%0 Journal Article %~ PubMed %A Wilder, Shawn M %A Le Couteur, David G %A Simpson, Stephen J %T Diet mediates the relationship between longevity and reproduction in mammals. %B Age %D 2013 %C Netherlands %I Springer Netherlands %V 35 %N 3 %P 921-927 %@ 1574-4647 %X The disposable soma hypothesis posits a negative correlation between longevity and reproduction, presumably because these aspects of fitness compete for a limited pool of nutrients. However, diet, which varies widely among animals, could affect the availability of key nutrients required for both reproduction and longevity, especially protein. We used a comparative database of mammal life history data to test the hypothesis that carnivores experience less of a negative relationship between reproduction and longevity than herbivores. Annual reproduction and adult mass were significant predictors of longevity among all mammals; although, the relative importance of reproduction and mass for explaining longevity varied among trophic levels. In herbivores, reproduction was a stronger predictor of longevity than mass. Carnivores showed the opposite pattern with reproduction explaining much less of the variation in longevity. Omnivores showed an intermediate pattern with mass and reproduction explaining similar amounts of variation in longevity. In addition, longevity and reproduction were significantly higher in omnivores than herbivores and carnivores, which were not different from each other. Higher dietary protein at higher trophic levels may allow mammals to avoid potential conflicts between reproduction and longevity. However, there may be potential costs of carnivorous diets that limit the overall performance of carnivores and explain the peak in reproduction and longevity for omnivores. %Z FOR Codes: 60801 110308 %0 Journal Article %~ PubMed %A Huang, Xin %A Hancock, Dale P %A Gosby, Alison K %A McMahon, Aisling C %A Solon, Samantha M C %A Le Couteur, David G %A Conigrave, Arthur D %A Raubenheimer, David %A Simpson, Stephen J %T Effects of dietary protein to carbohydrate balance on energy intake, fat storage and heat production in mice. %B Obesity %D 2013 %C United States %I Wiley-Blackwell Publishing, Inc. %V 21 %N 1 %P 85-92 %@ 1930-739X %X %Z FOR Codes: 60603 110107 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Robinson, Maxine %A Leverton, Ann %A Creasey, Helen %A Waite, Louise %A Atkins, Kerry %A McLachlan, Andrew J %T Adherence, persistence and continuation with cholinesterase inhibitors in Alzheimer's disease. %B Australasian Journal on Ageing %D 2012 %C Australia %I Wiley-Blackwell Publishing Asia %V 31 %N 3 %P 164-169 %@ 1741-6612 %X 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. %Z FOR Codes: 111502 110308 %0 Journal Article %~ PubMed %A Le Couteur, David G %A McLachlan, Andrew J %A Quinn, Ronald J %A Simpson, Stephen J %A de Cabo, Rafael %T Aging Biology and Novel Targets for Drug Discovery. %B Journals of Gerontology. Series A: Biological Sciences & Medical Sciences %D 2012 %C United States %I Oxford University Press %V 67 %N 2 %P 168-174 %@ 1758-535X %X Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become "blockbusters." To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process. %Z FOR Codes: 111599 110308 30401 %0 Journal Article %~ PubMed %A Le Couteur, David G %A McLachlan, Andrew J %A de Cabo, Rafael %T Aging, Drugs, and Drug Metabolism. %B Journals of Gerontology. Series A: Biological Sciences & Medical Sciences %D 2012 %C United States %I Oxford University Press %V 67 %N 2 %P 137-139 %@ 1758-535X %X %Z FOR Codes: 111502 111702 %0 Journal Article %~ PubMed %A Baur, Joseph A %A Ungvari, Zoltan %A Minor, Robin K %A Le Couteur, David G %A de Cabo, Rafael %T Are sirtuins viable targets for improving healthspan and lifespan? %B Nature Reviews. Drug Discovery %D 2012 %C United Kingdom %I Nature Publishing Group %V 11 %N 6 %P 443-461 %@ 1474-1784 %X Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1. %Z FOR Codes: 110308 111501 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Handelsman, David J %T DNA damage, NF-κB and accelerated aging %B Asian Journal of Andrology %D 2012 %C United States %I Nature Publishing Group %V 14 %N 6 %P 811¿812 %@ 1745-7262 %X %Z FOR Codes: 110308 110306 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Le Couteur, David G %A Kouladjian, Lisa %A Hilmer, Sarah N %T Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. %B Clinics in Geriatric Medicine %D 2012 %C United States %I W.B. Saunders Co. %V 28 %N 2 %P 237-253 %@ 0749-0690 %X Different styles of interventions can reduce medication exposure in older adults. However, the evidence for their clinical effectiveness and sustainability is conflicting and lacking. There are some data to guide clinicians on which medicines are more likely to be inappropriate in older people, which medicines are more likely to cause ADWEs, and which medicines should be tapered slowly rather than stopped. To reduce the likelihood of clinically significant adverse events, clinicians should undertake a step-wise approach to discontinuing medications and do so under appropriate supervision. Further research to determine the most effective ways to discontinue medications, and to provide a better understanding of the clinical benefits of various interventions is required. Large RCTs evaluating multidisciplinary interventions and clinical outcomes of changes in medicines regimen across different settings are required to confirm the findings of the studies performed so far. %Z FOR Codes: 111502 110308 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Le Couteur, David G %A Abernethy, Darrell R %A Hilmer, Sarah N %T Drug Burden Index and Beers Criteria: Impact on Functional Outcomes in Older People Living in Self-Care Retirement Villages. %B Journal of Clinical Pharmacology %D 2012 %C United States %I Sage Publications, Inc. %V 52 %N 2 %P 258-265 %@ 1552-4604 %X 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. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Le Couteur, David G %A Naganathan, Vasi %A Cumming, Robert G %A Creasey, Helen %A Waite, Louise M %A Sharma, Anita %A Blyth, Fiona M %A Hilmer, Sarah N %T Effects of drug burden index on cognitive function in older men. %B Journal of Clinical Psychopharmacology %D 2012 %C United States %I Lippincott Williams & Wilkins %V 32 %N 2 %P 273-277 %@ 1533-712X %X We aimed to assess the relationship between Drug Burden Index (DBI), a risk assessment tool that measures anticholinergic and sedative medication exposure and cognitive performance, and cognitive impairment in older people. The study population consisted of community-dwelling older men, 70 years or older, living in Sydney, Australia. The Addenbrooke''s Cognitive Examination (ACE) and the Trail Making Task (TMT) cognitive tests were performed, and participants were categorized as having intact cognition, mild cognitive impairment, or dementia using clinical diagnostic criteria. The analyses were restricted to participants with English-speaking background (n = 987) and to the subgroup whose cognition was intact (n = 887). In the study group, DBI exposure was not associated with poorer performance on the ACE (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.66-1.47) or the TMT (OR, 0.71; 95% CI, 0.40-1.24) tests, after controlling for covariates. Similarly, DBI exposure was not associated with cognitive impairment (OR, 1.34; 95% CI, 0.83-2.16). There was no association between increasing DBI scores and poorer performance on any of the outcomes. On subgroup analysis of cognitively intact subgroup, DBI exposure or increasing DBI scores were not associated with poorer performance on the ACE or the TMT tests. In this study of community-dwelling older men, DBI was not associated with limitations on objective cognitive performance measures or with a clinical diagnosis of mild cognitive impairment or dementia. %Z FOR Codes: 111502 110308 %0 Journal Article %~ PubMed %A Gnjidic, D %A Hilmer, S N %A Blyth, F M %A Naganathan, V %A Cumming, R G %A Handelsman, D J %A McLachlan, A J %A Abernethy, D R %A Banks, E %A Le Couteur, D G %T High-risk prescribing and incidence of frailty among older community-dwelling men. %B Clinical pharmacology and therapeutics %D 2012 %C United States %I Nature Publishing Group %V 91 %N 3 %P 521-528 %@ 1532-6535 %X Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ?70 years of age. High-risk prescribing was defined as polypharmacy (?5 medicines), hyperpolypharmacy (?10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men. %Z FOR Codes: 111702 111503 %0 Journal Article %A Gnjidic, Danijela %A Hilmer, Sarah %A Le Couteur, David %T High-risk prescribing in older people: More harm than good? %B Aging Health %D 2012 %C United Kingdom %I Future Medicine Ltd. %V 8 %N 4 %P 325-327 %@ 1745-509X %X %Z FOR Codes: 111502 111702 %0 Journal Article %~ PubMed %A Bell, J Simon %A Le Couteur, David G %A McLachlan, Andrew J %A Chen, Timothy F %A Moles, Rebekah J %A Basger, Benjamin J %A Hilmer, Sarah N %T Improving medicine selection for older people - Do we need an Australian classification for inappropriate medicines use? %B Australian Family Physician %D 2012 %C Australia %I Royal Australian College of General Practitioners %V 41 %N 1-2 %P 9-10 %@ 0300-8495 %X General practitioners manage complex medicine regimens and multiple comorbidities in older people. While medicine use usually leads to benefits for older people, the process of prescribing medicines is becoming increasingly complex. The quality use of medicines (QUM) is one of the four central objectives of Australia''s National Medicines Policy. The National Strategy for the Quality Use of Medicines, launched in 2002, outlines key approaches and principles to achieve QUM. %Z FOR Codes: 111502 %0 Book Section %A Svistounov, Dmitri %A Zykova, Svetlana N. %A Cogger, Victoria %A Warren, Alessandra %A McMahon, Aisling %A Fraser, Robyn %A Le Couteur, David %T Liver Sinusoidal Endothelial Cells and Regulation of Blood Lipoproteins %B Dyslipidemia - From Prevention to Treatment %D 2012 %C Croatia %I InTech %V %N %P 263-278 %@ 9789533079042 %E Kelishadi, Roya %X %Z FOR Codes: 110307 110106 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Stanaway, Fiona F %A Cumming, Robert %A Waite, Louise %A Blyth, Fiona %A Naganathan, Vasi %A Handelsman, David J %A Le Couteur, David G %T Mild Cognitive Impairment Predicts Institutionalization among Older Men: A Population-Based Cohort Study. %B PLoS One %D 2012 %C United States %I Public Library of Science %V 7 %N 9 %P e46061 %@ 1932-6203 %X %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Gnjidic, D %A Le Couteur, D G %A Hilmer, S N %T Off-Label Use of Medicines: Time for Action. %B Clinical Pharmacology and Therapeutics %D 2012 %C United States %I Nature Publishing Group %V 92 %N 2 %P 157 %@ 1532-6535 %X %Z FOR Codes: 111502 110308 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Hilmer, Sarah N %A Blyth, Fiona M %A Naganathan, Vasi %A Waite, Louise %A Seibel, Markus J %A McLachlan, Andrew J %A Cumming, Robert G %A Handelsman, David J %A Le Couteur, David G %T Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. %B Journal of Clinical Epidemiology %D 2012 %C United States %I Elsevier Inc. %V 65 %N 9 %P 989-995 %@ 0895-4356 %X OBJECTIVE: This study aimed to determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in community-dwelling older men. STUDY DESIGN AND SETTING: Older men aged ???70 years (n=1,705), enrolled in the Concord Health and Aging in Men Project were studied. Receiver operating characteristic curve analysis using the Youden Index and the area under the curve was performed to determine discriminating number of medications in relation to each outcome. RESULTS: The highest value of the Youden Index for frailty was obtained for a cutoff point of 6.5 medications compared with a cutoff of 5.5 for disability and 3.5 for cognitive impairment. For mortality and incident falls, the highest value of Youden Index was obtained for a cutoff of 4.5 medications. For every one increase in number of medications, the adjusted odds ratios were 1.13 (95% confidence interval [CI]=1.06-1.21) for frailty, 1.08 (95% CI=1.00-1.15) for disability, 1.09 (95% CI=1.04-1.15) for mortality, and 1.07 (95% CI=1.03-1.12) for incident falls. There was no association between increasing number of medications and cognitive impairment. CONCLUSION: The study supports the use of five or more medications in the current definition of polypharmacy to estimate the medication-related adverse effects for frailty, disability, mortality, and falls. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Litchfield, Melisa J %A Cumming, Robert G %A Smith, David P %A Naganathan, Vasi %A Le Couteur, David G %A Waite, Louise M %A Blyth, Fiona M %A Handelsman, David J %T Prostate-specific antigen levels in men aged 70 years and over: findings from the CHAMP study. %B Medical Journal of Australia %D 2012 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 196 %N 6 %P 395-398 %@ 1326-5377 %X To describe values of serum prostate-specific antigen (PSA) in older men without diagnosed prostate cancer, categorised by age and country of birth, and to describe self-reported prostate cancer screening. %Z FOR Codes: 111404 110308 %0 Journal Article %~ PubMed %A Mitchell, Sarah J %A Huizer-Pajkos, Aniko %A Cogger, Victoria C %A McLachlan, Andrew J %A Le Couteur, David G %A Jones, Brett %A de Cabo, Rafael %A Hilmer, Sarah N %T The Influence of Old Age and Poloxamer-407 on the Hepatic Disposition of Diazepam in the Isolated Perfused Rat Liver. %B Pharmacology %D 2012 %C Switzerland %I S. Karger AG %V 90 %N 5-6 %P 233-241 %@ 1423-0313 %X %Z FOR Codes: 1115 %0 Journal Article %~ PubMed %A Svistounov, Dmitri %A Warren, Alessandra %A McNerney, Gregory P %A Owen, Dylan M %A Zencak, Dusan %A Zykova, Svetlana N %A Crane, Harry %A Huser, Thomas %A Quinn, Ronald J %A Smedsrød, BÃ¥rd %A Le Couteur, David G %A Cogger, Victoria C %T The Relationship between Fenestrations, Sieve Plates and Rafts in Liver Sinusoidal Endothelial Cells. %B PLoS One %D 2012 %C United States %I Public Library of Science %V 7 %N 9 %P e46134 %@ 1932-6203 %X %Z FOR Codes: 601 %0 Journal Article %~ PubMed %A Fraser, Robin %A Cogger, Victoria C %A Dobbs, Bruce %A Jamieson, Hamish %A Warren, Alessandra %A Hilmer, Sarah N %A Le Couteur, David G %T The liver sieve and atherosclerosis. %B Pathology %D 2012 %C United Kingdom %I Informa Healthcare %V 44 %N 3 %P 181-186 %@ 0031-3025 %X %Z FOR Codes: 606 %0 Journal Article %~ PubMed %A Sørensen, Karen Kristine %A McCourt, Peter %A Berg, Trond %A Crossley, Clive %A Le Couteur, David %A Wake, Kenjiro %A Smedsrød, BÃ¥rd %T The scavenger endothelial cell: a new player in homeostasis and immunity. %B American Journal of Physiology: Regulatory, Integrative and Comparative Physiology %D 2012 %C United States %I American Physiological Society %V 303 %N 12 %P R1217-R1230 %@ 1522-1490 %X %Z FOR Codes: 60104 111601 %0 Journal Article %~ PubMed %A Hilmer, Sarah N %A Gnjidic, Danijela %A Le Couteur, David G %T Thinking through the medication list - appropriate prescribing and deprescribing in robust and frail older patients. %B Australian Family Physician %D 2012 %C Australia %I Royal Australian College of General Practitioners %V 41 %N 12 %P 924-928 %@ 0300-8495 %X %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Simpson, Stephen J %T Adaptive Senectitude: The Prolongevity Effects of Aging. %B The journals of gerontology. Series A, Biological sciences and medical sciences %D 2011 %C United States %I Oxford University Press %V 66 %N 2 %P 179-82 %@ 1758-535X %X In the past, it has been assumed that all the biological and medical changes that occur in old age are deleterious. It has therefore been concluded that treatment and prevention of such changes in old age should increase healthspan and delay death. However, accruing epidemiological and clinical trial evidence in older humans suggests that this is not the case. Some studies have shown that antioxidants and hormone supplements increase mortality, whereas high blood pressure, obesity, and metabolic syndrome are often associated with improved outcomes in very elderly people. Perhaps, some of these supposedly detrimental changes accompanying old age are in fact evolutionary adaptations to prolong life after reproduction in humans. Indeed, a form of reverse antagonistic pleiotropy or adaptive senectitude might be occurring. Some common biological and medical changes in old age might actually enhance longevity and represent novel targets for improving health in older people. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Mitchell, Sarah J %A Huizer-Pajkos, Aniko %A Cogger, Victoria C %A McLachlan, Andrew J %A Le Couteur, David G %A Jones, Brett %A de Cabo, Rafael %A Hilmer, Sarah N %T Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats. %B Journals of Gerontology. Series A: Biological Sciences & Medical Sciences %D 2011 %C United States %I Oxford University Press %V 66 %N 4 %P 400-408 %@ 1758-535X %X We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer (14)C-acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 ?? 0.04, old; 0.59 ?? 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k(1) (0.34 ?? 0.10 s(-1), old; 0.61 ?? 0.38 s(-1), young; p < .05) and the permeability-surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 ?? 0.006 mL/s/g, old; 0.048 ?? 0.014 mL/s/g, young; p < .005). There was no difference in k(3), the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver. %Z FOR Codes: 111502 %0 Book Section %A McMahon, Aisling %A Hing, Alfred J %A Cogger, Victoria %A Le Couteur, David %T Animal models of early atherosclerosis: How to translate the data into clinical perspectives %B Silent Vasculopathy in Childhood: Should Clinicians Care? %D 2011 %C India %I Transworld Research Network %V %N %P 39-64 %@ 9788178955216 %X %Z FOR Codes: 110201 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Blyth, Fiona M %A Cumming, Robert G %A Naganathan, Vasi %A Handelsman, David J %A Waite, Louise M %A Sambrook, Philip N %A Creasey, Helen M %A Seibel, Markus J %A Le Couteur, David G %T Back pain in older male Italian-born immigrants in Australia: The importance of socioeconomic factors. %B European Journal of Pain %D 2011 %C United Kingdom, Belg %I Elsevier Ltd %V 15 %N 1 %P 70-76 %@ 1532-2149 %X 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 70 years and over. There were 189 (62%) Italian-born men and 507 (63%) Australian-born men who reported experiencing back pain in the past 12 months. 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 12 months 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. %Z FOR Codes: 111702 %0 Journal Article %~ PubMed %A Travison, Thomas G %A Nguyen, Anh-Hoa %A Naganathan, Vasi %A Stanaway, Fiona F %A Blyth, Fiona M %A Cumming, Robert G %A Le Couteur, David G %A Sambrook, Philip N %A Handelsman, David J %T Changes in Reproductive Hormone Concentrations Predict the Prevalence and Progression of the Frailty Syndrome in Older Men: The Concord Health and Ageing in Men Project. %B Journal of Clinical Endocrinology and Metabolism %D 2011 %C United States %I The Endocrine Society %V 96 %N 8 %P 2464-2474 %@ 1945-7197 %X Frailty, a syndrome of multiple morbidity, weakness, and immobility in aging, is an increasingly urgent threat to public health. Single measures of low serum androgen have been associated with frailty in men, but the contributory role of hormonal changes with time is unassessed. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A McLachlan, Andrew J %A Bath, Sally %A Naganathan, Vasi %A Hilmer, Sarah N %A Le Couteur, David G %A Gibson, Stephen J %A Blyth, Fiona M %T Clinical pharmacology of analgesic medicines in older people: impact of frailty and cognitive impairment. %B British Journal of Clinical Pharmacology %D 2011 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 71 %N 3 %P 351-364 %@ 1365-2125 %X 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. %Z FOR Codes: 111503 %0 Journal Article %A Le Couteur, David %A Banks, Emily %A Gnjidic, Danijela %A McLachlan, Andrew %T Deprescribing %B Australian Prescriber %D 2011 %C Australia %I National Prescribing Service Ltd. %V 34 %N 6 %P 182–185 %@ 0312-8008 %X %Z FOR Codes: 111503 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Benson, Vicky L %A McMahon, Aisling C %A Blyth, Fiona %A Handelsman, David J %A Seibel, Markus J %A Kennerson, Marina %A Naganathan, Vasi %A Cumming, Robert G %A de Cabo, Rafael %T Determinants of Serum-Induced SIRT1 Expression in Older Men: The CHAMP Study. %B Journals of Gerontology. Series A: Biological Sciences & Medical Sciences %D 2011 %C United States %I Oxford University Press %V 66 %N 1 %P 3-8 %@ 1758-535X %X Circulating factors that have an effect on SIRT1 expression are influenced by caloric restriction. To determine the association between frailty and such circulating factors, we measured serum-induced SIRT1 expression from a nested cohort of frail (n = 77) and robust (n = 82) participants from Concord Health and Ageing in Men Project, a population-based study of community-dwelling men older than 70 years. Serum-induced SIRT1 expression was not different between frail and robust men (103.1 ?? 17.0 versus 100.4 ?? 19.3 ??g/L). However, subsequent analyses showed that men with the lowest values (first quartile) were less likely to be frail (odds ratio = 0.5, 95% confidence interval = 0.2-1.0, p = .04) and had higher total body lean mass (p = .001) than the other participants. Serum-induced SIRT1 expression did not correlate with age, diseases, medications, albumin, fasting glucose, or lipids. Overall, there was no association between frailty and serum-induced SIRT1 expression; however, post hoc analysis suggested that there might be a paradoxical association between low serum-induced SIRT1 expression and robustness. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Cumming, Robert G %A Naganathan, Vasi %A Blyth, Fiona M %A Handelsman, David J %A Le Couteur, David G %A Waite, Louise M %A Creasey, Helen M %A Seibel, Markus J %A Sambrook, Philip N %T Ethnicity and falls in older men: low rate of falls in Italian-born men in Australia. %B Age and Ageing %D 2011 %C United Kingdom %I Oxford University Press %V 40 %N 5 %P 595-601 %@ 0002-0729 %X past research suggests that fall rates in older persons may differ by ethnicity. The aim of this study was to compare the incidence of falls between older male Italian-born immigrants and their Australian-born counterparts. %Z FOR Codes: 111706 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Cogger, Victoria C %A Dobbs, Bruce %A Fraser, Robin %T Fenestrations and lipoproteins. %B Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology %D 2011 %C United States %I Elsevier Inc. %V 20 %N 3 %P 191-3; author reply 193-4 %@ 1879-1336 %X %Z FOR Codes: 60104 %0 Journal Article %~ PubMed %A Benseler, Volker %A Warren, Alessandra %A Vo, Michelle %A Holz, Lauren E %A Tay, Szun S %A Le Couteur, David G %A Breen, Eamon %A Allison, Anthony C %A van Rooijen, Nico %A McGuffog, Claire %A Schlitt, Hans J %A Bowen, David G %A McCaughan, Geoffrey W %A Bertolino, Patrick %T Hepatocyte entry leads to degradation of autoreactive CD8 T cells. %B Proceedings of the National Academy of Sciences of the United States of America %D 2011 %C United States %I National Academy of Sciences %V 108 %N 40 %P 16735-40 %@ 0027-8424 %X Although most self-reactive T cells are eliminated in the thymus, mechanisms to inactivate or control T cells specific for extrathymic antigens are required and exist in the periphery. By investigating the site in which autoreactive T cells are tolerized, we identify a unique mechanism of peripheral deletion in which na??ve autoreactive CD8 T cells are rapidly eliminated in the liver after intrahepatic activation. T cells actively invade hepatocytes, enter endosomal/lysosomal compartments, and are degraded. Blockade of this process leads to accumulation of autoreactive CD8 T cells in the liver and breach of tolerance, with the development of autoimmune hepatitis. Cell into cell invasion, or emperipolesis, is a long-observed phenomenon for which a physiological role has not been previously demonstrated. We propose that this "suicidal emperipolesis" is a unique mechanism of autoreactive T-cell deletion, a process critical for the maintenance of tolerance. %Z FOR Codes: 110704 110703 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Gnjidic, Danijela %A Blyth, Fiona M %A Le Couteur, David G %A Naganathan, Vasi %A Waite, Louise %A Seibel, Markus J %A Handelsman, David J %A Sambrook, Philip N %A Cumming, Robert G %T How fast does the Grim Reaper walk? Receiver operating characteristics curve analysis in healthy men aged 70 and over. %B BMJ %D 2011 %C United Kingdom %I BMJ Publishing Group %V 343 %N %P d7679 %@ 1468-5833 %X To determine the speed at which the Grim Reaper (or Death) walks. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Blyth, F M %A Cumming, R G %A Nicholas, M K %A Creasey, H %A Handelsman, D J %A Le Couteur, D G %A Naganathan, V %A Sambrook, P N %A Seibel, M J %A Waite, L M %T Intrusive pain and worry about health in older men: The CHAMP study. %B Pain %D 2011 %C Netherlands, United States %I Elsevier BV %V 152 %N 2 %P 447-52 %@ 0304-3959 %X The role of anxiety in pain is less well understood than the role of depression. Based on recent conceptual thinking about worry and pain, we explored the relationship between pain status and worry about health and anxiety in 1217 community-dwelling men aged 70 years or older who participated in the baseline phase of the Concord Health and Ageing in Men Project study, a large population-based epidemiological study of healthy ageing based in Sydney, Australia. We hypothesised that worry about health would be associated with having persistent pain, and that the association would be stronger in the presence of co-existing pain-related interference with activities (intrusive pain). Of men in the study, 12.5% had persistent and intrusive pain, 22.4% were worried about their health, and 6.3% had anxiety. We found a strong association between worry about health and pain that was both persistent and intrusive, and that remained after accounting for age, number of comorbidities, depression, self-rated health status, arthritis, and gait speed (adjusted odds ratio 2.9; 95% confidence interval 1.8-4.7), P<0.0001). The corresponding adjusted odds ratio for the association between anxiety and pain was 2.3 (95% confidence interval 1.0-4.8; P=0.0363). These findings suggest that at a population level, subthreshold anxiety and pain are strongly related, and worry about health occurs much more commonly than anxiety itself. To our knowledge, this is the first study to explore, specifically, the relationship between pain status and worry about health in older men. In older community-dwelling men, pain was robustly associated with worry about health, highlighting the potential importance of subthreshold anxiety-related psychological factors. %Z FOR Codes: 111706 170106 %0 Journal Article %~ PubMed %A Mitchell, Sarah J %A Huizer-Pajkos, Aniko %A Cogger, Victoria C %A McLachlan, Andrew J %A Le Couteur, David G %A Hilmer, Sarah N %T Poloxamer 407 increases the recovery of paracetamol in the isolated perfused rat liver. %B Journal of pharmaceutical sciences %D 2011 %C United States %I John Wiley & Sons, Inc. %V 100 %N 1 %P 334-40 %@ 1520-6017 %X The role of the fenestrated liver sinusoidal endothelial cells (LSECs) in the hepatic disposition of paracetamol was investigated in isolated perfused livers from rats treated with poloxamer 407 (P407), a surfactant that causes extensive defenestration of the LSECs. Bolus doses containing tracer amounts of (14)C-paracetamol and reference markers (Evans Blue, (3)H-sucrose) were injected into control rats and rats that had been administered P407 via intra-peritoneal injection 24 ???h prior to experimentation. Scanning electron microscopy confirmed a reduced number of fenestrations in rats treated with P407. The recovery of paracetamol was significantly increased in P407 rats compared to controls (0.72????????0.07 P407 vs. 0.67????????0.04 control, p??? or =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 (FFM(DXA)) 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 FFM(DXA) 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 FFM(DXA) 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 FFM(DXA) for overweight participants but underestimated FFM(DXA) 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 FFM(DXA) 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. %Z FOR Codes: 111502 110308 %0 Journal Article %A Le Couteur, David %A Ford, Gary A %A McLachlan, Andrew %T Evidence, Ethics and Medication Management in Older People %B Journal of Pharmacy Practice and Research %D 2010 %C Australia %I Society of Hospital Pharmacists of Australia %V 40 %N 2 %P 148-152 %@ 1445937X %X %Z FOR Codes: 111599 111702 220106 %0 Book Section %A Everitt, Arthur %A Heilbronn, Leonie K %A Le Couteur, David %T Food Intake, Life Style, Aging and Human Longevity %B Calorie Restriction, Ageing and Longevity %D 2010 %C Germany, United Stat %I Springer Science + Business Media B.V. %V %N %P 15-42 %@ 9789048185559 %E Rattan, Suresh I S %E de Cabo, Rafael %E Le Couteur, David %E Everitt, Arthur %X %Z FOR Codes: 111102 %0 Book Section %A Everitt, Arthur %A Brown-Borg, Holly M %A Le Couteur, David %A Bartke, Andrzej %T Food Restriction, Hormones, Genes and Aging %B Calorie Restriction, Ageing and Longevity %D 2010 %C Germany, United Stat %I Springer Science + Business Media B.V. %V %N %P 217-232 %@ 9789048185559 %E Rattan, Suresh I S %E de Cabo, Rafael %E Le Couteur, David %E Everitt, Arthur %X %Z FOR Codes: 110306 60412 111103 %0 Journal Article %~ PubMed %A Rochat, Stephane %A Cumming, Robert G %A Blyth, Fiona %A Creasey, Helen %A Handelsman, David %A Le Couteur, David G %A Naganathan, Vasi %A Sambrook, Philip N %A Seibel, Markus J %A Waite, Louise %T Frailty and use of health and community services by community-dwelling older men: the Concord Health and Ageing in Men Project. %B Age and Ageing %D 2010 %C United Kingdom %I Oxford University Press %V 39 %N 2 %P 228-233 %@ 0002-0729 %X BACKGROUND: frailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated. METHODS: the cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria. RESULTS: overall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status. CONCLUSION: frailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive interventions. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Bleicher, K %A Cumming, R G %A Naganathan, V %A Seibel, M J %A Sambrook, P N %A Blyth, F M %A Le Couteur, D G %A Handelsman, D J %A Creasey, H M %A Waite, L M %T Lifestyle factors, medications, and disease influence bone mineral density in older men: findings from the CHAMP study. %B Osteoporosis International %D 2010 %C United Kingdom %I Springer UK %V 22 %N 9 %P 2421-2437 %@ 1433-2965 %X Aging alone is not the only factor accounting for poor bone health in older men. There are modifiable factors and lifestyle choices that may influence bone health and result in higher bone density and lower fracture risk even in very old men. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Warren, Alessandra %A Cogger, Victoria C %A Arias, Irwin M %A McCuskey, Robert S %A Le Couteur, David G %T Liver sinusoidal endothelial fenestrations in caveolin-1 knockout mice. %B Microcirculation %D 2010 %C United Kingdom %I John Wiley & Sons Ltd. %V 17 %N 1 %P 32-38 %@ 1549-8719 %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. %Z FOR Codes: 60110 110106 110201 %0 Journal Article %~ PubMed %A Hairi, Noran N %A Cumming, Robert G %A Naganathan, Vasi %A Handelsman, David J %A Le Couteur, David G %A Creasey, Helen %A Waite, Louise M %A Seibel, Markus J %A Sambrook, Philip N %T Loss of Muscle Strength, Mass (Sarcopenia), and Quality (Specific Force) and Its Relationship with Functional Limitation and Physical Disability: The Concord Health and Ageing in Men Project. %B Journal of the American Geriatrics Society %D 2010 %C United States %I Wiley-Blackwell Publishing, Inc. %V 58 %N 11 %P 2055-2062 %@ 0002-8614 %X OBJECTIVES: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men. DESIGN: Cross-sectional study of older men participating in the Concord Health and Ageing in Men Project (CHAMP). SETTING: Elderly men living in a defined geographical region in Sydney, Australia. PARTICIPANTS: One thousand seven hundred five community-dwelling men aged 70 and older who participated in the baseline assessments of CHAMP. MEASUREMENTS: 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. RESULTS: 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. CONCLUSION: Muscle strength is the single best measure of age-related muscle change and is associated with physical disability in IADLs and functional limitation. %Z FOR Codes: 111702 %0 Journal Article %~ PubMed %A Pallardó, Federico V %A Lloret, Ana %A Lebel, Michel %A d'Ischia, Marco %A Cogger, Victoria C %A Le Couteur, David G %A Gadaleta, Maria Nicola %A Castello, Giuseppe %A Pagano, Giovanni %T Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. %B Biogerontology %D 2010 %C Netherlands %I Springer Netherlands %V 11 %N 4 %P 401-419 %@ 1389-5729 %X Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted. %Z FOR Codes: 60104 %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Denning, Gerene M %A Lau, Gee W %A Grimm, Michael C %A Hilmer, Sarah N %A Le Couteur, David G %T Pathogenesis of the hyperlipidemia of Gram-negative bacterial sepsis may involve pathomorphological changes in liver sinusoidal endothelial cells. %B International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases %D 2010 %C United Kingdom, Unit %I Elsevier Ltd %V 14 %N 10 %P e857-67 %@ 1878-3511 %X The Gram-negative bacterium Pseudomonas aeruginosa is one of the most common opportunistic pathogens, especially after liver transplantation. Pathophysiological alterations of liver sinusoidal endothelial cells (LSECs) have far-reaching repercussions on the liver and on metabolism. LSECs are perforated with fenestrations, pores that facilitate the transfer of lipoproteins and macromolecules between blood and hepatocytes. Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) and the P. aeruginosa toxin, pyocyanin, have marked effects on LSECs. Initial loss of LSEC porosity (defenestration) induced by P. aeruginosa pyocyanin and LPS may confer subsequent immune tolerance to circulating bacterial antigens and toxins. This review collates the known immune responses of the liver to Gram-negative bacterial toxins, with a focus on LSECs. Hyperlipidemia is an important response to Gram-negative bacterial sepsis. The mechanisms proposed for sepsis-associated hyperlipidemia include tissue lipoprotein lipase inhibition and upregulated hepatic triglyceride production. In this review, we propose defenestration of the LSECs by bacterial toxins as an additional mechanism for the hyperlipidemia of sepsis. Given the role of LSECs in hyperlipidemia and liver allograft rejection, LSEC changes induced by P. aeruginosa toxins including LPS and pyocyanin may have significant clinical implications. %Z FOR Codes: 60502 110307 60199 %0 Journal Article %~ PubMed %A Bleicher, Kerrin %A Naganathan, Vasi %A Cumming, Robert G %A Seibel, Markus J %A Sambrook, Philip N %A Blyth, Fiona M %A Le Couteur, David G %A Handelsman, David J %A Waite, Louise M %A Creasey, Helen M %T Prevalence and treatment of osteoporosis in older Australian men: findings from the CHAMP study. %B The Medical Journal of Australia %D 2010 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 193 %N 7 %P 387-391 %@ 0025-729X %X OBJECTIVE: To determine the proportion of older Australian men who meet the Pharmaceutical Benefits Scheme (PBS) criteria for osteoporosis treatment and are receiving effective treatment. DESIGN AND 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 focusing on the health of older men. Data were collected through questionnaires and clinical assessments. Bone mineral density (BMD) of the hip and spine was measured by dual x-ray absorptiometry (DXA). Vertebral deformities were identified from DXA lateral vertebral fracture assessment images. The study was conducted at Concord Hospital, Sydney, between January 2005??and May 2007. PARTICIPANTS: 1705??community-dwelling men aged 70??years or over from a defined geographical region around Concord Hospital. MAIN OUTCOME MEASURES: Prevalence of vertebral deformities; previous minimal trauma fractures; BMD T-scores ??? - 3; falls in the previous 12??months; use of bisphosphonates and calcium and vitamin D supplements. RESULTS: Of the 1705??men seen at baseline, 1626??completed all DXA scans and 401??(25%) met one or more of the PBS criteria for osteoporosis treatment. Ninety per cent of the men who met the PBS criteria were unaware they had osteoporosis. Of the men eligible for PBS-subsidised treatment, 39??(10%) reported use of a bisphosphonate, 56??(14%) had taken calcium supplements, and 28??(7%) had taken vitamin D supplements. Only three men had taken calcium, vitamin D and bisphosphonates in combination. CONCLUSIONS: Despite a high prevalence of osteoporosis in elderly Australian men, awareness, diagnosis and treatment of the condition remain very low. %Z FOR Codes: 110322 110306 %0 Journal Article %~ PubMed %A Le Couteur, David G %T Red yeast rice for dyslipidemia in statin-intolerant patients. %B Annals of Internal Medicine %D 2010 %C United States %I American College of Physicians %V 152 %N 2 %P 134-135 %@ 0003-4819 %X %Z FOR Codes: 111502 %0 Journal Article %~ PubMed %A Nabipour, I %A Cumming, R %A Handelsman, D J %A Litchfield, M %A Naganathan, V %A Waite, L %A Creasey, H %A Janu, M %A Le Couteur, D %A Sambrook, P N %A Seibel, M J %T Socioeconomic status and bone health in community-dwelling older men: the CHAMP Study. %B Osteoporosis International %D 2010 %C United Kingdom %I Springer UK %V 22 %N 5 %P 1343-1353 %@ 1433-2965 %X The association between socioeconomic status (SES) and bone health, specifically in men, is unclear. Based upon data from the large prospective Concord Health in Ageing Men Project (CHAMP) Study of community-dwelling men aged 70 years or over, we found that specific sub-characteristics of SES, namely, marital status, living circumstances, and acculturation, reflected bone health in older Australian men. %Z FOR Codes: 111702 111706 1117 %0 Book Section %A Le Couteur, David %A Sinclair, David A %A Cogger, Victoria %A McMahon, Aisling C %A Warren, Alessandra %A Everitt, Arthur %A Lebel, Michel %A de Cabo, Rafael %T The Aging Liver and the Effects of Long Term Caloric Restriction %B Calorie Restriction, Ageing and Longevity %D 2010 %C Germany, United Stat %I Springer Science + Business Media B.V. %V %N %P 191-216 %@ 9789048185559 %E Rattan, Suresh I S %E de Cabo, Rafael %E Le Couteur, David %E Everitt, Arthur %X %Z FOR Codes: 110307 111103 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Blyth, Fiona M %A Creasey, Helen M %A Handelsman, David J %A Naganathan, Vasi %A Sambrook, Philip N %A Seibel, Markus J %A Waite, Louise M %A Cumming, Robert G %T The Association of Alanine Transaminase With Aging, Frailty, and Mortality. %B The journals of gerontology. Series A, Biological sciences and medical sciences %D 2010 %C United States %I Oxford University Press %V 65 %N 7 %P 712-7 %@ 1758-535X %X The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53-2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45-5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging. %Z FOR Codes: 111799 110307 %0 Book Section %A Le Couteur, David %A Kendig, Hal %A Naganathan, Vasikaran %A McLachlan, Andrew %T The Ethics of Prescribing to Older People %B Medication Management in Older Adults %D 2010 %C United States %I Springer Science + Business Media B.V. %V %N %P 29-42 %@ 9781603274579 %E Koch, Susan %E Gloth, F. Michael %E Ray, Rhonda %X %Z FOR Codes: 220106 111503 %0 Journal Article %~ PubMed %A Sabaretnam, Tharani %A Kritharides, Leonard %A O'Reilly, Jennifer N %A Le Couteur, David G %T The effect of aging on the response of isolated hepatocytes to hydrogen peroxide and tert-butyl hydroperoxide. %B Toxicology in vitro : an international journal published in association with BIBRA %D 2010 %C United Kingdom, Fran %I Pergamon %V 24 %N 1 %P 123-8 %@ 1879-3177 %X Aging is associated with increased susceptibility to oxidative stress. To study this in the liver and to elucidate underlying mechanisms, hepatocytes from young (4-6 months) and old (24-26 months) rats were exposed to two oxidants, hydrogen peroxide and tert-butyl hydroperoxide. ATP content and mitochondrial activity were lower in old hepatocytes and decreased further with oxidative stress. Expression of Cu/Zn superoxide dismutase, Mn superoxide dismutase and catalase was not substantially influenced by oxidative stress in young and old hepatocytes, whereas glutathione peroxidase 1 expression was markedly increased only in young hepatocytes. Oxidative stress in young hepatocytes led to increased expression of apoE and movement of apoE to the early endosomes. In old hepatocytes, oxidative stress did not increase apoE expression and apoE was co-localized with early endosomes under control conditions. The results show that old age is associated with impaired hepatocyte responses of mitochondria, ATP, glutathione peroxidase 1 and apoE to oxidative stress. %Z FOR Codes: 601 %0 Journal Article %~ PubMed %A O'Reilly, Jennifer N %A Cogger, Victoria C %A Fraser, Robin %A Le Couteur, David G %T The effect of feeding and fasting on fenestrations in the liver sinusoidal endothelial cell. %B Pathology %D 2010 %C United Kingdom, Australia %I Informa Healthcare %V 42 %N 3 %P 255-258 %@ 0031-3025 %X AIMS: Fenestrations are pores in the liver sinusoidal endothelial cell that facilitate the transfer of substrates between blood and hepatocytes. The aim of this study was to determine the effect of nutritional state on the morphology of fenestrations. METHODS: Scanning electron microscopy was used to investigate fenestrations in livers from fasted and fed rats. RESULTS: Fasting for 48 hours in rats was associated with an increase in the diameter of fenestrations from 90.7 +/- 11.7 nm in the fed state to 99.0 +/- 12.11 nm (p < 0.005). There was a concomitant reduction in the frequency of fenestrations from 8.45 +/- 2.43 to 7.39 +/- 2.28 fenestrations per microm(2) (p =0.05). CONCLUSIONS: Fasting was associated with increased diameter of fenestrations. The results provide evidence that fenestrations are dynamic structures that respond in vivo to physiological stimuli such as nutritional status. %Z FOR Codes: 60112 111103 110307 %0 Journal Article %~ PubMed %A Sabaretnam, Tharani %A O'Reilly, Jennifer %A Kritharides, Leonard %A Le Couteur, David %T The effect of old age on apolipoprotein E and its receptors in rat liver. %B Age (Dordrecht, Netherlands) %D 2010 %C Netherlands, United %I Springer Netherlands %V 32 %N 1 %P 69-77 %@ 1574-4647 %X Apolipoprotein E (apoE) is associated with aging and some age-related diseases. The majority of apoE is produced by hepatocytes for the receptor-mediated uptake of lipoproteins. Here, the effects of age on the hepatic expression and distribution of apoE and its receptors were determined using immunofluorescence, Western blots, and quantitative PCR in rat liver tissue and isolated hepatocytes. The expression of apoE mRNA and protein was not influenced significantly by aging. Immunofluorescence studies in isolated hepatocytes showed that apoE was more likely to be co-localized with early endosomes, golgi, and microtubules in isolated old hepatocytes. The mRNA expression of the receptor involved in sequestration of apoE, heparan sulfate proteoglycan was reduced in old age, without any significant effect on the expression of either the low-density lipoprotein receptor or low density-lipoprotein receptor-related protein. Old age is associated with changes in hepatic apoE intracellular trafficking and heparan sulfate proteoglycan expression that might contribute to age-related disease. %Z FOR Codes: 1102 %0 Journal Article %~ PubMed %A Cogger, Victoria C %A McNerney, Gregory P %A Nyunt, Tun %A Deleve, Laurie D %A McCourt, Peter %A Smedsrød, Bård %A Couteur, David G Le %A Huser, Thomas R %T Three dimensional structured illumination microscopy of liver sinusoidal endothelial cell fenestrations. %B Journal of structural biology %D 2010 %C United States %I Academic Press %V 171 %N 3 %P 382-8 %@ 1095-8657 %X Fenestrations are pores in liver sinusoidal endothelial cells that filter substrates and debris between the blood and hepatocytes. Fenestrations have significant roles in aging and the regulation of lipoproteins. However their small size (<200 nm) has prohibited any functional analysis by light microscopy. We employed structured illumination light microscopy to observe fenestrations in isolated rat liver sinusoidal endothelial cells with great clarity and spatial resolution. With this method, the three-dimensional structure of fenestrations (diameter 123+/-24 nm) and sieve plates was elucidated and it was shown that fenestrations occur in areas of abrupt cytoplasmic thinning (165+/-54 nm vs. 292+/-103 nm in non-fenestrated regions, P<0.0001). Sieve plates were not preferentially co-localized with fluorescently labeled F-actin stress fibers and endothelial nitric oxide synthase but appeared to occur in primarily attenuated non-raft regions of the cell membrane. Labyrinthine structures were not seen and all fenestrations were short cylindrical pores. In conclusion, three-dimensional structured illumination microscopy has enabled the unlimited power of fluorescent immunostaining and co-localization to reveal new structural and functional information about fenestrations and sieve plates. %Z FOR Codes: 60112 %0 Journal Article %~ PubMed %A Kwong, Po Wan %A Cumming, Robert G %A Chan, Lewis %A Seibel, Markus J %A Naganathan, Vasi %A Creasey, Helen %A Le Couteur, David %A Waite, Louise M %A Sambrook, Philip N %A Handelsman, David %T Urinary incontinence and quality of life among older community-dwelling Australian men: the CHAMP study. %B Age and Ageing %D 2010 %C United Kingdom %I Oxford University Press %V 39 %N 3 %P 349-354 %@ 0002-0729 %X OBJECTIVE: to describe the prevalence and impact on quality of life of urinary incontinence in a population-based cohort of older community-dwelling Australian men. SUBJECTS: the population comprised 1,705 men aged >or=70 years participating in the Concord Health and Ageing in Men Project, a population-based study of urban older Australian men. METHODS: data were collected between January 2005 and June 2007, and the participation rate was 47%. Data on demographics, medical history and from the 12-item Short Form Health Survey (SF-12) and International Consultation on Incontinence Questionnaire were collected. Urinary incontinence was defined as urinary leakage at least two times a week over the past 4 weeks. RESULTS: the prevalence of urinary incontinence was 14.8%, increasing from 12.0% for men aged 70-74 years old to 16.3% for those aged >or=90 years, with urgency incontinence being the most frequent type of urinary incontinence. Daily urine leakage was reported by 3% of men. Men with incontinence had lower overall SF-12 scores with greater impact on the physical (PCS) than the mental (MCS) components of that scale. After adjusting for age, number of co-morbidities, enlarged prostate and prostate cancer, men with incontinence had worse PCS (43.6 vs 45.9) and MCS scores (52.2 vs 54.6) compared with continent men. CONCLUSION: urinary incontinence is common among older community-dwelling men and is associated with worse quality of life with greater impact on physical than mental factors. As the population ages, urinary incontinence prevalence will increase and increased resources will be needed to address this growing problem. %Z FOR Codes: 111702 110312 110308 %0 Journal Article %~ PubMed %A Massip, Laurent %A Garand, Chantal %A Paquet, Eric R %A Cogger, Victoria C %A O'Reilly, Jennifer N %A Tworek, Leslee %A Hatherell, Avril %A Taylor, Carla G %A Thorin, Eric %A Zahradka, Peter %A Le Couteur, David G %A Lebel, Michel %T Vitamin C restores healthy aging in a mouse model for Werner syndrome. %B FASEB journal : official publication of the Federation of American Societies for Experimental Biology %D 2010 %C United States %I Federation of American Societies for Experimental %V 24 %N 1 %P 158-72 %@ 1530-6860 %X 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-kappaB, as well as protein kinase Cdelta and Hif-1alpha 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 PPARalpha. 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. %Z FOR Codes: 1115 %0 Journal Article %~ PubMed %A Hilmer, Sarah N %A Seale, J Paul %A Le Couteur, David G %A Crampton, Roslyn %A Liddle, Christopher %T Do medical courses adequately prepare interns for safe and effective prescribing in New South Wales public hospitals? %B Internal medicine journal %D 2009 %C Australia %I Wiley-Blackwell Publishing Asia %V 39 %N 7 %P 428-34 %@ 1444-0903 %X To assess ability of interns immediately before starting clinical practice in New South Wales (NSW) teaching hospitals to prescribe medications safely and appropriately and to describe their impressions of the adequacy of their clinical pharmacology training in medical school. %Z FOR Codes: 111502 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Cumming, Robert G %A Le Couteur, David G %A Handelsman, David J %A Naganathan, Vasi %A Abernethy, Darrell R %A Hilmer, Sarah N %T Drug Burden Index and physical function in older Australian men. %B British Journal of Clinical Pharmacology %D 2009 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 68 %N 1 %P 97-105 %@ 0306-5251 %X 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. %Z FOR Codes: 111503 110308 %0 Journal Article %~ PubMed %A Smedsrød, Bård %A Le Couteur, David %A Ikejima, Kenichi %A Jaeschke, Hartmut %A Kawada, Norifumi %A Naito, Makoto %A Knolle, Percy %A Nagy, Laura %A Senoo, Haruki %A Vidal-Vanaclocha, Fernando %A Yamaguchi, Noriko %T Hepatic sinusoidal cells in health and disease: update from the 14th International Symposium. %B Liver International %D 2009 %C Denmark %I Wiley-Blackwell Munksgaard %V 29 %N 4 %P 490-501 %@ 1478-3231 %X This review aims to give an update of the field of the hepatic sinusoid, supported by references to presentations given at the 14th International Symposium on Cells of the Hepatic Sinusoid (ISCHS2008), which was held in Tromsø, Norway, August 31-September 4, 2008. The subtitle of the symposium, ''Integrating basic and clinical hepatology'', signified the inclusion of both basal and applied clinical results of importance in the field of liver sinusoidal physiology and pathophysiology. Of nearly 50 oral presentations, nine were invited tutorial lectures. The authors of the review have avoided writing a ''flat summary'' of the presentations given at ISCHS2008, and instead focused on important novel information. The tutorial presentations have served as a particularly important basis in the preparation of this update. In this review, we have also included references to recent literature that may not have been covered by the ISCHS2008 programme. The sections of this review reflect the scientific programme of the symposium (http://www.ub.uit.no/munin/bitstream/10037/1654/1/book.pdf): 1. Liver sinusoidal endothelial cells. 2. Kupffer cells. 3. Hepatic stellate cells. 4. Immunology. 5. Tumor/metastasis. Symposium abstracts are referred to by a number preceded by the letter A. %Z FOR Codes: 69999 %0 Journal Article %~ PubMed %A O'Reilly, Jennifer N %A Cogger, Victoria C %A Le Couteur, David G %T Old age is associated with ultrastructural changes in isolated rat liver sinusoidal endothelial cells. %B Journal of electron microscopy %D 2009 %C Japan %I Oxford University Press %V 59 %N 0 %P 65-9 %@ 1477-9986 %X Old age is associated with ultrastructural changes in the hepatic sinusoid called pseudocapillarization, which include defenestration and thickening of the sinusoidal endothelium. We investigated whether such changes also occur in isolated and cultured liver sinusoidal endothelial cells. Liver sinusoidal endothelial cells were isolated from young (6-10 months, n = 4) and old (24-26 months, n = 4) F344 rats and fenestrations evaluated using scanning electron microscopy. Fenestration diameter was reduced in old age from 194 +/- 1 nm to 185 +/- 1 nm (P < 0.001) and there was an age-related increase in the number fused fenestrations and large gaps. Age-related changes in the diameter of fenestrations in the liver sinusoidal endothelial cell are maintained following isolation and culture. This suggests that this age-related change may be intrinsic to the liver endothelial cell and/or irreversible. %Z FOR Codes: 110307 %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Denning, Gerene M %A Lau, Gee W %A Grimm, Michael C %A Hilmer, Sarah N %A Le Couteur, David G %T Pseudomonas aeruginosa and the hyperlipidaemia of sepsis. %B Pathology %D 2009 %C United Kingdom, Australia %I Informa Healthcare %V 41 %N 7 %P 615-621 %@ 0031-3025 %X Pathophysiological alterations of liver sinusoidal endothelial cells (LSECs) impact liver and metabolism. LSEC fenestrations are pores facilitating lipoproteins and macromolecule transfer between blood and hepatocytes. The Gram negative bacterium Pseudomonas aeruginosa is one of the most common opportunistic nosocomial pathogens, especially in post-liver transplant recipients. Gram negative bacterial endotoxin (lipopolysaccharide, LPS) and the P. aeruginosa toxin, pyocyanin, have marked effects on LSECs, including loss of porosity (defenestration). Currently proposed mechanisms for sepsis-hyperlipidaemia, an important response to Gram negative bacterial sepsis, include tissue lipoprotein-lipase inhibition and increased hepatic triglyceride production. Owing to the well-substantiated role of LSECs in liver-allograft rejection and hyperlipidaemia, we propose defenestration of the LSEC is an additional cellular mechanism for sepsis-hyperlipidaemia, including pseudomonal sepsis post-liver transplantation. %Z FOR Codes: 110704 110316 110801 %0 Journal Article %~ PubMed %A Sabaretnam, Tharani %A Harris, Matthew J %A Kockx, Maaike %A Witting, Paul K %A Le Couteur, David G %A Kritharides, Leonard %T The Effects Of Hydrogen Peroxide And Apolipoprotein E Isoforms On Apolipoprotein E Trafficking In Hepg2 Cells. %B Clinical and experimental pharmacology & physiology %D 2009 %C Australia %I Wiley-Blackwell Publishing Asia %V 36 %N 12 %P e96-102 %@ 1440-1681 %X 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 micromol/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 micromol/L) than that needed to induce changes in intracellular apoE mRNA expression, apoE protein levels and markers of oxidative stress (250-1000 micromol/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. %Z FOR Codes: 601 %0 Journal Article %A Le Couteur, David %A Everitt, Arthur %A Lebel, M %T The aging liver %B Geriatrics & Ageing %D 2009 %C Canada %I Geriatrics and Aging %V 12 %N %P 319-322 %@ 1488-8408 %X %Z FOR Codes: 110312 111702 %0 Journal Article %~ PubMed %A McLachlan, A J %A Hilmer, S N %A Le Couteur, D G %T Variability in response to medicines in older people: phenotypic and genotypic factors. %B Clinical Pharmacology and Therapeutics %D 2009 %C United States %I Nature Publishing Group %V 85 %N 4 %P 431-433 %@ 1532-6535 %X %Z FOR Codes: 111503 %0 Journal Article %~ PubMed %A Cumming, Robert G %A Handelsman, David %A Seibel, Markus J %A Creasey, Helen %A Sambrook, Philip %A Waite, Louise %A Naganathan, Vasi %A Couteur, David Le %A Litchfield, Melisa %T Cohort profile: The Concord Health and Ageing in Men Project (CHAMP). %B International journal of epidemiology %D 2008 %C GREAT CLARENDON ST, OXFORD, ENGLAND, OX2 6D %I Oxford Univ Press %V 38 %N 0 %P 374-8 %@ 0300-5771 %X %Z FOR Codes: 111706 111404 %0 Journal Article %~ PubMed %A Warren, Alessandra %A Chaberek, Slawomir %A Ostrowski, Kazimierz %A Cogger, Victoria C %A Hilmer, Sarah N %A McCuskey, Robert S %A Fraser, Robin %A Le Couteur, David G %T Effects of old age on vascular complexity and dispersion of the hepatic sinusoidal network. %B Microcirculation %D 2008 %C United Kingdom %I Informa Healthcare %V 15 %N 3 %P 191-202 %@ 1073-9688 %X OBJECTIVES: In old age, there are marked changes in both the structure of the liver sinusoidal endothelial cell and liver perfusion. The objective of this study was to determine whether there are also aging changes in the microvascular architecture and vascular dispersion of the liver that might influence liver function. METHODS: Vascular corrosion casts and light micrographs of young (4 months) and old (24 months) rat livers were compared. Fractal and Fourier analyses and micro-computed tomography were used. Vascular dispersion was determined from the dispersion number for sucrose and 100-nm microspheres in impulse response experiments. RESULTS: Age did not affect sinusoidal dimensions, sinusoidal density, or dispersion number. There were changes in the geometry and complexity of the sinusoidal network as determined by fractal dimension and degree of anisotropy. CONCLUSIONS: There are small, age-related changes in the architecture of the liver sinusoidal network, which may influence hepatic function and reflect broader aging changes in the microcirculation. However, sinusoidal dimensions and hepatic vascular dispersion are not markedly influenced by old age. %Z FOR Codes: 110308 110307 %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Cogger, Victoria C %A Kwun, Sun Young %A O'Reilly, Jennifer N %A Le Couteur, David G %A Hilmer, Sarah N %T Liver sinusoidal endothelial cells and acute non-oxidative hepatic injury induced by Pseudomonas aeruginosa pyocyanin. %B International Journal of Experimental Pathology %D 2008 %C United Kingdom %I Wiley-Blackwell %V 89 %N 6 %P 410-418 %@ 1365-2613 %X 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 muM 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. %Z FOR Codes: 110801 110704 110307 %0 Journal Article %~ PubMed %A Iyer, Shoba %A Naganathan, Vasi %A McLachlan, Andrew %A Le Couteur, David %T Medication Withdrawal Trials in People Aged 65 Years and Older : A Systematic Review. %B Drugs & Aging %D 2008 %C New Zealand %I Adis International Ltd. %V 25 %N 12 %P 1021-1031 %@ 1170-229X %X The objective of this review was to assess the benefits and risks of medication withdrawal in older people as documented in published trials of medication withdrawal. This was done by systematic review of the evidence from clinical trials of withdrawal of specific classes of medications in patient populations with a mean age of >/=65 years. We identified all relevant articles published between 1966 and 2007 initially through electronic searches on PubMed and manual searches of review articles. Numerous search terms related to the withdrawal of medication in older people were utilized. Clinical trials identified were reviewed according to predetermined inclusion/exclusion criteria. Only trials that focused on the withdrawal of specific classes of medication were included. Thirty-one published studies (n = 8972 subjects) met the inclusion criteria, including four randomized and placebo-controlled studies (n = 448 subjects) of diuretic withdrawal, nine open-label and prospective observational studies (n = 7188 subjects) of withdrawal of antihypertensives (including diuretics), 16 studies (n = 1184 patients) of withdrawal of sedative, antidepressant, cholinesterase inhibitor and antipsychotic medications, and 1 study each of withdrawal of nitrates and digoxin. These studies were of heterogeneous study design, patient selection criteria and follow-up. Withdrawal of diuretics was maintained in 51-100% of subjects and was unsuccessful primarily when heart failure was present. Adverse effects from medication withdrawal were infrequently encountered. After withdrawal of antihypertensive therapy, many subjects (20-85%) remained normotensive or did not require reinstatement of therapy for between 6 months and 5 years, and there was no increase in mortality. Withdrawal of psychotropic medications was associated with a reduction in falls and improved cognition. In conclusion, there is some clinical trial evidence for the short-term effectiveness and/or lack of significant harm when medication withdrawal is undertaken for antihypertensive, benzodiazepine and psychotropic agents in older people. %Z FOR Codes: 111502 111702 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Warren, Alessandra %A Cogger, Victoria C %A Smedsrød, Bård %A Sørensen, Karen K %A De Cabo, Rafael %A Fraser, Robin %A McCuskey, Robert S %T Old age and the hepatic sinusoid. %B Anatomical Record %D 2008 %C United States %I John Wiley & Sons %V 291 %N 6 %P 672-683 %@ 1932-8494 %X Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial cell, sporadic deposition of collagen and basal lamina in the extracellular space of Disse, and increased numbers of fat engorged, nonactivated stellate cells. In addition, there is endothelial up-regulation of von Willebrand factor and ICAM-1 with reduced expression of caveolin-1. These changes have been termed age-related pseudocapillarization. The effects of old age on Kupffer cells are inconsistent, but impaired responsiveness is likely. There are functional implications of these aging changes in the hepatic sinusoid. There is reduced sinusoidal perfusion, which will impair the hepatic clearance of highly extracted substrates. Blood clearance of a variety of waste macromolecules takes place in liver sinusoidal endothelial cells (LSECs). Previous studies indicated either that aging had no effect, or reduced the endocytic capacity of LSECs. However, a recent study in mice showed reduced endocytosis in pericentral regions of the liver lobules. Reduced endocytosis may increase systemic exposure to potential harmful waste macromolecules such as advanced glycation end products Loss of fenestrations leads to impaired transfer of lipoproteins from blood to hepatocytes. This provides a mechanism for impaired chylomicron remnant clearance and postprandial hyperlipidemia associated with old age. Given the extensive range of substrates metabolized by the liver, age-related changes in the hepatic sinusoid and microcirculation have important systemic implications for aging and age-related diseases. %Z FOR Codes: 110308 110307 %0 Journal Article %~ PubMed %A Blyth, Fiona M %A Rochat, Stephane %A Cumming, Robert G %A Creasey, Helen %A Handelsman, David J %A Couteur, David G Le %A Naganathan, Vasi %A Sambrook, Philip N %A Seibel, Markus J %A Waite, Louise M %T Pain, frailty and comorbidity on older men: The CHAMP study. %B Pain %D 2008 %C Netherlands %I Elsevier BV %V 140 %N 0 %P 224-30 %@ 0304-3959 %X Intrusive pain is likely to have a serious impact on older people with limited ability to respond to additional stressors. Frailty is conceptualised as a functional and biological pattern of decline accumulating across multiple physiological systems, resulting in a decreased capacity to respond to additional stressors. We explored the relationship between intrusive pain, frailty and comorbid burden in 1705 community-dwelling men aged 70 or more who participated in the baseline phase of the CHAMP study, a large epidemiological study of healthy ageing based in Sydney, Australia. 9.4% of men in the study were frail (according to the commonly-used Cardiovascular Health Study frailty criteria).Using a combination of self-report and clinical measures, we found an association between frailty and intrusive pain that remained after accounting for demographic characteristics, number of comorbidities, self-reported depressed mood and arthritis (adjusted odds ratio 1.7 (95% confidence interval (CI) 1.1-2.7), p=0.0149). The finding that adjusting for depressed mood, but not a history of arthritis, attenuated the relationship between frailty and intrusive pain points to a key role for central mechanisms. Additionally, men with the highest overall health burden (frail plus high comorbid burden) were most likely to report intrusive pain (adjusted odds ratio 3.0 (95% CI 1.6-5.5), p=0.0004). These findings provide support for the concept that intrusive pain is an important challenge for older men with limited capacity to respond to additional physical stressors. To our knowledge, this is the first study to explore specifically the relationship between pain and frailty. %Z FOR Codes: 111706 111404 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Kendig, Hal %T Pharmaco-epistemology for the prescribing geriatrician. %B Australasian Journal on Ageing %D 2008 %C Australia %I Wiley-Blackwell Publishing Asia %V 27 %N 1 %P 3-7 %@ 1741-6612 %X 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. %Z FOR Codes: 111502 110308 %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Shimmon, Ronald %A Dawson, Michael %A Hilmer, Sarah %A Le Couteur, David %T Reactions of Pseudomonas aeruginosa pyocyanin with reduced glutathione. %B Acta biochimica Polonica %D 2008 %C Poland %I Polskie Towarzystwo Biochemiczne %V 55 %N 3 %P 571-80 %@ 0001-527X %X Pseudomonas aeruginosa is the most common cause of chronic and recurrent lung infections in patients with cystic fibrosis (CF) whose sputa contain copious quantities of P. aeruginosa toxin, pyocyanin. Pyocyanin triggers tissue damage mainly by its redox cycling and induction of reactive oxygen species (ROS). The reactions between reduced glutathione (GSH) and pyocyanin were observed using absorption spectra from spectrophotometry and the reaction products analysed by nuclear magnetic resonance imaging. Pyocyanin reacted with GSH non-enzymatically at 37 degrees C resulting in the production of red-brown products, spectophotometrically visible as a 480 nm maximum absorption peak after 24 h of incubation. The reaction was concentration-dependent on reduced glutathione but not on pyocyanin. Minimizing the accessibility of oxygen to the reaction decreased its rate. The anti-oxidant enzyme catalase circumvented the reaction. Proton-NMR analysis demonstrated the persistence of the original aromatic ring and the methyl-group of pyocyanin in the red-brown products. Anti-oxidant agents having thiol groups produced similar spectophotometrically visible peaks. The presence of a previously unidentified non-enzymatic GSH-dependent metabolic pathway for pyocyanin has thus been identified. The reaction between pyocyanin and GSH is concentration-, time-, and O(2)-dependent. The formation of H(2)O(2) as an intermediate and the thiol group in GSH seem to be important in this reaction. %Z FOR Codes: 1101 1108 1103 %0 Journal Article %~ PubMed %A Pearson, Kevin J %A Baur, Joseph A %A Lewis, Kaitlyn N %A Peshkin, Leonid %A Price, Nathan L %A Labinskyy, Nazar %A Swindell, William R %A Kamara, Davida %A Minor, Robin K %A Perez, Evelyn %A Jamieson, Hamish A %A Zhang, Yongqing %A Dunn, Stephen R %A Sharma, Kumar %A Pleshko, Nancy %A Woollett, Laura A %A Csiszar, Anna %A Ikeno, Yuji %A Le Couteur, David %A Elliott, Peter J %A Becker, Kevin G %A Navas, Placido %A Ingram, Donald K %A Wolf, Norman S %A Ungvari, Zoltan %A Sinclair, David A %A de Cabo, Rafael %T Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. %B Cell metabolism %D 2008 %C United States %I Cell Press %V 8 %N 2 %P 157-168 %@ 1932-7420 %X A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Martinez, Inigo %A Nedredal, Geir I %A Oie, Cristina I %A Warren, Alessandra %A Johansen, Oddmund %A Le Couteur, David G %A Smedsrød, Baard %T The influence of oxygen tension on the structure and function of isolated liver sinusoidal endothelial cells. %B Comparative Hepatology %D 2008 %C United Kingdom %I BioMed Central Ltd %V 7 %N 4 %P 0 %@ 1476-5926 %X ABSTRACT: BACKGROUND: Liver sinusoidal endothelial cells (LSECs) are specialized scavenger cells, with crucial roles in maintaining hepatic and systemic homeostasis. Under normal physiological conditions, the oxygen tension encountered in the hepatic sinusoids is in general considerably lower than the oxygen tension in the air; therefore, cultivation of freshly isolated LSECs under more physiologic conditions with regard to oxygen would expect to improve cell survival, structure and function. In this study LSECs were isolated from rats and cultured under either 5% (normoxic) or 20% (hyperoxic) oxygen tensions, and several morpho-functional features were compared. RESULTS: Cultivation of LSECs under normoxia, as opposed to hyperoxia improved the survival of LSECs and scavenger receptor-mediated endocytic activity, reduced the production of the pro-inflammatory mediator, interleukin-6 and increased the production of the anti-inflammatory cytokine, interleukin-10. On the other hand, fenestration, a characteristic feature of LSECs disappeared gradually at the same rate regardless of the oxygen tension. Expression of the cell-adhesion molecule, ICAM-1 at the cell surface was slightly more elevated in cells maintained at hyperoxia. Under normoxia, endogenous generation of hydrogen peroxide was drastically reduced whereas the production of nitric oxide was unaltered. Culture decline in high oxygen-treated cultures was abrogated by administration of catalase, indicating that the toxic effects observed in high oxygen environments is largely caused by endogenous production of hydrogen peroxide. CONCLUSION: Viability, structure and many of the essential functional characteristics of isolated LSECs are clearly better preserved when the cultures are maintained under more physiologic oxygen levels. Endogenous production of hydrogen peroxide is to a large extent responsible for the toxic effects observed in high oxygen environments. %Z FOR Codes: 110307 110299 %0 Journal Article %~ PubMed %A Cogger, Victoria C %A Arias, Irwin M %A Warren, Alessandra %A McMahon, Aisling C %A Kiss, Debra L %A Avery, Vicky M %A Le Couteur, David G %T The response of fenestrations, actin and caveolin-1 to vascular endothelial growth factor in SK Hep1 cells (a liver endothelial cell line). %B American journal of physiology. Gastrointestinal and liver physiology %D 2008 %C United States %I American Physiological Society %V 295 %N %P G137-G145 %@ 0193-1857 %X To study the regulation of fenestrations by vascular endothelial growth factor in liver sinusoidal endothelial cells, SK Hep1 cells were transfected with green fluorescence protein (GFP)-actin and GFP-caveolin-1. SK Hep1 cells had pores; some of which appeared to be fenestrations (diameter 55 +/- 28 nm, porosity 2.0 +/- 1.4%), rudimentary sieve plates, bristle-coated micropinocytotic vesicles and expressed caveolin-1, von Willebrand factor, vascular endothelial growth factor receptor-2, endothelial nitric oxide synthase and clathrin, but not CD31. There was avid uptake of formaldehyde serum albumin, consistent with endocytosis. Vascular endothelial growth factor caused an increase in porosity to 4.8 +/- 2.6% (P < 0.01) and pore diameter to 104 +/- 59 nm (P < 0.001). GFP-actin was expressed throughout the cells, whereas GFP-caveolin-1 had a punctate appearance; both responded to vascular endothelial growth factor by contraction toward the nucleus over hours in parallel with the formation of fenestrations. SK Hep1 cells resemble liver sinusoidal endothelial cells, and the vascular endothelial growth factor-induced formation of fenestration-like pores is preceded by contraction of actin cytoskeleton and attached caveolin-1 toward the nucleus. %Z FOR Codes: 110307 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Cogger, Victoria C %A McCuskey, Robert S %A de Cabo, Rafael %A Smedsrod, Bard %A Sorensen, Karen K %A Warren, Alessandra %A Fraser, Robin %T Age-related changes in the liver sinusoidal endothelium are a mechanism for dyslipidemia. %B Annals of the New York Academy of Sciences %D 2007 %C United States %I New York Acad Sciences %V 1114 %N %P 79-87 %@ 0077-8923 %X 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. %Z FOR Codes: 111603 %0 Journal Article %~ PubMed %A Jamieson, H %A Cogger, V %A Twigg, S %A McLennan, S %A Warren, A %A Cheluvappa, R %A Hilmer, S %A Fraser, R %A de Cabo, R %A Le Couteur, D %T Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes. %B Diabetologia %D 2007 %C Germany %I Springer-Verlag %V 50 %N 9 %P 1969-76 %@ 0012-186X %X Diabetes mellitus is associated with extensive vascular pathology, yet little is known about its long-term effects on liver sinusoidal endothelial cells (LSECs). Potential diabetic changes in LSECs are important because of the role played by fenestrations in the LSECs in hepatic disposition of lipoproteins. %Z FOR Codes: 110307 %0 Journal Article %~ PubMed %A Hilmer, Sarah N %A Cogger, Victoria C %A Le Couteur, David G %T Basal activity of Kupffer cells increases with old age. %B The journals of gerontology. Series A, Biological sciences and medical sciences %D 2007 %C United States %I Gerontological Society of America %V 62 %N 9 %P 973-978 %@ 1079-5006 %X Age-related changes in Kupffer cell numbers and function may have important implications for systemic immune responses and hepatic function. We compared numbers of Kupffer cells in the hepatic sinusoids and phagocytic function of Kupffer cells in isolated perfused livers of young, middle-aged, and old rats. On light microscopy, the number of Kupffer cells per 29,500 mum(2) field increased with increasing age (young 2.0 +/- 0.2, n = 8; middle aged 3.3 +/- 0.3, n = 7; old 5.5 +/- 0.6, n = 7). After a single pass through the liver, the ratio of the fractional recovery of 500 nm polystyrene microspheres to that of sucrose decreased significantly with increasing age: young rats, 89 +/- 35% (n = 7); middle-aged rats, 58 +/- 18% (n = 9); and old rats, 49 +/- 24% (n = 10), suggesting increased Kupffer cell phagocytic activity. In old age, increased Kupffer cell numbers and activity were observed in the basal state. %Z FOR Codes: %0 Journal Article %~ PubMed %A Jamieson, Hamish A %A Hilmer, Sarah N %A Cogger, Victoria C %A Warren, Alessandra %A Cheluvappa, Rajkumar %A Abernethy, Darrell R %A Everitt, Arthur V %A Fraser, Robin %A de Cabo, Rafael %A Le Couteur, David G %T Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid. %B Experimental Gerontology %D 2007 %C United States %I Elsevier Inc. %V 42 %N 4 %P 374-378 %@ 0531-5565 %X Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrand''s factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression. %Z FOR Codes: 110307 111702 %0 Journal Article %~ PubMed %A Hilmer, Sarah N %A McLachlan, Andrew J %A Le Couteur, David G %T Clinical pharmacology in the geriatric patient. %B Fundamental & clinical pharmacology %D 2007 %C England %I Blackwell Science %V 21 %N 3 %P 217-30 %@ 0767-3981 %X Geriatric patients are a subset of older people with multiple comorbidities that usually have significant functional implications. Geriatric patients have impaired homeostasis and wide inter-individual variability. Comprehensive geriatric assessment captures the complexity of the problems that characterize frail older patients and can be used to guide management, including prescribing. Prescribing for geriatric patients requires an understanding of the efficacy of the medication in frail older people, assessment of the risk of adverse drug events, discussion of the harm:benefit ratio with the patient, a decision about the dose regime and careful monitoring of the patient''s response. This requires evaluation of evidence from clinical trials, application of the evidence to frail older people through an understanding of changes in pharmacokinetics and pharmacodynamics, and attention to medication management issues. Given that most disease occurs in older people, and that older people are the major recipients of drug therapy in the Western world, increased research and a better evidence base is essential to guide clinicians who manage geriatric patients. %Z FOR Codes: 110502 %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Hilmer, Sarah N %A Kwun, Sun Young %A Cogger, Victoria C %A Le Couteur, David G %T Effects of old age on hepatocyte oxygenation. %B Annals of the New York Academy of Sciences %D 2007 %C United States %I Wiley- Blackwell Publishing Inc. %V 1114 %N 0 %P 88-92 %@ 0077-8923 %X 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. %Z FOR Codes: %0 Journal Article %~ PubMed %A Everitt, Arthur V %A Le Couteur, David G %T Life Extension by Calorie Restriction in Humans. %B Annals of the New York Academy of Sciences %D 2007 %C United States. %I Wiley-Blackwell Publishing Ltd. %V 1114 %N 0 %P 428-33 %@ 0077-8923 %X 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. %Z FOR Codes: %0 Journal Article %~ PubMed %A Latimer Hill, Elizabeth %A Cumming, Robert G %A Lewis, Ray %A Carrington, Susan %A Le Couteur, David G %T Sleep disturbances and falls in older people. %B The journals of gerontology. Series A, Biological sciences and medical sciences %D 2007 %C United States %I Gerontological Society of America %V 62 %N 1 %P 62-66 %@ 1079-5006 %X BACKGROUND: Sleep disturbances are common in older people and may contribute to risk of falling. METHODS: Cross-sectional studies were performed in hostels and with an Internet-based survey. Questionnaires on falls and sleep disturbances were undertaken with clinical measures of cognition, mobility, blood pressure, and vision in the participants in hostels. RESULTS: There were 150 participants in hostels (mean age 81 +/- 8 years) and 150 respondents to the Internet survey (mean age 70 +/- 5 years). Sleep disturbances were reported by most participants in both the hostel and Internet studies. In hostel participants, falls were associated with poor sleep quality (odds ratio = 4.5, 95% confidence interval, 1.9-12.2; p =.002) and number of nocturnal awakenings (2.5 +/- 1.5 vs 2.0 +/- 1.4, p =.04). Other risk factors for falls in these persons included Geriatric Depression Scale score, pain, Timed Get Up and Go Test score, and the use of diuretics. In the Internet respondents, risk factors for falls included poor health rating and the use of spectacles, bifocals, and walking aids; fewer falls were reported by those participants without any sleep disturbances. CONCLUSIONS: Sleep disturbances are common in older people and are associated with their risk of falling. Internet-based surveys may be a useful adjunct method for research in older people. %Z FOR Codes: %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Jamieson, Hamish A %A Hilmer, Sarah N %A Muller, Michael %A Le Couteur, David G %T The effect of Pseudomonas aeruginosa virulence factor, pyocyanin, on the liver sinusoidal endothelial cell. %B Journal of gastroenterology and hepatology %D 2007 %C 54 University St,P O %I Blackwell Science Asia %V 22 %N 8 %P 1350-1351 %@ 1440-1746 %X %Z FOR Codes: %0 Journal Article %~ PubMed %A Cheluvappa, Rajkumar %A Hilmer, Sarah N %A Kwun, Sun Young %A Jamieson, Hamish A %A O'reilly, Jennifer N %A Muller, Michael %A Cogger, Victoria C %A Le Couteur, David G %T The effect of old age on liver oxygenation and the hepatic expression of VEGF and VEGFR2. %B Experimental gerontology %D 2007 %C United States %I Elsevier Inc. %V 42 %N 10 %P 1012-9 %@ 0531-5565 %X In old age, the liver contains less ATP and hypoxia-responsive genes are upregulated. Age-related changes in hepatic perfusion and the liver sinusoidal endothelial cell (LSEC) could contribute to this altered hepatic oxygen-dependent metabolism by causing intrahepatocytic hypoxia. Furthermore, age-related changes in the LSEC (''pseudocapillarization'') have been partially induced by ATP depletion. To investigate whether there is intracellular hypoxia in the old rat liver, pimonidazole immunohistochemistry in intact livers and ATP levels in isolated LSECs were studied from young and old rats. There were no age-related changes. To determine whether defenestration of the LSEC could impair oxygen diffusion, pimonidazole immunohistochemistry was performed in rats treated with poloxamer 407. Despite defenestration, there was no change in pimonidazole staining. Immunohistochemistry was then performed to determine whether there are age-related changes in VEGF and VEGFR2. VEGF staining was not associated with age. However, there was an increase in perisinusoidal VEGFR2 expression with increasing age. In conclusion, liver hypoxia does not occur in old age and LSEC pseudocapillarization does not constitute an oxygen-diffusion barrier. There are no age-related changes in VEGF expression but an increase in perisinusoidal VEGFR2 expression, which has implications for the effects of aging on the hepatic sinusoid. %Z FOR Codes: %0 Journal Article %A Fisher, A %A Davis, M W %A Rubenach, S %A Le Couteur, David %A McLean, A J %T The site-specific epidemiology of hip fracture in the Australian Capital Territory with projections for the first half of the 21st century: Implications for clinical management and health services planning %B Australasian Journal of Ageing %D 2007 %C Australia %I Wiley-Blackwell %V 26 %N %P 45-51 %@ 1440-6381 %X %Z FOR Codes: 110308