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The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co‐medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic–pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low‐ and middle‐income countries related to health‐care and clinical trials are outlined. Involving older adults, their caregivers and health‐care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally. [ABSTRACT FROM AUTHOR]

Nutrition profoundly influences the risk for many age‐related diseases. Whether nutrition influences human aging biology directly is less clear. Studies in different animal species indicate that reducing food intake ("caloric restriction" [CR]) can increase lifespan and delay the onset of diseases and the biological hallmarks of aging. Obesity has been described as "accelerated aging" and therefore the lifespan and health benefits generated by CR in both aging and obesity may occur via similar mechanisms. Beyond calorie intake, studies based on nutritional geometry have shown that protein intake and the interaction between dietary protein and carbohydrates influence age‐related health and lifespan. Studies where animals are calorically restricted by providing free access to diluted diets have had less impact on lifespan than those studies where animals are given a reduced aliquot of food each day and are fasting between meals. This has drawn attention to the role of fasting in health and aging, and exploration of the health effects of various fasting regimes. Although definitive human clinical trials of nutrition and aging would need to be unfeasibly long and unrealistically controlled, there is good evidence from animal experiments that some nutritional interventions based on CR, manipulating dietary macronutrients, and fasting can influence aging biology and lifespan. [ABSTRACT FROM AUTHOR]

The NAD+‐dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late‐life health and overall lifespan, though of these members, a role for sirtuin‐2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under‐expressed. Here, we sought to test whether SIRT2 over‐expression would impact the overall health and lifespan of mice on a nonprogeroid, wild‐type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high‐fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2‐Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity. [ABSTRACT FROM AUTHOR]

Objectives: The aims of this study were to assess oral health‐related quality of life (OHRQoL) in a cohort of older Australian men and explore the association between their general health conditions, socio‐demographic factors and OHRQoL. Methods: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of Australian men, initiated in 2005–2006 with an initial sample of 1705 men 70 years or over. Participants completed a self‐administered health and socio‐demographic questionnaire and attended an interview and clinical assessment at baseline and each of three follow‐up assessments. Information on oral health and responses to the Oral Health Impact Profile (OHIP‐14) were collected in the 4th follow‐up in which 778 men completed the OHIP‐14 questionnaire and 614 men had a dental assessment. The prevalence of oral health impact was defined as a response of fairly often or very often to one or more of the OHIP‐14 questions. Mean OHIP‐14 scores were calculated for the 14 questions and used as the dependent variable in the regression analyses. Zero‐inflated Poisson regression was used to estimate prevalence rate ratios (PRR). Results: Only 10% of men presented oral health impacts. In multivariate regression modelling, being born in Italy/Greece (PRR: 2.16, 95% CI: 1.93–2.42) or in other countries (PRR: 2.12, 95% CI: 1.89–2.38), having poor self‐rated general health (PRR: 1.38, 95% CI: 1.24–1.53), having poor mental wellbeing (PRR: 1.14, 95% CI: 1.04–1.24), having ≥6 depressive symptoms (PRR: 1.18, 95% CI: 1.05–1.32), being a current smoker (PRR: 1.34, 95% CI: 1.06–1.70) and having more decayed tooth surfaces (PRR:1.01, 95% CI: 1.00–1.02) were associated with higher impact scores. Conclusions: Overall, older Australian men exhibit good oral health‐related quality of life. The inter‐relationship between perceptions of general health and well‐being, health and oral health variables and social background supports policy objectives of closer integration of general health and oral health services for older Australian men. [ABSTRACT FROM AUTHOR]

Aims: Comprehensively investigate prescribing in usual care of hospitalized older people with respect to polypharmacy; potentially inappropriate medications (PIMs) according to Beers criteria; and cumulative anticholinergic and sedative medication exposure calculated with Drug Burden Index (DBI). Specifically, to quantify exposure to these measures on admission, changes between admission and discharge, associations with adverse outcomes and medication costs. Methods: Established new retrospective inpatient cohort of 2000 adults aged ≥75 years, consecutively admitted to 6 hospitals in Sydney, Australia, with detailed information on medications, clinical characteristics and outcomes. Conducted cross‐sectional analyses of index admission data from cohort. Results: Cohort had mean (standard deviation) age 86.0 (5.8) years, 59% female, 21% from residential aged care. On admission, prevalence of polypharmacy was 77%, PIMs 34% and DBI > 0 in 53%. From admission to discharge, mean difference (95% confidence interval) in total number of medications increased 1.05 (0.92, 1.18); while prevalence of exposure to PIMs (−3.8% [−5.4, −2.1]) and mean DBI score (−0.02 [−0.04, −0.01]) decreased. PIMs and DBI score were associated with increased risks (adjusted odds ratio [95% confidence interval]) of falls (PIMs 1.63 [1.28, 2.08]; DBI score 1.21[1.00, 1.46]) and delirium (PIMs 1.76 [1.38, 1.46]; DBI score 1.42 [1.19, 1.71]). Each measure was associated with increased risk of adverse drug reactions (polypharmacy 1.42 [1.19, 1.71]; PIMs 1.87 [1.40, 2.49]; DBI score 1.90 [1.55, 2.15]). Cost (AU$/patient/hospital day) of medications contributing to PIMs and DBI was low ($0.29 and $0.88). Conclusion: In this large cohort of older inpatients, usual hospital care results in an increase in number of medications and small reductions in PIMs and DBI, with variable associations with adverse outcomes. [ABSTRACT FROM AUTHOR]

Objective: To investigate geriatricians' views about issues facing geriatric medicine, and the preparedness of the health‐care system during the COVID‐19 pandemic. Methods: An online survey of heads of geriatric medicine departments in hospitals in Australia and New Zealand undertaken in May 2020. Results: The majority of hospitals had admitted one or more patients with suspected COVID‐19. Most geriatricians believed their hospital was 'adequately' or 'well prepared' for the pandemic. Inpatient capacity increased to manage acute, post‐acute and rehabilitative care of older patients with COVID‐19. Non‐inpatient services for older people were reduced and telehealth‐instituted widely. Increases in work hours, on‐call and staffing levels were reported. Geriatricians voiced major concerns about the preparedness of residential aged care facilities to manage the pandemic. Conclusions: The COVID‐19 pandemic impacted on geriatricians and the provision of geriatric medicine services. Many issues that subsequently affected older people were predicted in advance. [ABSTRACT FROM AUTHOR]

Aim: The aim was to assess two macronutrient interventions in a 2 × 2 factorial dietary design to determine their effects on oral health. Materials and Methods: Participants (65–75 years old) with a body mass index between 20 and 35 kg/m2 of a larger randomized control trial who consented to an oral health assessment were recruited. They had ad libitum access to one of four experimental diets (omnivorous higher fat or higher carbohydrate, semi‐vegetarian higher fat or higher carbohydrate) for 4 weeks. The periodontal examination included periodontal probing depth (PPD), clinical attachment level (CAL), and bleeding on probing. Oral plaque and gingival crevicular fluid (GCF) were collected before and after the intervention. Results: Between baseline and follow up, the number of sites with a CAL <5 mm (mean difference [MD] −5.11 ± 9.68, p =.039) increased and the GCF amount (MD −23.42 ± 39.42 Periotron Units [PU], p =.050) decreased for the semi‐vegetarian high‐fat diet. For the mean proportion of sites with PPD reduction of >1 mm and CAL gain of >1 mm, significant differences were calculated between the diets investigated. The clinical parameters were not associated with changes in the oral microbiota. Conclusions: The results of this study provided evidence that a semi‐vegetarian high‐fat diet provides benefits to clinical parameters of periodontal health. This study is registered in ClinicalTrials.gov (ACTRN12616001606471). [ABSTRACT FROM AUTHOR]

Objectives: To examine nationwide trends in delirium mortality in Australia and the United States between 2006 and 2016. Methods: Delirium mortality data for Australian and United States populations were obtained from World Health Organization Mortality Database. Mortality trends were assessed using joinpoint regression. Results: Age‐adjusted delirium mortality increased by 16.35%/year and 4.04%/year in Australia and the United States, respectively. Average annual age‐adjusted delirium mortality rate (per 1 000 000 population) was 2.90 in Australia, and 1.06 in the United States. Death rates from delirium increased with age. Mortality was consistently higher in men than women, but the rate of annual increase was greater in women. Conclusions: Our study provided important population‐level data on delirium and its outcomes in Australia and the United States. Reported death rates attributed to delirium increased over the 11‐year period in both countries and were consistently higher in Australia than the United States. There were distinct age and sex differences in mortality trends. [ABSTRACT FROM AUTHOR]

Background/Importance: Stroke and dementia are important causes of death in the United States and may be interrelated as competing risks for mortality. No previous studies have simultaneously compared age‐ and sex‐specific mortality trends between stroke and subtypes of dementia at a population level. Insights gained from this study can help identify high‐risk populations and inform healthcare service requirements for managing stroke and dementia in the United States. Objectives: To examine nationwide trends in mortality from stroke and subtypes of dementia in the United States by age group and sex. Design Population‐based cross‐sectional study. Setting U.S. mortality data from 2007 to 2016. Participants: All U.S. residents whose primary cause of death was stroke, Alzheimer's disease, vascular dementia, or Lewy body dementia. Measurements: Age‐adjusted mortality, mortality trends among men and women were analyzed separately using joinpoint regression. Results: From 2007 to 2016, age‐adjusted stroke mortality fell by 21.6%. Age‐adjusted mortality (per 1,000,000) for Alzheimer's disease, vascular dementia, and Lewy body dementia increased by 1.2‐fold, 2‐fold, and 3‐fold, respectively. Annual age‐adjusted stroke mortality decreased by an average rate of 2.67% per year, while annual age‐adjusted mortality for Alzheimer's disease, vascular dementia, and Lewy body dementia increased by an average rate of 2.06%, 4.90%, and 12.13% per year, respectively. Mortality from stroke and dementia increased with age. Greater reductions in stroke mortality and greater increases in dementia mortality were seen in women than men; and in older than younger (<65 years) people. Conclusions: There has been a striking rising trend in dementia mortality coincident with a reduction in stroke mortality in the United States. There are persistent age and sex disparities in stroke and dementia mortality trends. Our findings support the pathophysiological relationship between stroke and dementia, and have important implications for future research, healthcare planning, and provision. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between home ownership and health in older men. Methods: Cross‐sectional analysis of 909 community‐dwelling Australian men (mean age: 81.3 ± 4.6) from the Concord Health and Ageing in Men Project (CHAMP, 2012‐2013). We considered self‐rated health, frailty status, multimorbidity, and anxiety and depressive symptoms which identify different dimensions of health. Results: Most participants were owner‐occupiers (89.7%). In age‐ and country of birth–adjusted analyses, not being an owner‐occupier was associated with an increased likelihood of depressive symptoms [prevalence ratio: 1.82, 95% confidence intervals 1.17 to 2.84]. There were no associations between home ownership and other health conditions. Conclusion: Lack of home ownership was associated with a higher prevalence of depressive symptoms, largely explained by poorer social support. Thus, targeting mental health programs at older divorced or separated men who do not own their own home could be an appropriate community‐based intervention. [ABSTRACT FROM AUTHOR]

Background: Several studies have examined the relationship between cognition and oral health in older populations. To further understand this relationship, we examined the associations between cognitive function, chewing capacity and the number of teeth present in community-dwelling older males in Australia.Methods: Data were obtained from cross-sectional analysis of fourth wave of the Concord Health and Ageing in Men Project (CHAMP). Participants were 369 community-dwelling males aged 78 years or over. Cognitive function was measured utilising the Mini-Mental State Examination (MMSE). Chewing capacity was determined on ability to chew food items of different textures, and oral health data were collected. Ordinal regression was used to analyse associations between MMSE (four categories) and chewing capacity and number of natural teeth present.Results: Overall, 67.5% of participants reported that they could chew all 11 listed food items. Participants with fewer than 20 teeth were statistically significantly more likely to have cognitive impairment (unadjusted odds ratio (OR) 1.87; 95% confidence interval (CI) 1.25-2.79, adjusted OR 1.62; 95% CI 1.07-2.43). Participants with limited chewing capacity were also more likely to have cognitive impairment (unadjusted OR 1.91; 95% CI 1.25-2.94, adjusted OR 1.61; 95% CI 1.03-2.49).Conclusions: This study suggests either that older men with fewer than 20 natural teeth and those with limited chewing capacity are more likely to have an associated cognitive impairment or that those with cognitive impairment are more likely to have fewer teeth and limited chewing capacity. Further longitudinal studies should clarify these relationships. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether poorer oral health, tooth loss and lower usage of dental services are associated with depressive symptoms in older Australian men. Methods: Cross‐sectional study of data collected from participants of the Concord Health and Ageing in Men Project. Depressive symptoms were evaluated by the Geriatric Depression Scale. Chewing capacity was estimated by ability to chew 11 food items. Results: The prevalence of depressive symptoms was 17.5%. Self‐evaluated oral health, chewing capacity and the number of natural and decayed teeth were associated with depressive symptoms. After adjusting for multiple confounders, chewing capacity (PR 1.93; 95% CI 1.34‐2.79) and decayed teeth (PR 1.68; 95% CI 1.03‐2.75) maintained a significant association with depressive symptoms. Conclusion: The direction of causality between oral health and depression is unclear; however, oral health may contribute to depression in older Australian men and depressive symptoms may limit chewing capacity and be aggravated by untreated dental decay. [ABSTRACT FROM AUTHOR]

Key points: Night time/active phase food restriction for 6 h impaired glucose intolerance in young male and female mice.Females displayed increased capacity for lipogenesis and triglyceride storage in response to a short daily fast.Females had lower fasting insulin levels and an increased potential for utilizing fat for energy through β‐oxidation compared to males.The need for the inclusion of both sexes, and the treatment of sex as an independent variable, is emphasized within the context of this fasting regime. There is growing interest in understanding the mechanistic significance and benefits of fasting physiology in combating obesity. Increasing the fasting phase of a normal day can promote restoration and repair mechanisms that occur during the post‐absorptive period. Most studies exploring the effect of restricting food access on mitigating obesity have done so with a large bias towards the use of male mice. Here, we disentangle the roles of sex, food intake and food withdrawal in the response to a short‐term daily fasting intervention, in which food was removed for 6 h in the dark/active phase of young, 8‐week‐old mice. We showed that the removal of food during the dark phase impaired glucose tolerance in males and females, possibly due to the circadian disruption induced by this feeding protocol. Although both sexes demonstrated similar patterns of food intake, body composition and various metabolic markers, there were clear sex differences in the magnitude and extent of these responses. While females displayed enhanced capacity for lipogenesis and triglyceride storage, they also had low fasting insulin levels and an increased potential for utilizing available energy sources such as fat for energy through β‐oxidation. Our results highlight the intrinsic biological and metabolic disparities between male and female mice, emphasizing the growing need for the inclusion of both sexes in scientific research. Furthermore, our results illustrate sex‐specific metabolic pathways that regulate lipogenesis, obesity and overall metabolic health. Key points: Night time/active phase food restriction for 6 h impaired glucose intolerance in young male and female mice.Females displayed increased capacity for lipogenesis and triglyceride storage in response to a short daily fast.Females had lower fasting insulin levels and an increased potential for utilizing fat for energy through β‐oxidation compared to males.The need for the inclusion of both sexes, and the treatment of sex as an independent variable, is emphasized within the context of this fasting regime. [ABSTRACT FROM AUTHOR]

Objective: To examine whether frailty in older men is associated with poorer oral health and lower levels of dental service utilisation.Background: Poor oral health has been associated with some frailty components. Less is known about the link between frailty and oral health outcomes.Methods: A cross-sectional analysis. Data were collected from 601 older men with both frailty status and oral health information. Frailty was defined as meeting three or more of the Cardiovascular Health Study criteria: weight loss, weakness, exhaustion, slowness and low activity. Dental service utilisation (DSU) behaviour was collected from self-response questionnaires and face-to-face interviews. Oral status (number of remaining and functional teeth, periodontal disease, active coronal decayed surface [ACDS] and self-rated oral health [SROH]) was recorded by two oral health therapists. The association between frailty and oral health behaviour and risk markers was modelled using logistic regression.Results: Nineteen per cent of the participants were identified as frail. There were significant associations between frailty and dentition status (odds ratio [OR]: 2.49, 95% confidence interval [CI]: (1.17-5.30), and frailty and ACDS (OR: 3.01, CI: 1.50-6.08) but only ACDS remained significant after adjusting for confounders (adjusted OR: 2.46, CI: 1.17-5.18). There was no association between frailty and DSU and frailty and SROH.Conclusion: Frailty was independently associated with the presence of dental caries. However, DSU, SROH and other oral health markers were not significantly associated with frailty after adjusting for confounders. The prevalence of periodontal disease was high regardless of their frailty status. [ABSTRACT FROM AUTHOR]

Outcomes of COVID-19 vaccines prioritised by older patients may include less severe disease, avoiding the need for hospitalisation and potentially reducing the functional impairment often seen after severe infections in older people. The COVID-19 pandemic brought development, evaluation and use of vaccines for older adults into the spotlight. It is difficult to extrapolate from data on responses of frail, older participants to other vaccines, particularly from vaccines that use different technologies (e.g., influenza, pneumococcal and varicella-zoster9). [Extracted from the article]

Aims: We investigated anticholinergic medicines use among older adults initiating dementia medicines. Methods: We used Pharmaceutical Benefits Scheme dispensing claims to identify patients who initiated donepezil, rivastigmine, galantamine or memantine between 1 January 2013 and 30 June 2017 (after a period of ≥180 days with no dispensing of these medicines) and remained on therapy for ≥180 days (n = 4393), and dispensed anticholinergic medicines in the 180 days before and after initiating dementia medicines. We further examined anticholinergic medicines prescribed by a prescriber other than the one initiating dementia medicines. Results: One‐third of the study cohort (1439/4393) was exposed to anticholinergic medicines up to 180 days before or after initiating dementia medicines. Among patients exposed to anticholinergic medicines, 46% (659/1439) had the same medicine dispensed before and after initiating dementia medicines. The proportion of patients dispensed anticholinergic medicines increased by 2.5% (95% confidence interval [CI]: 1.3–3.7) after initiating dementia medicines. Antipsychotics use increased by 10.1% (95% CI: 7.6–12.7) after initiating dementia medicines; driven by increased risperidone use (7.3%, 95% CI: 5.3–9.3). Nearly half of patients dispensed anticholinergic medicines in the 180 days after (537/1133), were prescribed anticholinergic medicines by a prescriber other than the one initiating dementia medicines. Conclusion: Use of anticholinergic medicines is common among patients initiating dementia medicines and this occurs against a backdrop of widespread campaigns to reduce irrational medicine combinations in this vulnerable population. Decisions about deprescribing medicines with questionable benefit among patients with dementia may be complicated by conflicting recommendations in prescribing guidelines. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present longitudinal study of community‐dwelling older men was to examine the association between cognitive status at baseline, and falls, fractures and bone loss over time. Methods: In the Concord Health and Aging in Men Project, 1705 community‐dwelling men aged 70–97 years had detailed baseline clinical assessment of cognitive status (dementia, mild cognitive impairment [MCI] and normal cognition), as well as depression, physical activity, neuromuscular function, health status, sociodemographics, comorbidities, medication use and serum 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D and parathyroid hormone levels. During a mean follow‐up period of 6 years, participants were contacted 4‐monthly to ascertain incident falls and fractures, the latter being confirmed by radiographic reports. Bone mineral density was measured by dual X‐ray absorptiometry at multiple time‐points. Results: At baseline, 120 men were assessed to have MCI and 93 men to have dementia. Over time, there were 162 first incident fractures, including 43 hip and 32 vertebral fractures. In univariate models, baseline dementia, but not MCI, predicted an increased incidence of hip fracture (HR 6.95, 95% CI 3.47–13.96), but not vertebral (HR 2.26, 95% CI 0.79–6.46) or non‐hip non‐vertebral fracture (HR 0.73, 95% CI 0.27–1.99). The strong risk of hip fractures associated with dementia remained after accounting for potential confounders (HR 4.44, 95% CI 1.97–9.98). In multivariate analyses, dementia (incidence rate ratio 2.26, 95% CI 1.70–2.99), but not MCI, was associated with an increased risk of falls compared with normal cognition. There was no association between baseline dementia and change in bone mineral density. Conclusions: Older men with dementia, but not MCI, have a greater tendency to fall and sustain hip fractures, but not any other types of fractures. Geriatr Gerontol Int 2018; 18: 1479–1484. [ABSTRACT FROM AUTHOR]

Background: The association rules method is a novel methodology to ascertain patterns of medication use and combinations associated with adverse drug events. Objectives: The aim of this case‐crossover study was to apply the association rules method to ascertain medication combinations contributing to the risk of fractures in older adults. Methods: A nationwide representative sample of New Zealanders aged ≥65 years was sourced from the pharmaceutical collection. The first‐time coded diagnosis of fracture was extracted from the National Minimum Dataset. Association rule method is a data mining technique that can be used to quickly traverse big datasets to identify a combination of items that co‐occur. The association rules method were applied to identify frequent 11 medication combinations in the case and the control periods (1‐14 days as hazard period, with 35‐day washout period), and the association of fractures with each frequent medication combination were tested by computing a matched odd ratio (OR) and its 95% CI. Results: We identified a total of 72 184 individuals (mean age 81.5 years) from 2005 to 2014 with incident fracture and exposed to at least 1 medication of interest. The association rules method revealed codeine phosphate (aOR = 11.50, 95% CI, 7.09‐15.20, concomitantly with ibuprofen), zopiclone (aOR = 2.34, 95% CI, 1.49‐3.67, concomitantly with morphine) and quetiapine (OR = 1.95, 95% CI, 1.28‐2.98, concomitantly with zopiclone) were associated with fractures. Conclusion: The association rules method identified medication exposure combinations containing psychotropic medications and codeine are frequently associated with fractures. This novel methodology applied to big data can be an important tool to ascertain medication combinations associated with adverse drug events. [ABSTRACT FROM AUTHOR]

Aims: To describe the natural history of post‐void residual urine volume (PVR) in community‐dwelling older men. Methods: The Concord Health and Ageing in Men Project involves a representative sample of community‐dwelling men aged 70 and older in a defined geographic area of Sydney, Australia. PVR were measured at baseline and 2‐year and 5‐year follow‐up. The measurements were considered valid when the voided volumes were 150 mL and over. Three‐hundred twenty‐nine men without conditions that are likely to alter PVR (neurological disorders, prostate cancer, and a history of urological treatment) were included in the analyses. Results: Baseline PVR were 0‐49 mL in 183 men, 50‐99 mL in 59 men, 100‐199 mL in 72 men, 200‐399 mL in 11 men, and 400 mL and over in 4 men. Thirteen out of 314 (4%) men with a baseline PVR of 0‐199 mL and 2 out of 11 (18%) men with a baseline PVR of 200‐399 mL had surgery for benign prostate enlargement (BPE) or indwelling catheterization over 5 years compared to three out of four men (75%) with a PVR of 400 mL and over. In all 101 men with a baseline PVR of less than 400 mL who did not receive urological treatment during follow‐up and had valid PVR data for both 2‐year and 5‐year follow‐up, PVR did not exceed 400 mL at either follow‐up time point. Conclusion: Conservative management may be appropriate for most older men with incidentally found elevated PVR of up to 400 mL. [ABSTRACT FROM AUTHOR]

In the latest "When I Say..." instalment, microlearning is defined with illustrative examples as a valuable pedagogy characterised by short duration and focused content. [ABSTRACT FROM AUTHOR]

Objective: To describe an oral health care programme for older people in Residential Aged Care Facilities (RACFs) to improve access to care and support facilities.Introduction: Different models of residential care have been proposed, but few have been comprehensive (providing on-site health promotion and service delivery) or sustainable.Methods: A partnership model of oral health care, with dental services plus oral health education, was integrated into the community outreach services of a metropolitan hospital department of aged care. The programme provided annual oral health education and training to staff, and on-site dental care to 10 (RACFs).Results: None of the RACFs had received organised education or on-site dental service care prior to the programme. At the completion of the third year of the programme, 607 residents (75% of the total bed capacity for the 10 RACFs) had received an annual oral health assessment, and 271 (46.5%) had received on-site dental care. More than 120 nursing and allied health staff had received education and training in oral health support to residents. Oral cleanliness, the proportion not experiencing dental pain and referral for additional care decreased significantly over the period, but dental caries experience and periodontal conditions remained a concern.Conclusions: Sustainable domiciliary oral health services and oral health education are feasible and practical using a partnership model within the Australian health system. Adaptability, continuity and the use of oral health therapists/dental hygienists in the coordination and management of the programme further contribute to viability. [ABSTRACT FROM AUTHOR]

Objective To explore differences between older male caregivers and non-caregivers on health status, health behaviours and well-being, including symptoms of anxiety. Methods Data were collected through self-completed questionnaires and face-to-face interviews with 1705 community living men aged ≥70 in the Concord Health and Ageing in Men Project. Results Eleven per cent of older men were caregivers, of whom 81.7% were looking after their wives or partners. Older male caregivers did not have worse physical health or more depressive symptoms than non-caregivers, but being a caregiver was associated with increased likelihood of reporting anxiety symptoms ( OR: 2.32, 95% CI: 1.39-3.87). Caregivers had similar levels and frequencies of leisure activities but did more housework activities than non-caregivers. Conclusion Higher anxiety levels were the main adverse health condition in older male caregivers. Strategies to assist minimising anxiety for caregivers should be a target of interventions. [ABSTRACT FROM AUTHOR]

Aims To describe the natural history of non-neurogenic overactive bladder (OAB) and urgency incontinence in community-dwelling older men. Methods A representative sample of 1,705 community-dwelling men aged 70 and older in a defined geographic area of Sydney, Australia, had their urinary symptoms assessed using the International Prostate Symptom Scores (IPSS) and the International Consultation of Incontinence Questionnaire (ICIQ) at baseline, 2-year follow-up, and 5-year follow-up. Four hundred and eighty-eight men without neurological diseases or prostate cancer during follow-up, or history of urological treatment at baseline were included in the analysis. Urgency incontinence was defined as leakage of urine occurring more than weekly in the above-defined population. OAB was defined as either urgency or urgency incontinence according to 2002 International Continence Society consensus. Results Of the men with OAB at baseline, 29% received treatment for OAB or benign prostatic enlargement over 5 years. Of the remaining men, 33% had sustained remission at 2-year and 5-year follow-ups without treatment. Of the men with OAB at 2-year follow-up, remission rate at 5-year follow-up was 53% in men without OAB at baseline and 27% in men with OAB at baseline ( P = 0.23). No statistically significant difference was found in baseline characteristics between men with sustained remission and men with persistent symptoms. Conclusions One in three older men with non-neurogenic OAB had sustained remission of symptoms without medical or surgical interventions. No significant predictor of sustained remission was identified. Neurourol. Urodynam. 36:443-448, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim To describe the age at which the geriatric syndromes and frailty become common in community-dwelling men. Methods The Concord Health and Ageing in Men Project involves a population-based sample of 1705 community-dwelling men aged 70 and over from a defined geographic region in Sydney. Data were obtained by physical performance tests, clinical examinations, and questionnaire to determine the prevalence of the following conditions by five-year age group. Results Poor mobility, recurrent falls, urinary incontinence, dementia and frailty phenotype were all uncommon (less than 10%) in men in their 70s, but the prevalence of each of these conditions exceeded 10% in men aged 85-89. The prevalence of Frailty Index-defined frailty, multimorbidity, polypharmacy and instrumental activities of daily living dependence was constantly high in all age groups. Conclusions The different health-care needs of the 'old old' aged 85 years and older should be accounted for in health service planning. [ABSTRACT FROM AUTHOR]

Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine ( NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57 BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase ( ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry ( ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity. [ABSTRACT FROM AUTHOR]

Isoniazid is the first-line treatment for tuberculosis; however, its use is limited by hepatotoxicity. Age-related differences in isoniazid pharmacokinetics and hepatotoxicity are uncertain. We aimed to investigate these in young (3 ± 0 months, n = 26) and old (23.0 ± 0.2 months, n = 27) male Fischer 344 rats following a low- or high-dose toxic regimen of isoniazid or vehicle (4 doses/day over 2 days; low: 100, 75, 75, 75 mg/kg; high: 150, 105, 105, 105 mg/kg i.p. every 3 h). Fifteen hours after the last dose, animals were euthanized and sera and livers were prepared for analysis. Isoniazid treatment increased serum hepatotoxicity markers (alanine and aspartate transaminase) in young animals but not in old animals, and only reached significance with the high dose in young animals. Isoniazid treatment caused a trend towards an increase in necrosis in young animals with both doses. In contrast, microvesicular steatosis was increased in old isoniazid-treated animals, reaching significance only with the low dose (steatosis prevalence in old: vehicle 1/9, isoniazid 4/5; P < 0.05). Among isoniazid-treated animals, concentrations of toxic intermediates acetylhydrazine and hydrazine were higher in old than young animals ( P < 0.05). With both doses, hepatic cytochrome P450 2E1 activity was higher in young animals compared with old ( P < 0.05). There were no other age effects seen on any of the other measured enzymes involved in isoniazid metabolism (N-acetyl transferase, amidase, glutathione-S-transferase). These results show age-related changes in isoniazid pharmacokinetics may contribute towards differential patterns of toxicity and confirm that standard hepatotoxicity markers do not detect isoniazid-induced microvesicular steatosis. [ABSTRACT FROM AUTHOR]

Aim To describe the prevalence and correlates of alcohol consumption and tobacco smoking among older Australian men. Method Self-reported alcohol and tobacco use was assessed among a random sample of community-dwelling men aged ≥70 years living in Sydney ( n = 1705) from 2005 to 2007. Logistic regression was used to compute odds ratios ( ORs) and 95% confidence intervals ( CIs) for factors associated with alcohol and tobacco use. Results The prevalence of heavy/excessive drinking was 19.2%, daily drinking 33.7%, and binge drinking 14.1%. Daily drinking was associated with chronic pain ( OR = 1.38, 95% CI: 1.07-1.78). Binge drinking was associated with anxiety ( OR = 1.93, 95% CI: 1.05-3.54) and being widowed ( OR = 1.74, 95% CI: 1.11-2.73). Six per cent of men were current smokers and 56.7% were former smokers. Former smoking was associated with polypharmacy ( OR = 1.47, 95% CI: 1.14-1.91) and each additional comorbid condition ( OR = 1.11, 95% CI: 1.03-1.19). Conclusions Nearly one-fifth of older men drank heavily or excessively. This highlights the need for public health initiatives to reduce alcohol consumption in older people. [ABSTRACT FROM AUTHOR]

Objectives To examine the associations between serum 25-hydroxyvitamin D (25 OHD) levels and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25 OHD), with type 2 diabetes mellitus ( DM) in community-living men aged 70 and older. Design Cross-sectional. Setting A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project ( CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants Community dwelling men aged 70 and older taking part in CHAMP (N = 1,659). Measurements Serum 25 OHD and 1,25 OHD levels, presence of DM, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, statin use, income, measures of health, depression, activity of daily living disabilities, parathyroid hormone, estimated glomerular filtration rate, phosphate, and calcium. Results The prevalence of DM was 20.0%. There was a significant association between low 25 OHD and 1,25 OHD levels and DM that remained after adjustment for a wide range of confounders and covariates of clinical significance such as comorbidity, renal function, calciotropic hormones, and medications. Conclusion 25 OHD and 1,25 OHD levels were associated with DM. The independent association between serum 25 OHD and 1,25 OHD concentrations and DM raises the question of whether each of the two vitamin D metabolites may influence DM through different biological mechanisms and pathways. [ABSTRACT FROM AUTHOR]

Objectives To explore associations between serum 25-hydroxyvitamin D (25( OH)D) levels and a wide range of health conditions, physical performance measures, disability, and mortality in a large epidemiological study to identify an optimum range for 25( OH)D concentrations. Design Cross-sectional study, with additional prospective data on falls and mortality. Setting Concord Health and Ageing in Men Project, Sydney, Australia. Participants Community-dwelling men aged 70 and older (N = 1,659). Measurements Serum 25( OH)D levels, general health status, self-reported diseases, physical performance measures, disability (activities of daily living and instrumental activities of daily living) and falls. Results Fair, poor, and very poor health; self-reported diabetes mellitus; hyperglycemia; depression; muscle weakness; poor balance; and all-cause mortality were all associated with serum 25( OH)D levels less than 50 nmol/L, even after adjustment for confounding. The findings also suggest that, in older men, for a wide range of health conditions, physical performance measures, disability, falls, and mortality, the optimum range of 25( OH)D is between 50.0 and 74.9 nmol/L, with no additional benefit for 25( OH)D levels of 75.0 nmol/L or greater. Conclusion Programs aimed at achieving an optimum range of serum 25( OH)D at levels between 50.0 and 74.9 nmol/L may have overall health benefits and such levels are adequate for older men. [ABSTRACT FROM AUTHOR]

Aim To explore the association between psychotropic drug use and alcohol drinking in community-dwelling older Australian men. Design and Methods We conducted a cross-sectional population-based study using baseline data collected between 2005 and 2007 from 1705 participants in the Concord Health and Ageing in Men Project ( CHAMP) conducted in Sydney, Australia. All participants were men aged ≥70 years. The prevalence of antidepressant and sedative or anxiolytic drug use was ascertained at clinical examinations and alcohol drinking was self-reported. Logistic regression models were used to compute the unadjusted and adjusted prevalence ratios and 95% confidence intervals for the association between sedative or anxiolytic use and antidepressant use with drinking patterns. Results In the study sample, 8.0% used an antidepressant, 5.7% used a sedative or anxiolytic, 33.7% were daily drinkers, 13.9% were binge drinkers, 19.2% were heavy drinkers and 11.0% were problem drinkers. Overall, 27.1% of antidepressant users were daily drinkers and 42.7% of sedative or anxiolytic users were daily drinkers. Sedative or anxiolytic use was associated with daily drinking (prevalence ratio = 1.42; 95% confidence intervals 1.09-1.76) but not with other drinking patterns. The associations between antidepressant use and alcohol drinking were not statistically significant. Discussion and Conclusions Potential psychotropic drug-alcohol interactions were common in older Australian men. Users of sedative or anxiolytic drugs were more likely to engage in daily drinking compared with non-users of sedative or anxiolytic drugs. Clinicians should monitor patients prescribed sedative or anxiolytic drugs for possible adverse events arising from concomitant use with alcohol. [ABSTRACT FROM AUTHOR]

Objective: Protein leverage plays a role in driving increased energy intakes that may promote weight gain. The influence of the protein to carbohydrate ratio (P:C) in diets of C57BL/6J mice on total energy intake, fat storage, and thermogenesis was investigated. Design and Methods: Male mice (9 weeks old) were provided ad libitum access to one of five isocaloric diets that differed in P:C. Food intake was recorded for 12 weeks. After 16 weeks, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were dissected, weighed, and the expression levels of key metabolic regulators were determined in BAT. In a separate cohort, body surface temperature was measured in response to 25 diets differing in protein, fat, and carbohydrate content. Results: Mice on low P:C diets (9:72 and 17:64) had greater total energy intake and increased WAT and BAT stores. Body surface temperature increased with total energy intake and with protein, fat, and carbohydrate, making similar contributions per kJ ingested. Expression of three key regulators of thermogenesis were downregulated in BAT in mice on the lowest P:C diet. Conclusions: Low-protein diets induced sustained hyperphagia and a generalized expansion of fat stores. Increased body surface temperature on low P:C diets was consistent with diet-induced thermogenesis (DIT) as a means to dissipate excess ingested energy on such diets, although this was not sufficient to prevent development of increased adiposity. Whether BAT was involved in DIT is not clear. Increased BAT mass on low P:C diets might suggest so, but patterns of thermogenic gene expression do not support a role for BAT in DIT, although they might reflect failure of thermogenic function with prolonged exposure to a low P:C diet. [ABSTRACT FROM AUTHOR]

Aim: To determine adherence, persistence and continuation beyond 6 months with cholinesterase inhibitors in Australians with Alzheimer's disease. Methods: Adherence and persistence with cholinesterase inhibitors were assessed by data linkage using the Pharmaceutical Benefits Scheme (PBS) Authority database and other health databases. Results: Over 18 000 people commenced cholinesterase inhibitors during 2004. Adherence was 79.4% while the medication possession ratio was 0.88. Some 70.3% of people filled all six scripts for the initial trial period of therapy. Some 57.3% of evaluable patients accessed funding beyond six prescriptions, indicating that their clinicians had declared that there was a two-point or more greater improvement in the Mini-Mental State Examination. Despite the high rate of continuation beyond 6 months, the rates of institutionalisation and death were no different to those reported in clinical trials. Conclusions: Persistence and adherence with cholinesterase inhibitors was reasonable once treatment was established. There was an unexpectedly high continuation rate beyond six prescriptions. [ABSTRACT FROM AUTHOR]

The article discusses the results of the Concord Health and Ageing in Men Project (CHAMP) cohort study that determines the levels of prostate-specific antigen (PSA) in men aged 70 years and above. The study shows that 11 percent of the 1,434 men had a PSA level that increased from 7.5 percent of men aged 70-74 years to 31.4 percent of men 90 years. It concludes that a significant number of men aged over 70 have recent prostate cancer tests.

The objectives of this study were to determine whether Drug Burden Index (DBI), a measure of individuals’ exposure to anticholinergic and sedative drugs, and Beers criteria, an explicit measure of potentially inappropriate drug use, are associated with function in older adults living in low-level care facilities; and to compare DBI with Beers criteria as a predictor of function in older people. The study population consisted of 115 residents living in low-level care facilities in Sydney, Australia. Data on demographics, drugs, and comorbidities were collected. Outcomes included objective measures of physical function Short Performance Physical Battery (SPPB) and grip strength. In total, 50 (44%) participants were exposed to DBI drugs, 51 (44%) participants received at least 1 Beers criteria drug, and 30 (26%) were exposed to both. After adjusting for confounders, for every unit increase in DBI, the SPPB score decreased by 1.3 (P = .04). DBI was not associated with weaker grip strength. Beers criteria were not associated with any of the outcomes. In older adults living in self-care retirement villages, DBI was associated with impairments in physical functioning. Exposure to Beers criteria drugs was common; however, Beers criteria did not predict functional outcomes in this population of older adults. [ABSTRACT FROM PUBLISHER]

Pain is highly prevalent in frail older people who often have multiple co-morbidities and multiple medicines. Rational prescribing of analgesics in frail older people is complex due to heterogeneity in drug disposition, comorbid medical conditions, polypharmacy and variability in analgesic response in this population. A critical issue in managing older people with pain is the need for judicious choice of analgesics based on a comprehensive medical and medication history. Care is needed in the selection of analgesic medicine to avoid drug-drug or drug-disease interactions. People living with dementia and cognitive impairment have suboptimal pain relief which in part may be related to altered pharmacodynamics of analgesics and challenges in the systematic assessment of pain intensity in this patient group. In the absence of rigorously controlled trials in frail older people and those with cognitive impairment a pharmacologically-guided approach can be used to optimize pain management which requires a systematic understanding of the pharmacokinetics and pharmacodynamics of analgesics in frail older people with or without changes in cognition. [ABSTRACT FROM AUTHOR]

Abstract: Back pain is common in older people and is associated with functional disability and poor self-rated health. Older persons are under-represented in back pain research, and research on back pain in older persons from ethnic minorities is particularly sparse. We investigated differences in back pain characteristics, effects and medication use in a population-based sample of 335 Italian-born immigrants and 849 Australian-born men aged 70years and over. There were 189 (62%) Italian-born men and 507 (63%) Australian-born men who reported experiencing back pain in the past 12months. Despite no difference in the reported prevalence of back pain between the two groups of men, Italian-born men were more likely to report that their pain was frequent, severe and chronic. Italian-born men were also more likely to report having other sites of pain and that they had limited their activities in the past 12months due to back pain. Despite these differences, the use of analgesic medication was the same in both groups. Multivariate analyses showed that differences in pain characteristics and effects between the two groups of men were explained by socioeconomic factors such as years of education and occupation history. [ABSTRACT FROM AUTHOR]

To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men. Cross-sectional study of older men participating in the Concord Health and Ageing in Men Project (CHAMP). Elderly men living in a defined geographical region in Sydney, Australia. One thousand seven hundred five community-dwelling men aged 70 and older who participated in the baseline assessments of CHAMP. Upper and lower extremity strength were measured using dynamometers for grip and quadriceps strength. Appendicular skeletal lean mass was assessed using dual X-ray absorptiometry. Muscle quality was defined as the ratio of strength to mass in upper and lower extremities. For each parameter, subjects in the lowest 20% of the distribution were defined as below normal. Functional limitation was assessed according to self-report and objective lower extremity performance measures. Physical disability was measured according to self-report questionnaire. After adjusting for important confounders, the prevalence ratio (PR) for poor quadriceps strength and self-reported functional limitation was 1.91 (95% confidence interval (CI)=1.10-2.40); for performance-based functional limitation the PR was 1.81 (95% CI=1.45-2.24). The adjusted PR for poor grip strength and physical disability in instrumental activities of daily living (IADLs) was 1.37 (95% CI=1.20-1.56). The adjusted PR for low skeletal lean mass (adjusted for fat mass) and physical disability in basic activities of daily living was 2.08 (95% CI=1.37-3.15). For muscle quality, the PR for lower extremity specific force and functional limitation and physical disability was stronger than upper extremity specific force. Muscle strength is the single best measure of age-related muscle change and is associated with physical disability in IADLs and functional limitation. [ABSTRACT FROM AUTHOR]

Prescribing in frail older people may be improved by application of the four tenets of medical ethics - beneficence, nonmaleficence, autonomy, justice - rather than solely those of evidence-based medicine. Evidence-based medicine provides data primarily on the efficacy of interventions. In younger adults, this is often sufficient to make a decision to prescribe medications. In frail older people, there are additional issues that need to be considered, such as individualisation of efficacy data, increased risk of adverse drug reactions, patients' views on risk and benefit, difficulties in assessing capacity to understand risk and benefit, consent to treatment, and concerns about the cost-effectiveness of interventions in the very old. In such situations, evidence-based medicine can be useful in informing the prescriber about the ethical principle of beneficence. However, the decision to prescribe or withdraw medications is also influenced by the other three tenets of medical ethics: non-maleficence (adverse drug reactions, polypharmacy), autonomy (consent, competency) and justice (appropriate allocation of healthcare resources). [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • Lean mass decreases with age while total body fat increases, leading to changes in the pharmacokinetics and pharmacodynamics of drugs. • Dual-energy X-ray absorptiometry (DXA) is a useful reference method to measure lean body weight but may not be readily utilized clinically. • Limited methods for measurement of lean body weight using easily obtainable participant characteristics, such as height and weight, have been validated for use in people aged ≥65 years. WHAT THIS STUDY ADDS • This study has shown that lean body weight can be estimated using three different equations from easily obtainable participant characteristics with results comparable to DXA-derived estimates. • These equations may be useful tools to estimate lean body weight in situations where DXA is not practical. AIMS Lean body weight (LBW) decreases with age while total body fat increases, altering drug pharmacokinetics. The aim of this study was to evaluate the ability of the LBW equation to predict dual-energy X-ray absorptiometry (DXA)-derived fat free mass (FFMDXA) in older community-dwelling males compared with that of two existing FFM equations: the Heitmann and Deurenberg equations. METHODS Data were obtained from 1655 older men enrolled in the Concord Health and Ageing in Men Project. The predictive performance of the LBW and FFM equations to predict FFMDXA accurately was assessed graphically using Bland–Altman plots and quantitatively for precision and bias using the method of Sheiner and Beal in all participants and in frailty and body mass index (BMI) subgroups. RESULTS The LBW and Heitmann equations consistently overestimated FFMDXA for all frailty and BMI subgroups with a mean difference [95% confidence interval (CI)] of 5.5 kg (−0.65, 11.63 kg) and 3.34 kg (−2.84, 9.64 kg), respectively. The Deurenberg equation overestimated FFMDXA for overweight participants but underestimated FFMDXA for not-frail participants, with a mean difference (95% CI) of 1 kg (−7.23, 5.25 kg) for all participants. CONCLUSION LBW and FFM estimated using these equations give results comparable to DXA-derived FFM. The LBW and Heitmann equations provide a more consistent estimate of FFMDXA in all frailty and BMI groups despite the Deurenberg equation having the smallest mean difference. Further studies to determine whether the LBW equation is a clinically useful substitute for weight when determining drug dose in older people appear warranted. [ABSTRACT FROM AUTHOR]

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS. [ABSTRACT FROM AUTHOR]

Microcirculation (2010) 17, 32–38. doi: 10.1111/j.1549-8719.2009.00004.x Objective: Fenestrations are pores in the liver sinusoidal endothelium that facilitate the transfer of particulate substrates between the sinusoidal lumen and hepatocytes. Fenestrations express caveolin-1 and have structural similarities to caveolae, therefore might be a form of caveolae and caveolin-1 may be integral to fenestration structure and function. Therefore, fenestrations were studied in the livers of caveolin-1 knockout mice. Methods: Scanning, transmission and immunogold electron microscopic techniques were used to study the liver sinusoidal endothelium and other tissues in caveolin-1 knockout and wild-type mice. Results: Comparison of fenestrations in wild-type and knockout mice did not reveal any differences on either scanning or transmission electron microscopy. The diameter of the fenestrations was not significantly different (74 ± 13 nm knockout mice vs 78 ± 12 nm wild-type mice) nor was the fenestration porosity (6.5 ± 2.1 knockout vs 7.3 ± 2.4% wild-type mice). In contrast, adipocytes and blood vessels in other tissues lacked caveolae in the knockout mice. Caveolin-1 immunogold of livers of wild-type mice indicated sparse expression in sinusoidal endothelial cells. Conclusions: The normal structure of fenestrations in the liver sinusoidal endothelium is not dependent upon caveolin-1 and fenestrations are not a form of caveolae. [ABSTRACT FROM AUTHOR]

1. The major source of apolipoprotein E (apoE) is the liver. In the present study, the effects of oxidative stress and apoE isoforms on apoE distribution and trafficking were established using the HepG2 liver tumour cell line. 2. Hydrogen peroxide (0, 25, 250 and 1000 μmol/L) was associated with rapid and concentration-dependent redistribution of apoE into the early endosomal compartment. This redistribution was achieved with a much lower concentration (25 μmol/L) than that needed to induce changes in intracellular apoE mRNA expression, apoE protein levels and markers of oxidative stress (250–1000 μmol/L). 3. Live cell imaging of apoE3–green fluorescent protein revealed a significant decrease in traffic velocity in response to oxidative stress. 4. The E4 isoform was associated with reduced trafficking velocity compared with the E3 isoform under basal conditions. 5. The results indicate that oxidative stress and apoE isoforms influence apoE trafficking and distribution within HepG2 cells. Altered apoE hepatocyte trafficking may provide a mechanistic link between oxidative stress, ageing and some diseases in older people. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Inappropriate medication use is common among the elderly. • Use of medications with anticholinergic and sedative properties is associated with functional impairments in older people. • Exposure to anticholinergic and sedative medications, measured with Drug Burden Index that includes the principles of dose–response and maximal effect, was associated with impairment in physical and cognitive function in two studies of older people in the USA. WHAT THIS STUDY ADDS • We evaluated Drug Burden Index in an Australian population of community-dwelling older men, The Concord Health and Ageing in Men Project that enrolled a random sample of community-dwelling men aged ≥70 years living in Sydney, Australia. • In this population, increasing Drug Burden Index was associated with objective impairments of physical performance and functional status. • The Drug Burden Index has broad applicability regardless of healthcare system, prescribing practices, gender or country. AIMS This study evaluated the associations of physical performance and functional status measures with the Drug Burden Index in older Australian men. The Drug Burden Index is a measure of total exposure to anticholinergic and sedative medications that incorporates the principles of dose–response and maximal effect. METHODS A cross-sectional survey was performed on community-dwelling older men enrolled in The Concord Health and Ageing in Men Project, Sydney, Australia. Outcomes included chair stands, walking speed over 6 m, 20-cm narrow walk speed, balance, grip strength and Instrumental Activities of Daily Living score (IADLs). RESULTS The study population consisted of 1705 men (age 76.9 ± 5.5 years). Of the 1527 (90%) participants who reported taking medications, 21% were exposed to anticholinergic and 13% to sedative drugs. The average Drug Burden Index in the study population was 0.18 ± 0.35. After adjusting for confounders (sociodemographics, comorbidities, cognitive impairment, depression), Drug Burden Index was associated with slower walking speed ( P < 0.05), slower narrow walk speed ( P < 0.05), balance difficulty ( P < 0.01), grip weakness ( P < 0.01) and poorer performance on IADLs ( P < 0.05). Associations with physical performance and function were stronger for the sedative than for the anticholinergic component of the Drug Burden Index. CONCLUSIONS Higher Drug Burden Index is associated with poorer physical performance and functional status in community-dwelling older Australian men. The Drug Burden Index has broad applicability as a tool for assessing the impact of medications on functions that determine independence in older people. [ABSTRACT FROM AUTHOR]

The liver sinusoidal endothelial cell (LSEC) is damaged by many toxins, including oxidants and bacterial toxins. Any effect on LSECs of the Pseudomonas aeruginosa virulence factor, pyocyanin, may be relevant for systemic pseudomonal infections and liver transplantation. In this study, the effects of pyocyanin on in vivo rat livers and isolated LSECs were assessed using electron microscopy, immunohistochemistry and biochemistry. In particular, the effect on fenestrations, a crucial morphological aspect of LSECs was assessed. Pyocyanin treatment induced a dose-dependent reduction in fenestrations in isolated LSECs. In the intact liver, intraportal injection of pyocyanin (11.9 μM in blood) was associated with a reduction in endothelial porosity from 3.4 ± 0.2% ( n = 5) to 1.3 ± 0.1% ( n = 7) within 30 min. There were decreases in both diameter and frequency of fenestrations in the intact endothelium. There was also a decrease in endothelial thickness from 175.8 ± 5.8 to 156.5 ± 4.0 nm, an endothelial pathology finding previously unreported. Hepatocyte ultrastructure, liver function tests and immunohistochemical markers of oxidative stress (3-nitrotyrosine and malondialdehyde) were not affected. Pyocyanin induces significant ultrastructural changes in the LSEC in the absence of immunohistochemical evidence of oxidative stress or hepatocyte injury pointing to a novel mechanism for pyocyanin pathogenesis. [ABSTRACT FROM AUTHOR]

Clinicians are becoming more reliant on their interpretation of clinical trial information to guide prescribing rather than their clinical skills. Thus to improve prescribing, it is increasingly important for clinicians to have an appreciation of epistemology (the science of knowledge and its interpretation) and the broader social context of knowledge. The insights of epistemologists can be useful in understanding the different ways in which clinical trials data are interpreted. [ABSTRACT FROM AUTHOR]

The liver sinusoidal endothelial cell (LSEC) influences the transfer of substrates between the sinusoidal blood and hepatocytes and has a major role in endocytosis; therefore, changes in the LSEC have significant implications for hepatic function. There are major morphological changes in the LSEC in old age called pseudocapillarization. These changes include increased LSEC thickness and reduced numbers of pores in the LSEC, which are called fenestrations. Pseudocapillarization has been found in old humans, rats, mice, and nonhuman primates. In addition, old age is associated with impaired LSEC endocytosis and increased leukocyte adhesion, which contributes to reduced hepatic perfusion. Given that fenestrations in the endothelium allow passage of some lipoproteins, including chylomicron remnants, age-related reduction in fenestrations impairs hepatic lipoprotein metabolism. In old rats, caloric restriction was associated with complete preservation of LSEC morphology and fenestrations. In conclusion, pseudocapillarization of the LSEC is a newly discovered aging change that, through its effects on lipoproteins, contributes to the association between old age, dyslipidemia, and vascular disease. [ABSTRACT FROM AUTHOR]

Long-term reduction in energy intake in the diet (calorie restriction [CR]) extends the life of the laboratory rat by about 25%. However, in humans there are no life-long studies of CR, but only short-term trials which indicate that 20% CR acting over periods of 2–6 years is associated with reduced body weight, blood pressure, blood cholesterol, and blood glucose—risk factors for the major killer diseases of cardiovascular disease and diabetes. In addition, recent research has shown that CR for 6 months is able to improve biomarkers for longevity (deep body temperature and plasma insulin) and thus should increase life expectancy. The magnitude of the life-extension effect of CR in humans can only be estimated. The Okinawans, the longest-lived people on earth, consume 40% fewer calories than the Americans and live only 4 years longer. Similarly, women in United States consume 25% fewer calories than men and live 5 years longer. From the survival studies of overweight and obese people, it is estimated that long-term CR to prevent excessive weight gain could add only 3–13 years to life expectancy. Thus the effects of CR on human life extension are probably much smaller than those achieved by medical and public health interventions, which have extended life by about 30 years in developed countries in the 20th century, by greatly reducing deaths from infections, accidents, and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Hepatic phase I drug metabolism is diminished in old age. It has been suggested that hepatocyte hypoxia and impaired bioenergetics in old age may contribute to this aging change. Therefore, we sought to determine whether old age was associated with in vivo hypoxia in the aged rat liver. Immunohistochemical studies with the nitroimidazole hypoxia marker, pimonidazole, were carried out in livers from young and old rats. Preliminary studies were performed on four young (4-month-old) and six old (2-year-old) F344 rats to directly visualize the distribution and intensity of pimonidazole staining. There were no significant differences in the distribution or in the intensity of pimonidazole immunohistochemical staining between young and aged rat livers. In conclusion, no major changes in hepatocyte oxygenation were seen in the aged rat liver, and the ATP changes are unlikely to be secondary to hepatocyte hypoxia or impaired oxygen diffusion into the liver. It is thus more likely that age-related reduction in liver ATP is attributable to mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]