Developing a storybook package for bereaved siblings: a pilot study of the effectiveness for enhancing the perceived knowledge and confidence of health and social care professionals in Hong Kong.

A pilot randomized controlled trial was conducted to examine the effectiveness of a storybook package for enhancing the perceived knowledge and confidence of health and social care professionals in working with bereaved child siblings and their parents before and after the loss. Open-ended questions were asked to collect feedback, and thematic analyses were conducted to generate the themes. Quantitative findings provided preliminary but not strong evidence of its effectiveness, but qualitative findings showed that participants perceived their knowledge about supporting bereaved siblings and their parents was enhanced and considered the storybook package a useful tool for facilitating their practice. Participants also reflected on how real and specific the stories in the storybook should be. This study is the first step in developing an evidence-based practice tool for health and social care professionals. Future studies are required to further examine its effectiveness for practice.

Identifying the areas of low self-reported confidence of internal medicine residents in geriatrics: a descriptive study of findings from a structured geriatrics skills assessment survey.

BACKGROUND: Currently, no standardized methods exist to assess the geriatric skills and training needs of internal medicine trainees to enable them to become confident in caring for older patients. This study aimed to describe the self-reported confidence and training requirements in core geriatric skills amongst internal medicine residents in Toronto, Ontario using a standardized assessment tool. METHODS: This study used a novel self-rating instrument, known as the Geriatric Skills Assessment Tool (GSAT), among incoming and current internal medicine residents at the University of Toronto, to describe self-reported confidence in performing, teaching and interest in further training with regard to 15 core geriatric skills previously identified by the American Board of Internal Medicine. RESULTS: 190 (75.1%) out of 253 eligible incoming (Year 0) and current internal medicine residents (Years 1-3) completed the GSAT. Year 1-3 internal medicine residents who had completed a geriatric rotation reported being significantly more confident in performing 13/15 (P < 0.001 to P = 0.04) and in teaching 9/15 GSAT skills (P < 0.001 to P = 0.04). Overall, the residents surveyed identified their highest confidence in administering the Mini-Mental Status Examination and lowest confidence in assessing fall risk using a gait and balance tool, and in evaluating and managing chronic pain. CONCLUSION: A structured needs assessment like the GSAT can be valuable in identifying the geriatric training needs of internal medicine trainees based on their reported levels of self-confidence. Residents in internal medicine could further benefit from completing a mandatory geriatric rotation early in their training, since this may improve their overall confidence in providing care for the mostly older patients they will work with during their residency and beyond.

Combination of Vancomycin and ß-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial.

BACKGROUND: In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal ß-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. METHODS: In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. RESULTS: We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. CONCLUSIONS: Combining an antistaphylococcal ß-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).

Physical activity and cognitive function of community Chinese elderly in Hong Kong (HK) and Guangzhou (GZ).

BACKGROUND: Some studies demonstrated that physical activity may have beneficial effect on cognitive function. The objective of the study was to estimate the association between physical activity and cognitive function in community-dwelling elderly Chinese in Hong Kong (HK) and Guangzhou (GZ). METHODS: In the neighborhood of HK and GZ, a convenience sample of 557 (260 in HK and 297 in GZ) older persons without dementia aged over 60 years (73.4 ± 6.5) was recruited. Physical activity was measured using a checklist. Information on physical activity participation, cognitive function, and other variables were collected. Multivariate linear regression analyses were performed to evaluate the association between physical activity and cognitive function. RESULTS: Total number of physical activities showed significant association with the delayed recall test (p 0.05) CONCLUSION: Physical activity may not be associated with better cognitive function among elderly Chinese independently of other factors.

ZIKA VIRUS INFECTION IN AUSTRALIA FOLLOWING A MONKEY BITE IN INDONESIA.

A traveller returning to Australia developed Zika virus infection, with fever, rash and conjunctivitis, with onset five days after a monkey bite in Bali, Indonesia. Flavivirus RNA detected on PCR from a nasopharyngeal swab was sequenced and identified as Zika virus. Although mosquito-borne transmission is also possible, we propose the bite as a plausible route of transmission. The literature for non-vector transmissions of Zika virus and other flaviviruses is reviewed.

Estrogen receptor α polymorphisms and the risk of cognitive decline: A 2-year follow-up study.

OBJECTIVE: The neuroprotective role of estrogen is supported by biochemical studies, but the results from clinical trials of estrogen replacement therapy on cognitive decline are controversial. One possible missing link might be the interindividual difference in estrogen receptor expression. In this study, the association of estrogen receptor α (ESR1) polymorphisms and cognitive decline was investigated. METHODS: Chinese older adults (n = 284) were recruited, and the cognitive profile was follow-up over 2-year period. Twenty ESR1 polymorphisms were investigated and correlated with the cognitive decline for the subjects. RESULTS: Significant association was found between ESR1 polymorphisms (rs9340799 [ESR1+351], rs1801132 [ESR1+975], rs6557171, rs9397456, and rs1884049) and subjects with no dementia (Clinical Dementia Rating, CDR 0) and very mild dementia (CDR 0.5). Several ESR1 polymorphisms were associated with cognitive decline as assessed by Chinese versions of Mini-Mental State Examination and Alzheimer Disease Association Scales-Cognitive Subscale. Different sets of ESR1 polymorphisms were associated with cognitive decline from CDR 0 to 0.5 and CDR 0.5 to 1. ESR1 polymorphisms (rs3853248, rs22334693 [ESR1+397], rs9340799 [ESR1+351], rs9397456, rs1801132 [ESR1+975], rs2179922, rs932477, and rs9341016) were associated with the deterioration of episodic memory among subjects with baseline CDR 0, indicating these polymorphisms might be markers for episodic memory decline at an earlier stage. CONCLUSION: This study showed association between ESR polymorphisms and cognitive decline or specific areas in cognitive profile. These findings might be useful in identifying individuals at risk for early intervention, and more research is required to elucidate the underlying mechanisms.

The utility of a non-verbal prospective memory measure as a sensitive marker for early-stage Alzheimer's disease in Hong Kong.

ABSTRACT Background: With the proportion of older adults in Hong Kong projected to double in size in the next 30 years, it is important to develop measures for detecting individuals in the earliest stage of Alzheimer's disease (AD, 0.5 in Clinical Dementia Rating, CDR). We tested the utility of a non-verbal prospective memory task (PM, ability to remember what one has to do when a specific event occurs in the future) as an early marker for AD in Hong Kong Chinese. Methods: A large community dwelling sample of older adults who are healthy controls (CDR 0, N = 125), in the earliest stage of AD (CDR 0.5, N = 125), or with mild AD (CDR 1, N = 30) participated in this study. Their reaction time/accuracy data were analyzed by mixed-factor analyses of variance to compare the performance of the three CDR groups. Logistic regression analyses were performed to test the discriminative power of these measures for CDR 0 versus 0.5 participants. Results: Prospective memory performance declined as a function of AD severity: CDR 0 > CDR 0.5 > CDR 1, suggesting the effects of early-stage AD and AD progression on PM. After partialling out the variance explained by psychometric measures (e.g., ADAS-Cog), reaction time/accuracy measures that reflected the PM still significantly discriminated between CDR 0 versus 0.5 participants in most of the cases. Conclusion: The effectiveness of PM measures in discriminating individuals in the earliest stage of AD from healthy older adults suggests that these measures should be further developed as tools for early-stage AD discrimination.

Bias in discriminating very mild dementia for older adults with different levels of education in Hong Kong.

BACKGROUND: Education has a profound effect on older adults' cognitive performance. In Hong Kong, some dementia screening tasks were originally designed for developed population with, on average, higher education. METHODS: We compared the screening power of these tasks for Chinese older adults with different levels of education. Community-dwelling older adults who were healthy (N = 383) and with very mild dementia (N = 405) performed the following tasks: Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscales, Verbal Fluency, Abstract Thinking, and Visual/Digit Span. Logistic regression was used to examine the power of these tasks to predict Clinical Dementia Rating (CDR 0.5 vs. 0). RESULTS: Logistic regression analysis showed that while the screening power of the total scores in all tasks was similar for high and low education groups, there were education biases in some items of these tasks. CONCLUSION: The differential screening power in high and low education groups was not identical across items in some tasks. Thus, in cognitive assessments, we should exercise great caution when using these potentially biased items for older adults with limited education.

Using cardiorespiratory fitness to operationalize vitality: a path analysis on the hierarchical structure of intrinsic capacity.

BACKGROUND: There is a lack of consensus about the operationalization of vitality, which is one of the intrinsic capacity (IC) domains. In particular, no study has investigated whether cardiorespiratory fitness (CRF) can be considered a vitality indicator. OBJECTIVE: To examine whether vitality is the upstream domain of IC, and establish the validity of CRF as a vitality indicator, using maximal oxygen consumption (VO2 max) as a representative. METHODS: 561 older adults from a longitudinal cohort study were included. Variables under consideration were VO2 max, other IC domains, instrumental activities of daily living (IADL), and handgrip strength, which was considered an already validated indicator of vitality. Using handgrip strength as the reference point, path analyses were performed to examine whether VO2 max followed a similar hierarchical structure in predicting change in IADL difficulty through other IC domains. RESULTS: The mean age of the participants was 75.5 years. The path model in which vitality was measured by VO2 max demonstrated adequate fit, which was similar to the model in which vitality was measured by handgrip strength. Regarding the path coefficients, the model using VO2 max demonstrated significant total and indirect effects. Notably, the indirect effect was due to the locomotor domain (standardized coefficient = -0.148, p < .001), but not the cognitive or psychological domain. CONCLUSION: Vitality is the upstream domain of IC. VO2 max can be considered an indicator to operationalize the vitality concept.

Transitions in intrinsic capacity among community-dwelling older people and their associated factors: a multistate modelling analysis.

OBJECTIVES: Trajectory of intrinsic capacity (IC) can be non-linear and discontinuous, which traditional linear models may not be able to handle. This study thus aimed to model the trajectory of IC as transitions between different IC states and examine their associated factors. METHODS: Longitudinal data from a sample of community-dwelling older people aged 60 years or above (n = 1,588) was analysed. A set of 14 self-reported items representing different domains of IC were administered annually to measure IC at four time points. Based on the number of impaired IC domains (i.e., cognitive, locomotor, vitality, sensory, and psychological), participants at each time point were classified into one of three IC states, namely state 1 (0 impaired domain), state 2 (1-2 impaired domains), and state 3 (3-5 impaired domains). Multistate modelling was used to identify factors associated with the transitions from one state to another. RESULTS: The mean age of participants was 75.0 years, and 77.4% of them were female. At baseline, 12.4% were in state 1, 51.8% were in state 2, and 35.8% were in state 3. 62.8% of participants experienced at least one transition between states, among which 12% experienced a transition every year. The transitions occurred mostly between adjacent IC states and could take place back and forth. Age, sex, marital status, perceived financial adequacy, number of chronic diseases, and self-rated health were the factors associated with the transitions. CONCLUSION: Findings may serve as a valuable reference for guiding future policies to optimize IC and promote healthy ageing using a person-centred approach.

Structured assessment of mental capacity to make financial decisions in Chinese older persons with mild cognitive impairment and mild Alzheimer disease.

Previous studies suggested that patients with mild cognitive impairment (MCI) or dementia can have impaired and declining financial skills and abilities. The purpose of this study is to test a clinically applicable method, based on the contemporary legal standard, to examine directly the mental capacity to make financial decisions and its component decision-making abilities among patients with MCI and early dementia. A total of 90 patients with mild Alzheimer disease (AD), 92 participants with MCI, and 93 cognitively normal control participants were recruited for this study. Their mental capacity to make everyday financial decisions was assessed by clinician ratings and the Chinese version of the Assessment of Capacity for Everyday Decision-Making (ACED). Based on the clinician ratings, only 53.5% were found to be mentally competent in the AD group, compared with 94.6% in the MCI group. However, participants with MCI had mild but significant impairment in understanding, appreciating, and reasoning abilities as measured by the ACED. The ACED provided a reliable and clinically applicable structured framework for assessment of mental capacity to make financial decisions.

Cognitive predictors for five-year conversion to dementia in community-dwelling Chinese older adults.

BACKGROUND: This study evaluates which cognitive measure is best for predicting incident dementia in a population-based random sample of Chinese older adults without dementia over a five-year period. METHODS: A total of 787 community-dwelling Chinese older adults without dementia in Hong Kong were assessed at baseline (T0), at two years (T1), and at five years (T2). RESULTS: The annual conversion rate to dementia was 1.6% and 6.3% for baseline normal participants and baseline mild cognitive impairment (MCI) participants, respectively. The Cantonese version of Mini-mental State Examination (CMMSE) scores declined significantly over time. In participants who progressed to dementia, Category Verbal Fluency Test (CVFT) scores dropped significantly from T0 to T1. A 1-SD drop of either CMMSE or CVFT in two years predicted dementia at five years with 91.5% sensitivity and 62.0% specificity. A stable CMMSE and CVFT at two years predicted a 91% chance of not progressing to clinical dementia at five years. CONCLUSION: In this community sample of Chinese older adults, a decline in cognitive screening tests in short term (two years) offered useful information in predicting dementia conversion over a longer period.

Effects of education on very mild dementia among Chinese people in Hong Kong: potential mediators in the Cantonese Mini-Mental State Examination tasks.

BACKGROUND: In Hong Kong, older Chinese adults generally have a low level of education. This study examined the effect of education on very mild Alzheimer's disease (AD), as quantified by Clinical Dementia Rating (CDR) scale (CDR 0.5 versus 0), in a Chinese community. The Cantonese version of the Mini-Mental State Examination (C-MMSE) was used to estimate cognitive abilities that were related to the level of education, and that in turn serve as protective factors for AD. METHODS: A total of 788 community-dwelling older adults (383 CDR 0 and 405 CDR 0.5) were recruited in this cross-sectional study, which was derived from a population-based prevalence project. The participants' number of years of education and C-MMSE scores were used to predict their CDR scores using logistic regression and the mediation effects of C-MMSE scores were analyzed. RESULTS: Consistent with previous studies, the chance of being rated as having very mild AD increased with age, but decreased with years of education, among the older adult community of Hong Kong. The effect of education on very mild dementia was weakened substantially when C-MMSE scores were included as mediating variables. CONCLUSIONS: The findings indicate that the protective effects of education on dementia were mediated by an enhancement of older adults' performance on some C-MMSE items, including attention and orientation to time and place.

Translation, Cultural Adaptation, and Validation of the Cantonese Version of SarQoL in Hong Kong's Older Population: An Interviewer-Administered Questionnaire for Assessing Sarcopenia-Specific Quality of Life in Fieldwork Practice.

Objective: This study examined the psychometric properties of the Cantonese version of the SarQoL® questionnaire. Participants: A total of 118 (including 60 non-sarcopenic and 58 sarcopenic) community-dwelling older adults aged 65 years or above with Cantonese as their mother tongue. Methods: Translation and cultural adaptation of the SarQoL were conducted using a standardized protocol. To validate the Cantonese SarQoL, psychometric properties including discriminative power, reliability (including internal consistency and test-retest reliability), and construct validity (including convergent and divergent validity), as well as floor and ceiling effects, were assessed. Results: The translation of the questionnaire was completed without significant difficulties. Results indicated that the Cantonese SarQoL had (1) good discriminative power (sarcopenic participants had lower overall scores, mean = 66.1 vs 75.0, p < 0.001; the overall score was negatively predictive of the presence of sarcopenia, adjusted OR = 0.949, 95% CI = [0.912, 0.983]), (2) good internal consistency (Cronbach's alpha = 0.835; correlations between domain and overall scores ranged from 0.576 to 0.868), (3) excellent test-retest agreement (intraclass correlation coefficient = 0.801), (4) good construct validity (convergent: moderate to strong correlations were found between the overall score and almost all of the SF-36 and EQ-5D domains; divergent: weaker correlations were found between the overall score and SF-36 social functioning, ρ = -0.098, and EQ-5D self-care, ρ = -0.331), and (5) no floor or ceiling effect. Conclusion: The Cantonese SarQoL is valid and reliable, and thus can be used as an interviewer-administered questionnaire for assessing sarcopenia-specific quality of life in fieldwork practice.

Rtt107 is required for recruitment of the SMC5/6 complex to DNA double strand breaks.

Genome integrity is maintained by a network of DNA damage response pathways, including checkpoints and DNA repair processes. In Saccharomyces cerevisiae, the BRCT domain-containing protein Rtt107/Esc4 is required for the restart of DNA replication after successful repair of DNA damage and for cellular resistance to DNA-damaging agents. In addition to its well characterized interaction with the endonuclease Slx4, Rtt107 interacts with a number of other DNA repair and recombination proteins. These include the evolutionarily conserved SMC5/6 complex, which is involved in numerous chromosome maintenance activities, such as DNA repair, chromosome segregation, and telomere function. The interaction between Rtt107 and the SMC5/6 complex was mediated through the N-terminal BRCT domains of Rtt107 and the Nse6 subunit of SMC5/6 and was independent of methyl methane sulfonate-induced damage and Slx4. Supporting a shared function in the DNA damage response, Rtt107 was required for recruitment of SMC5/6 to DNA double strand breaks. However, this functional relationship did not extend to other types of DNA lesions such as protein-bound nicks. Interestingly, Rtt107 was phosphorylated when SMC5/6 function was compromised in the absence of DNA-damaging agents, indicating a connection beyond the DNA damage response. Genetic analyses revealed that, although a subset of Rtt107 and SMC5/6 functions was shared, these proteins also contributed independently to maintenance of genome integrity.

Capacity to make decisions on medication management in Chinese older persons with mild cognitive impairment and mild Alzheimer's disease.

BACKGROUND: This study aimed to assess if decisional capacity and the four decision-making abilities related to decisions concerning medication management were impaired among community-dwelling Chinese older persons in Hong Kong with amnestic mild cognitive impairment (MCI) and mild Alzheimer's disease (AD), as compared with cognitively normal older adults. METHODS: Two hundred and ninety-one Chinese community-dwelling older adults were recruited. The four decision-making abilities and decisional capacity were assessed by using the Chinese version of the Assessment of Capacity for Everyday Decision-Making (ACED) and independent clinician ratings based on the definition in the UK Mental Capacity Act 2005, respectively. RESULTS: Ninety-nine participants (34%) were diagnosed with MCI and ninety-five (33%) with mild AD. Although almost all (96%) of the participants in the MCI group were found to be mentally competent to make decisions on medication management in clinician ratings, their decision-making abilities as measured by the ACED were significantly lower than those of the cognitively normal controls. CONCLUSIONS: Results from this study suggest that abilities related to decisions on medication management are impaired before the clinical diagnosis of dementia is made. Use of specific and structured assessment of the relevant decisional abilities may enhance clinical judgment.

A US Time and Motion Pilot Study of Nebulized COPD Therapy in an Inpatient and a Long-Term Care Setting.

INTRODUCTION: There is a lack of quantitative data on healthcare professionals' (HCPs) time dedicated to nebulized chronic obstructive pulmonary disease (COPD) therapy in inpatient and long-term care (LTC) settings. Using time and motion methodology, we quantified HCP time and opportunity costs (time and materials) associated with nebulized COPD therapy in inpatient and LTC settings and estimated efficiencies of changing to once-daily therapy. METHODS: A case report form was built to reflect local nebulization workflow. Primary outcomes were mean active HCP time per predefined task and mean total active HCP time associated with short-acting beta agonist (SABA) and SABA/short-acting muscarinic antagonist (SAMA) combination nebulization processes. RESULTS: Twenty observations occurred within each setting. Inpatient observations included three SABA and 17 SABA/SAMA (from 18 different patients), and LTC observations included five SABA and 15 SABA/SAMA (from eight different patients). Mean total process time was 16.12 min in the inpatient setting (95% CI 14.48-17.76) and 21.0 min in the LTC setting (95% CI 18.8-23.2), with the actual nebulization comprising over 50% of process time for both. In LTC, CIs suggest a difference by cognitive impairment status: mean 24.1 min (95% CI 21.3-26.9) if cognitively impaired versus 19.0 min (95% CI 16.1-21.8) if not. In the inpatient setting, the estimated process time/admission was 7.8 h; a once-daily nebulized drug would require only 2.3 h. In LTC, the estimated process time was 32.1 h/month; a once-daily nebulized drug would require only 13.7 h/month. Estimated nebulization cost was $243/admission for current versus $72 for once-daily dosing in inpatient, and $1177/month versus $504 in LTC. CONCLUSIONS: The nebulization process for COPD patients in both inpatient and LTC settings consumes considerable HCP time. A switch from SABA or SABA/SAMA to a drug with a once-daily nebulization frequency could generate substantial time savings depending on the setting and site characteristics.

Intrinsic capacity and 10-year mortality: Findings from a cohort of older people.

BACKGROUND AND OBJECTIVES: Longitudinal data with regard to the association between intrinsic capacity (IC) and mortality is required for prevention efforts. We examined the association between IC and 10-year mortality among older people. RESEARCH DESIGN AND METHODS: We recruited a cohort of 2032 Chinese people aged 70 years and older, 1371 of them could be traced over follow-up, of which 1096 died within 10 years. Of those who were traceable, 846 were complete cases regarding the data for the exposure, outcome and covariates. Multiple imputation was used to handle missing data. Nine indicators were included to represent the construct of IC. All-cause mortality was collected from the Death Registry. Multivariable Cox proportional hazard regression model and Kaplan-Meier estimator were used to assess the association between IC and mortality. RESULTS: The mean age of the 2032 participants was 79.7 years and 51 % were female. Compared with those in the lowest (best) quartile of IC, those in the highest (worst) quartile were associated with 1.48-fold (95 % CI 1.21-1.82) higher risk of mortality, after adjustment for sociodemographic variables. When past medical illnesses were further adjusted, the hazard ratio was attenuated (1.41; 95 % CI 1.15-1.73). Kaplan-Meier estimator for survival probability similarly showed a graded mortality pattern. The association between IC and mortality remained similar when the analysis was confined to community-dwelling older people. DISCUSSION AND IMPLICATIONS: IC is associated with mortality in a dose-response fashion. Assessment of IC should be instituted in community and institutional settings to enable formulation of early interventions.

Loss of H3 K79 trimethylation leads to suppression of Rtt107-dependent DNA damage sensitivity through the translesion synthesis pathway.

Genomic integrity is maintained by the coordinated interaction of many DNA damage response pathways, including checkpoints, DNA repair processes, and cell cycle restart. In Saccharomyces cerevisiae, the BRCA1 C-terminal domain-containing protein Rtt107/Esc4 is required for restart of DNA replication after successful repair of DNA damage and for cellular resistance to DNA-damaging agents. Rtt107 and its interaction partner Slx4 are phosphorylated during the initial phase of DNA damage response by the checkpoint kinases Mec1 and Tel1. Because the natural chromatin template plays an important role during the DNA damage response, we tested whether chromatin modifications affected the requirement for Rtt107 and Slx4 during DNA damage repair. Here, we report that the sensitivity to DNA-damaging agents of rtt107Δ and slx4Δ mutants was rescued by inactivation of the chromatin regulatory pathway leading to H3 K79 trimethylation. Further analysis revealed that lack of Dot1, the H3 K79 methyltransferase, led to activation of the translesion synthesis pathway, thereby allowing the survival in the presence of DNA damage. The DNA damage-induced phosphorylation of Rtt107 and Slx4, which was mutually dependent, was not restored in the absence of Dot1. The antagonistic relationship between Rtt107 and Dot1 was specific for DNA damage-induced phenotypes, whereas the genomic instability caused by loss of Rtt107 was not rescued. These data revealed a multifaceted functional relationship between Rtt107 and Dot1 in the DNA damage response and maintenance of genome integrity.

Estradiol-mediated suppression of CYP1B1 expression in mouse MA-10 Leydig cells is independent of protein kinase A and estrogen receptor.

Estrogens have multifaceted roles in mammalian testis. In the present study, we focused on estradiol as a potential regulator of testicular cytochrome P450 1B1 (CYP1B1) expression and investigated the possible mechanisms involved in the estradiol-mediated suppression. CYP1B1 protein levels were measured in the testes of rats that were treated with 17ß-estradiol benzoate (1.5 mg/kg) at different stages of development. In addition, CYP1B1 mRNA levels were measured in mouse MA-10 Leydig tumor cells treated with (a) various concentrations of 17ß-estradiol benzoate, (b) 17ß-estradiol benzoate in the presence of exogenous luteinizing hormone (LH), or (c) 17ß-estradiol benzoate in the presence of ICI 182,780, a competitive steroidal antagonist of estrogen receptors (ERs). Treatment of neonatal, pubertal, or adult rats with 17ß-estradiol benzoate was associated with a reduction of approximately 90% in testicular CYP1B1 protein content compared to age-matched controls. Treatment of MA-10 cells with 17ß-estradiol benzoate (10-500 nM) produced a concentration- and time-dependent decrease in CYP1B1 mRNA levels, but had no effect on LH receptor mRNA levels or on protein kinase A (PKA) activity. However, 17ß-estradiol benzoate (10-500 nM), regardless of the concentration tested, failed to attenuate the LH-elicited increase in CYP1B1 mRNA or PKA activity in MA-10 cells that were co-treated with LH and estradiol. Similarly, ICI 182,780 (10-1000 µM) did not reverse the suppressive effect of estradiol on CYP1B1 mRNA expression in MA-10 cells co-treated with estradiol and ICI 182,780. The results indicate that downregulation of testicular CYP1B1 by estradiol was independent of PKA activity and was not mediated by ERs in MA-10 cells.