitude less virulent than wild-type virus when inoculated directly into the brain. No infectious gE2-del virus was recovered from dorsal root ganglia (DRG) after multiple routes of inoculation; however, gE2-del DNA was detected by PCR in lumbosacral DRG at a low copy number in some mice. Importantly, no recurrent vaginal shedding of gE2-del DNA was detected in immunized guinea pigs. Intramuscular immunization outperformed subcutaneous immunization in all parameters evaluated, although individual differences were not significant, and two intramuscular immunizations were more protective than one. Immunized animals had reduced vaginal disease, vaginal titers, DRG infection, recurrent genital lesions, and recurrent vaginal shedding of HSV-2 DNA; however, protection was incomplete. A combined modality immunization using live virus and HSV-2 glycoprotein C and D subunit antigens in guinea pigs did not totally eliminate recurrent lesions or recurrent vaginal shedding of HSV-2 DNA. The gE2-del virus used as an immunotherapeutic vaccine in previously HSV-2-infected guinea pigs greatly reduced the frequency of recurrent genital lesions. Therefore, the gE2-del virus is safe, other than when injected at high titer into the brain, and is efficacious as a prophylactic and immunotherapeutic vaccine.
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http://dx.doi.org/10.1128/JVI.07203-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318599PMC
April 2012

Herpes simplex virus type 2 glycoprotein E is required for efficient virus spread from epithelial cells to neurons and for targeting viral proteins from the neuron cell body into axons.

Virology 2010 Sep 3;405(2):269-79. Epub 2010 Jul 3.

Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6073, USA.

The HSV-2 lifecycle involves virus spread in a circuit from the inoculation site to dorsal root ganglia and return. We evaluated the role of gE-2 in the virus lifecycle by deleting amino acids 124-495 (gE2-del virus). In the mouse retina infection model, gE2-del virus does not spread to nuclei in the brain, indicating a defect in anterograde (pre-synaptic to post-synaptic neurons) and retrograde (post-synaptic to pre-synaptic neurons) spread. Infection of neuronal cells in vitro demonstrates that gE-2 is required for targeting viral proteins from neuron cell bodies into axons, and for efficient virus spread from epithelial cells to axons. The mouse flank model confirms that gE2-del virus is defective in spread from epithelial cells to neurons. Therefore, we defined two steps in the virus lifecycle that involve gE-2, including efficient spread from epithelial cells to axons and targeting viral components from neuron cell bodies into axons.
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http://dx.doi.org/10.1016/j.virol.2010.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923263PMC
September 2010

Kaposi's sarcoma-associated herpesvirus-encoded LANA can interact with the nuclear mitotic apparatus protein to regulate genome maintenance and segregation.

J Virol 2008 Jul 16;82(13):6734-46. Epub 2008 Apr 16.

Department of Microbiology and the Abramson Comprehensive Cancer Center, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Kaposi's sarcoma-associated herpesvirus (KSHV) genomes are tethered to the host chromosomes and partitioned faithfully into daughter cells with the host chromosomes. The latency-associated nuclear antigen (LANA) is important for segregation of the newly synthesized viral genomes to the daughter nuclei. Here, we report that the nuclear mitotic apparatus protein (NuMA) and LANA can associate in KSHV-infected cells. In synchronized cells, NuMA and LANA are colocalized in interphase cells and separate during mitosis at the beginning of prophase, reassociating again at the end of telophase and cytokinesis. Silencing of NuMA expression by small interfering RNA and expression of LGN and a dominant-negative of dynactin (P150-CC1), which disrupts the association of NuMA with microtubules, resulted in the loss of KSHV terminal-repeat plasmids containing the major latent origin. Thus, NuMA is required for persistence of the KSHV episomes in daughter cells. This interaction between NuMA and LANA is critical for segregation and maintenance of the KSHV episomes through a temporally controlled mechanism of binding and release during specific phases of mitosis.
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http://dx.doi.org/10.1128/JVI.00342-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447046PMC
July 2008

A potential alpha-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1alpha in normoxia.

J Virol 2007 Oct 18;81(19):10413-23. Epub 2007 Jul 18.

Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.

Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth. Kaposi's sarcoma, associated with increased angiogenesis, is a highly vascularized, endothelial cell-derived tumor. Previously, we have shown that the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) targets the HIF-1alpha suppressors von Hippel-Lindau protein and p53 for degradation via its suppressor of cytokine signaling-box motif, which recruits the EC5S ubiquitin complex. Here we further show that HIF-1alpha was aberrantly accumulated in KSHV latently infected primary effusion lymphoma (PEL) cells, as well as HEK293 cells infected with KSHV, and also show that a potential alpha-helical amino-terminal domain of LANA was important for HIF-1alpha nuclear accumulation in normoxic conditions. Moreover, we have now determined that this association was dependent on the residues 46 to 89 of LANA and the oxygen-dependent degradation domain of HIF-1alpha. Introduction of specific small interfering RNA against LANA into PEL cells also resulted in a diminished nuclear accumulation of HIF-1alpha. Therefore, these data show that LANA can function not only as an inhibitor of HIF-1alpha suppressor proteins but can also induce nuclear accumulation of HIF-1alpha during KSHV latent infection.
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http://dx.doi.org/10.1128/JVI.00611-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045494PMC
October 2007

Proteomic analysis of the Kaposi's sarcoma-associated herpesvirus terminal repeat element binding proteins.

J Virol 2006 Sep;80(18):9017-30

Department of Microbiology and Abramson Comprehensive Cancer Center, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.

Terminal repeat (TR) elements of Kaposi's sarcoma-associated herpesvirus (KSHV), the potential origin sites of KSHV replication, have been demonstrated to play important roles in viral replication and transcription and are most likely also critical for the segregation of the KSHV genome to daughter cells. To search for the cellular proteins potentially involved in KSHV genome maintenance, we performed affinity chromatography analysis, using KSHV TR DNA as the affinity ligand. Proteomic analysis was then carried out to identify the TR-interacting proteins. We identified a total of 123 proteins from both KSHV-positive and -negative cells, among which most were identified exclusively from KSHV-positive cells. These proteins were categorized as proliferation/cell cycle regulatory proteins, proteins involved in spliceosome components, such as heterogeneous nuclear ribonuclear proteins, the DEAD/H family, the switch/sucrose nonfermenting protein family, splicing factors, RNA binding proteins, transcription regulation proteins, replication factors, modifying enzymes, and a number of proteins that could not be broadly categorized. To support the proteomic results, the presence of four candidate proteins, ATR, BRG1, NPM1 and PARP-1, in the elutions was further characterized in this study. The binding and colocalization of these proteins with the TR were verified using chromatin immunoprecipitation and immunofluorescence in situ hybridization analysis. These newly identified TR binding proteins provide a number of clues and potential links to understanding the mechanisms regulating the replication, transcription, and genome maintenance of KSHV. This study will facilitate the generation and testing of new hypotheses to further our understanding of the mechanisms involved in KSHV persistence and its associated pathogenesis.
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http://dx.doi.org/10.1128/JVI.00297-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1563930PMC
September 2006

Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus recruits uracil DNA glycosylase 2 at the terminal repeats and is important for latent persistence of the virus.

J Virol 2006 Nov 23;80(22):11178-90. Epub 2006 Aug 23.

Department of Microbiology and Tumor Virology Program of the Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.

Latency-associated nuclear antigen (LANA) of KSHV is expressed in all forms of Kaposi's sarcoma-associated herpesvirus (KSHV)-mediated tumors and is important for TR-mediated replication and persistence of the virus. LANA does not exhibit any enzymatic activity by itself but is critical for replication and maintenance of the viral genome. To identify LANA binding proteins, we used a LANA binding sequence 1 DNA affinity column and determined the identities of a number of proteins associated with LANA. One of the identified proteins was uracil DNA glycosylase 2 (UNG2). UNG2 is important for removing uracil residues yielded after either misincorporation of dUTP during replication or deamination of cytosine. The specificity of the 'LANA-UNG2 interaction was confirmed by using a scrambled DNA sequence affinity column. Interaction of LANA and UNG2 was further confirmed by in vitro binding and coimmunoprecipitation assays. Colocalization of these proteins was also detected in primary effusion lymphoma (PEL) cells, as well as in a cotransfected KSHV-negative cell line. UNG2 binds to the carboxyl terminus of LANA and retains its enzymatic activity in the complex. However, no major effect on TR-mediated DNA replication was observed when a UNG2-deficient (UNG(-/-)) cell line was used. Infection of UNG(-/-) and wild-type mouse embryonic fibroblasts with KSHV did not reveal any difference; however, UNG(-/-) cells produced a significantly reduced number of virion particles after induction. Interestingly, depletion of UNG2 in PEL cells with short hairpin RNA reduced the number of viral genome copies and produced infection-deficient virus.
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http://dx.doi.org/10.1128/JVI.01334-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1642147PMC
November 2006

Kaposi's sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions.

J Virol 2006 Aug;80(16):7965-75

Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA, USA.

Hypoxia can induce lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) in primary effusion lymphoma (PEL) cells. However, the molecular mechanism of lytic reactivation of KSHV by hypoxia remains unclear. Here we show that the latency-associated nuclear antigen (LANA), which plays a crucial role in modulating viral and cellular gene expression, directly associated with a low oxygen responder, hypoxia-inducible factor-1 alpha (HIF-1 alpha). LANA enhanced not only the transcriptional activities of HIF-1 alpha but also its mRNA level. Coimmunoprecipitation and immunofluorescence studies documented a physical interaction between LANA and HIF-1 alpha in transiently transfected 293T cells as well as in PEL cell lines during hypoxia. Through sequence analysis, several putative hypoxia response elements (HRE-1 to -6) were identified in the essential lytic gene Rta promoter. Reporter assays showed that HRE-2 (-1130 to -1123) and HRE-5 and HRE-6 (+234 to +241 and +812 to +820, respectively, within the intron sequence) were necessary and sufficient for the LANA-mediated HIF-1 alpha response. Electrophoretic mobility shift assays showed HIF-1 alpha-dependent binding of a LANA protein complex specifically to the HRE-2, -5, and -6 motifs within the promoter regulatory sequences. This study demonstrates that hypoxia-induced KSHV lytic replication is mediated at least in part through cooperation of HIF-1 alpha with LANA bound to the HRE motifs of the Rta promoter.
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http://dx.doi.org/10.1128/JVI.00689-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1563785PMC
August 2006

Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen induces chromosomal instability through inhibition of p53 function.

J Virol 2006 Jan;80(2):697-709

Department of Microbiology and Abramson Comprehensive Cancer Center, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.

Kaposi's sarcoma-associated herpesvirus (KSHV) is predominantly associated with three human malignancies, KS, primary effusion lymphoma, and multicentric Castleman's disease. These disorders are linked to genomic instability, known to be a crucial component of the oncogenic process. Latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a latent protein consistently expressed in all KSHV-associated diseases. LANA is important in viral genome maintenance and is associated with cellular and viral proteins to regulate viral and cellular gene expression. LANA interacts with the tumor suppressor genes p53 and pRb, indicating that LANA may target these proteins and promote oncogenesis. In this study, we generated cell lines which stably expressed LANA to observe the effects of LANA expression on cell phenotype. LANA expression in these stable cell lines showed a dramatic increase in chromosomal instability, indicated by the presence of increased multinucleation, micronuclei, and aberrant centrosomes. In addition, these stable cell lines demonstrated an increased proliferation rate and as well as increased entry into S phase in both stable and transiently transfected LANA-expressing cells. Additionally, p53 transcription and its transactivation activity were suppressed by LANA expression in a dose-dependent manner. LANA may therefore promote chromosomal instability by suppressing the functional activities of p53, thereby facilitating KSHV-mediated pathogenesis and cancer.
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http://dx.doi.org/10.1128/JVI.80.2.697-709.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1346846PMC
January 2006