ORCID Profile
0000-0002-4227-5817
Current Organisations
Concord RG Hospital
,
University of Sydney
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Publisher: Springer Science and Business Media LLC
Date: 07-10-2009
Publisher: Public Library of Science (PLoS)
Date: 24-09-2012
Publisher: Elsevier BV
Date: 05-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2008
DOI: 10.1016/J.PAIN.2008.08.011
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.2165/00003088-200544020-00004
Abstract: The fenestrated sinusoidal endothelium ('liver sieve') and space of Disse in the healthy liver do not impede the transfer of most substrates, including drugs and oxygen, from the sinusoidal lumen to the hepatocyte. Plasma components transfer freely in both directions through the endothelial fenestrations and into the space of Disse. The endothelium is attenuated, there is no basement membrane and there is minimum collagen in the space of Disse, thus minimising any barriers to substrate diffusion. Both cirrhosis and aging are associated with marked structural changes in the sinusoidal endothelium and space of Disse that are likely to influence bulk plasma transfer into the space of Disse, and diffusion through the endothelium and space of Disse. These changes, termed capillarisation and pseudocapillarisation in cirrhosis and aging, respectively, impede the transfer of various substrates. Capillarisation is associated with exclusion of albumin, protein-bound drugs and macromolecules from the space of Disse, and the progressive transformation of flow-limited to barrier-limited distribution of some substrates. There is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging.
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.EXGER.2007.06.001
Abstract: 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.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.CMET.2016.10.021
Abstract: Diet influences health and patterns of disease in populations. How different diets do this and why outcomes of diets vary between in iduals are complex and involve interaction with the gut microbiome. A major challenge for predicting health outcomes of the host-microbiome dynamic is reconciling the effects of different aspects of diet (food composition or intake rate) on the system. Here we show that microbial community assembly is fundamentally shaped by a dichotomy in bacterial strategies to access nitrogen in the gut environment. Consequently, the pattern of dietary protein intake constrains the host-microbiome dynamic in ways that are common to a very broad range of diet manipulation strategies. These insights offer a mechanism for the impact of high protein intake on metabolic health and form the basis for a general theory of the impact of different diet strategies on host-microbiome outcomes.
Publisher: Wiley
Date: 10-03-2009
DOI: 10.1111/J.1478-3231.2009.01979.X
Abstract: 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 (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.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Oxford University Press (OUP)
Date: 12-03-2021
Abstract: Although characteristic changes in amino acid concentrations occur in obesity and sarcopenia, amino acids concentrations have not been reported in sarcopenic obesity. We studied n = 831 men aged 75 years and older from the 5-year follow-up of the Concord Health and Ageing in Men Project. Sarcopenia was defined using the Foundation of the National Institutes of Health criteria and obesity was defined as & % fat mass. There were 31 men (3.7%) who had sarcopenic obesity. Branched chain amino acids were elevated in the obese (but not sarcopenic) group (n = 348) but reduced in both the sarcopenic (but not obese) (n = 44) and the sarcopenic obese groups. Apart from this, most of the amino acid concentrations were between those for the obese and the sarcopenic groups. Yet despite low concentrations of branched chain amino acids, the sarcopenic obese group had indications of insulin resistance and diabetes mellitus (fasting glucose and insulin concentrations, homeostatic model assessment, and percentage of participants taking diabetes medications) that were similar to the obese group. In summary, sarcopenic obese participants did not have a unique amino acid signature. In obesity, elevated branched chain amino acids are not a prerequisite for insulin resistance and diabetes if obesity is associated with sarcopenia.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2000
Abstract: Parkinson's disease (PD) has been associated with exposure to pesticides and oxidative injury. The involvement of paraoxonase in both pesticide metabolism and lipid peroxidation suggests that it may play a role in the pathogenesis of PD. We examined the frequency of polymorphic alleles of the PON1 and PON2 genes in a s le of caucasian subjects with PD. The frequency distribution of these genotypes did not differ significantly between patients and controls, including those who had reported exposure to pesticides.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.IJCARD.2015.05.045
Abstract: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. Community-dwelling men, aged ≥ 70 years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR = 0.40 (95% CI: 0.21-0.95)] and institutionalization risk (HR=0.31 95% CI: 0.09-0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.JAUT.2009.08.005
Abstract: Hepatocytes, the predominant cell type in the liver, are the main cell infected by the hepatitis C virus (HCV) and represent important targets for immune therapy. Although early studies suggested that this parenchymal cell expresses low levels of class I MHC molecules, hepatocytes are emerging as important players in intrahepatic immune responses. Not only do they express high levels of molecules important in antigen presentation, but their expression of these molecules in vivo is also polarized towards the lumen of the sinusoids, thus maximising the efficiency of T cell activation. Electron micrographs indicate that interactions between T cells and hepatocytes occur in vivo via fenestrations in the sinusoidal endothelial layer. In this article, we will review the data showing that hepatocytes function as antigen presenting cells in vivo, and explore the fate of T cells activated by this cell type. We propose that primary activation of naïve CD8+ T cells by hepatocytes is a critical event occurring during the very early stages of a HCV infection, that contributes to progression to viral persistence via the removal of virus-specific T cells from the T cell repertoire.
Publisher: SAGE Publications
Date: 28-09-2010
DOI: 10.1345/APH.1P310
Abstract: The drug burden index (DBI) is an evidence-based tool that utilizes pharmacologic principles to calculate an in idual's total exposure to anticholinergic and sedative medications. Higher DBI has been associated with functional impairment in observational studies of older people. To assess the impact of providing information about DBI to general practitioners (GPs) on prescribing for older people. This was a cluster randomized controlled trial with 3 months of follow-up. Participants were volunteers aged ≥70 years, living in self-care retirement villages in Sydney, Australia. The study intervention involved a letter and phone call to GPs, using DBI to prompt them to consider cessation or dose reduction of anticholinergic and sedative medications. The primary study outcome was to assess the impact of information about DBI on prescribing practices of the GPs. A total of 115 participants were enrolled, 57 in the intervention group (from 6 sites) and 58 in the control group (from 6 sites). At baseline, 19 of 57 participants in the intervention group and 31 of 58 participants in the control group had a DBI (p 0.05). At follow-up, a DBI change was observed in 16 participants. DBI decreased in 12 participants, 6 (32%) in the intervention group, and 6 (19%) in the control group. GPs identified the following barriers to reducing anticholinergic and sedative drugs: uncomfortable altering prescriptions initiated by specialists unable to influence patients' attitudes unaware of patients' medications and strong clinical indication. The intervention targeting GPs' prescribing practices was less effective than anticipated in reducing anticholinergic and sedative drug exposure, and barriers were identified. Future studies should explore multidisciplinary interventions, engaging patients, specialists, GPs, and pharmacists.
Publisher: Wiley
Date: 04-2008
Publisher: Wiley
Date: 26-07-2016
DOI: 10.1002/JBMR.2904
Abstract: This study aimed to examine progressive temporal relationships between changes in major reproductive hormones across three waves of a cohort study of older men and (1) changes in bone mineral density (BMD) and (2) incident fractures (any, hip or non-vertebral) over an average of 6 years of follow-up. The CHAMP cohort of men aged 70 years and older were assessed at baseline (2005 to 2007, n = 1705), 2-year follow-up (n = 1367), and 5-year follow-up (n = 958). Serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) (by liquid chromatography-tandem mass spectrometry [LC-MS/MS]), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (by immunoassay) were measured at all time-points, whereas free testosterone (cFT) was calculated using a well-validated formula. Hip BMD was measured by dual-energy X-ray absorptiometry (DXA) at all three time-points, and fracture data were verified radiographically. Statistical modeling was done using general estimating equations (GEEs). For total hip BMD, univariable analyses revealed inverse associations with temporal changes in serum SHBG, FSH, and LH and positive associations for serum E1 and cFT across the three time-points. In models adjusted for multiple covariables, serum SHBG (β = -0.029), FSH (β = -0.065), LH (β = -0.049), E1 (β = 0.019), and cFT (β = 0.033) remained significantly associated with hip BMD. However for femoral neck BMD, only FSH (β = -0.048) and LH (β = -0.036) remained associated in multivariable-adjusted models. Temporal change in serum SHBG, but not T, E2, or other hormonal variables, was significantly associated with any, nonvertebral or hip fracture incidence in univariable analyses. In multivariable-adjusted models, temporal increase in serum SHBG over time remained associated with any fracture (β = 0.060) and hip fracture (β = 0.041) incidence, but not nonvertebral fracture incidence. These data indicate that a progressive increase in circulating SHBG over time predicts bone loss and fracture risk in older men. Further studies are warranted to further characterize changes in circulating SHBG as a mechanism and/or biomarker of bone health during male ageing. © 2016 American Society for Bone and Mineral Research.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2014
Publisher: Wiley
Date: 2016
DOI: 10.1111/JGS.13877
Abstract: To investigate the effects of number of medications and Drug Burden Index (DBI) on transitions between frailty stages and death in community-dwelling older men. Cohort study. Sydney, Australia. Community-dwelling men aged 70 and older (N=1,705). Self-reported questionnaires and clinic visits were conducted at baseline and 2 and 5 years. Frailty was assessed at all three waves according to the modified Fried frailty phenotype. The total number of regular prescription medications and DBI (a measure of exposure to sedative and anticholinergic medications) were calculated over the three waves. Data on mortality over 9 years were obtained. Multistate modeling was used to characterize the transitions across three frailty states (robust, prefrail, frail) and death. Each additional medication was associated with a 22% greater risk of transitioning from the robust state to death (adjusted 95% confidence interval (CI)=1.06-1.41). Every unit increase in DBI was associated with a 73% greater risk of transitioning from the robust state to the prefrail state (adjusted 95% CI=1.30-2.31) and a 2.75 times greater risk of transitioning from the robust state to death (adjusted 95% CI=1.60-4.75). There was no evidence of an adjusted association between total number of medications or DBI and the other transitions. Although the possibility of confounding by indication cannot be excluded, additional medications were associated with greater risk of mortality in robust community-dwelling older men. Greater DBI was also associated with greater risk of death and transitioning from the robust state to the prefrail state.
Publisher: Oxford University Press (OUP)
Date: 14-05-2008
DOI: 10.1093/IJE/DYN071
Publisher: Elsevier BV
Date: 04-1999
Publisher: Elsevier BV
Date: 06-2015
Publisher: American Physiological Society
Date: 15-12-2012
DOI: 10.1152/AJPREGU.00686.2011
Abstract: To maintain homeostasis, the animal body is equipped with a powerful system to remove circulating waste. 1 This review presents evidence that the scavenger endothelial cell (SEC) is responsible for the clearance of blood-borne waste macromolecules in vertebrates. SECs express pattern-recognition endocytosis receptors (mannose and scavenger receptors), and in mammals, the endocytic Fc gamma-receptor IIb2. This cell type has an endocytic machinery capable of super-efficient uptake and degradation of physiological and foreign waste material, including all major classes of biological macromolecules. In terrestrial vertebrates, most SECs line the wall of the liver sinusoid. In phylogenetically older vertebrates, SECs reside instead in heart, kidney, or gills. SECs, thus, by virtue of their efficient nonphagocytic elimination of physiological and microbial substances, play a critical role in the innate immunity of vertebrates. In major invertebrate phyla, including insects, the same function is carried out by nephrocytes. The concept of a dual-cell principle of waste clearance is introduced to emphasize that professional phagocytes (macrophages in vertebrates hemocytes in invertebrates) eliminate larger particles ( .5 μm) by phagocytosis, whereas soluble macromolecules and smaller particles are eliminated efficiently and preferentially by clathrin-mediated endocytosis in nonphagocytic SECs in vertebrates or nephrocytes in invertebrates. Including these cells as important players in immunology and physiology provides an additional basis for understanding host defense and tissue homeostasis.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.EXGER.2005.06.012
Abstract: Age-related changes in the hepatic sinusoid of the rat, human and baboons called pseudocapillarization have been discovered and are important because they are considered to be implicated in the pathogenesis of some age-related diseases. In this study, we investigated whether similar changes occur in the livers of old mice. Livers of young (3-4 months) and old (20-24 months) mice were perfusion-fixed and studied using electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old mice (154+/-4 versus 244+/-8 nm, P<0.001). There was a reduction in fenestrations within the endothelium (porosity decreased from 4.1+/-0.3 to 2.2+/-0.2%, P<0.001). There was perisinusoidal staining with Sirius red in old mice, however, expression of laminin and von Willebrands factor was similar in young and old mice. Novel perisinusoidal fat-engorged stellate cells were found extensively in the old mice. This study confirmed that pseudocapillarization is a widespread aging change in the liver, now documented in several species including the mouse. Mice are an appropriate animal model for studying aging and the hepatic sinusoid.
Publisher: Oxford University Press (OUP)
Date: 10-12-2013
Abstract: Posttranslational modifications of circulating proteins such as immunoglobulins may prove to be important biomarkers of aging.
Publisher: Oxford University Press (OUP)
Date: 27-10-2015
Abstract: Comorbidity and multimorbidity are common in older people. Here we used a novel analytic approach called Association Rules together with network analysis to evaluate multimorbidity (two or more disorders) and comorbidity in old age. A population-based cross-sectional study was undertaken where 17 morbidities were analyzed using network analysis, cluster analysis, and Association Rules methodology. A comorbidity interestingness score was developed to quantify the richness and variability of comorbidities associated with an index condition. The participants were community-dwelling men aged 70 years or older from the Concord Health and Ageing in Men Project, Sydney, Australia, with complete data (n = 1,464). The vast majority (75%) of participants had multimorbidity. Several morbidity clusters were apparent (vascular cluster, metabolic cluster, neurodegenerative cluster, mental health and other cluster, and a musculoskeletal and other cluster). Association Rules revealed unexpected comorbidities with high lift and confidence linked to index diseases. Anxiety and heart failure had the highest comorbidity interestingness scores while obesity, hearing impairment, and arthritis had the lowest (zero) scores. We also performed Association Rules analysis for the geriatric syndromes of frailty and falls to determine their association with multimorbidity. Frailty had a very complex and rich set of frequent and interesting comorbidities, while there were no frequent and interesting sets associated with falls. Old age is characterized by a complex pattern of multimorbidity and comorbidity. Single disease definitions do not account for the prevalence and complexity of multimorbidity in older people and a new lexicon may be needed to underpin research and health care interventions for older people.
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.BONE.2011.08.026
Abstract: Weight loss is associated with bone loss however, it is unclear whether loss of fat or loss of lean body mass plays the key role in this relationship. The aim of this longitudinal analysis was to clarify the relationship between hip BMD, hip BMC and whole body BMC with changes in fat and lean tissue mass in older men. The Concord Health and Aging in Men Project (CHAMP) is a population-based study in Sydney, Australia, involving 1705 men aged 70-97 years. Bone mineral density (BMD) of the total hip, and bone mineral content (BMC) of the hip and whole body (WB), lean mass and fat mass were measured with Dual X-ray Absorptiometry (DXA). Multivariate linear regression models were used to assess relationships. Over 2.2 years of follow-up, 368(33%) men lost at least 2% of their body weight, which included a mean loss of 0.8 kg/year of lean body mass and 0.9 kg/year of fat body mass. Fat loss was strongly associated with BMD loss in men who lost weight. As a group, weight losers lost 1.0% of hip BMD annually compared to 0.2% in men who gained weight, with each kilo of fat loss associated with 0.6%/year hip BMD loss (p<0.0001). Lean mass was not associated with hip BMD loss in weight losers, however, lean mass change was associated with BMD change in men who gained weight (0.3% hip BMD increase per kilo increase of lean mass p<0.01). Maintaining body weight is important for bone health in elderly men. Body fat plays an important role in this relationship, which may reflect the additional metabolic function of adipose tissue.
Publisher: Oxford University Press (OUP)
Date: 11-10-2010
Abstract: 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.
Publisher: Oxford University Press (OUP)
Date: 29-03-2021
Abstract: Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment and whether they are paralleled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, and citalopram n = 6–8/group) for 4–6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, and total distance), middle zone distance (increased anxiety), and nesting score (reduced activities of daily living) in mice of both ages and sexes (p & .001). Old animals had a greater decline in nesting score (p & .05) and midzone distance (p & .001) than young animals. Grip strength declined more in males than females (p & .05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of the pathogenesis of functional impairment from polypharmacy may improve management strategies in both sexes.
Publisher: Springer Science and Business Media LLC
Date: 06-2012
DOI: 10.1038/NRD3738
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.JHEP.2006.08.022
Abstract: The liver sinusoidal endothelial cell (LSEC) is increasingly recognized as having an important role in hepatic immunity. However, the responses of LSECs and the hepatic sinusoid in immune-mediated hepatitis are poorly described. We studied a transgenic mouse model of acute immune-mediated hepatitis: Met-Kb mice injected with T cells from Des-TCR mice. Hepatitis was characterized by lymphocyte infiltrates causing severe but transient liver damage. There were marked changes in the ultrastructure of the LSEC five days after injection of the T cells that coincided with the peak of the hepatitis. The porosity of fenestrations in the LSEC decreased and the endothelium became thickened. LSECs appeared to be markedly activated. These changes were associated with narrowing of the space of Disse, loss of hepatocellular microvilli and deposition of basal lamina. Lymphocytes were seen passing through fenestrations. Loss of fenestration in the LSEC prevented hepatitis induced by a second injection of lymphocytes on day 5. Structural changes in the LSEC occur during the peak of a mouse model of immune-mediated hepatitis. These changes were associated with attenuation of subsequent liver damage, suggesting that they may influence immunological responses mediated by LSECs or the passage of lymphocytes through LSEC fenestrations.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.CGER.2012.01.006
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
Abstract: Evidence about the association between treatment with high-risk medicines and frailty in older in iduals 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.
Publisher: The Endocrine Society
Date: 12-2014
DOI: 10.1210/JC.2014-2464
Abstract: The causal relationship between metabolic syndrome and reproductive hormones is unclear. This study sought to examine the cross-sectional, longitudinal, and predictive associations between reproductive hormones and SHBG and metabolic syndrome in older men. Men ages 70 years and older from the Concord Health and Ageing in Men Project study (n = 1705) were assessed at baseline and 2-year follow-up. At baseline, T, dihydrotestosterone (DHT), estradiol, and estrone were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Metabolic syndrome was defined using the P National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. In cross-sectional data, significant associations between each of T, SHBG, DHT, and calculated free testosterone (cFT) with the metabolic syndrome remained significant after multivariate adjustment. In longitudinal analyses, however, only lower SHBG was significantly associated with incident metabolic syndrome over the 2-year follow-up (P for linear trend = .04). Although low serum T, DHT, SHBG, and cFT were associated cross-sectionally with metabolic syndrome among community-dwelling older men, over a 2-year follow-up period only SHBG remained significant after multivariate adjustment. This suggests that lowered circulating androgens (T and DHT) may be biomarkers rather than causally related to incident metabolic syndrome.
Publisher: Physiological Society of Japan
Date: 2004
Abstract: Wash-in experiments, which may be useful for the study of the disposition of substrates in the liver, have not been well described. To investigate physiological models for wash-in curves, we performed experiments on the perfused livers of male Wistar rats anesthetized with pentobarbital. Test perfusate contained (14)C-sucrose as the extracellular marker and (3)H-glucose. Liver perfusions were performed with background glucose concentrations of 5.7, 10.7, 51.2, or 108.5 mM. Outflow time-activity curves were analyzed with the use of four models. The V(max) and K(m) for the influx of glucose were 1.1 +/- 0.03 micromol/s/g and 41 +/- 3 mM with the Crone-Renkin early extraction model 1.4 +/- 0.04 micromol/s/g and 36 +/- 3 mM with dispersion model analysis 1.8 +/- 0.1 micromol/s/g and 25 +/- 4 mM with the Goresky distributed model to fit differentiated wash-in curves and 2.7 +/- 0.6 micromol/s/g and 28 +/- 21 mM with compartmental analysis. There was reasonable agreement between the four models, and they yielded results similar to those reported for glucose uptake in other preparations.
Publisher: Oxford University Press (OUP)
Date: 07-04-2010
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S42255-021-00393-9
Abstract: Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.
Publisher: Wiley
Date: 26-08-2005
DOI: 10.1111/J.1365-2036.2005.02623.X
Abstract: The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.
Publisher: Oxford University Press (OUP)
Date: 17-07-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CELL.2015.02.033
Abstract: The notion of dietary balance is fundamental to health yet is not captured by focusing on the intake of energy or single nutrients. Advances in nutritional geometry have begun to unravel and integrate the interactive effects of multiple nutrients on health, lifespan, aging, and reproduction.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
DOI: 10.1016/J.PAIN.2014.06.009
Abstract: The evidence on the patterns of nonsteroidal anti-inflammatory drug (NSAID) use according to pain prevalence and clinical guidelines in older people is sparse. This cross-sectional study examined the patterns of NSAID use according to pain prevalence and concordance with clinical guideline recommendations for safe NSAID use in older people, in relation to duration of use, patterns of use, concomitant use of proton pump inhibitors (PPIs), and prevalence of specific drug interactions. Community-dwelling men (n=1696) age ≥ 70 years living in Sydney were studied. 8.2% (n=139) of participants reported regular NSAID use compared with 2.9% (n=50) reporting as-needed use. The mean treatment duration for regular NSAID use was 4.9 years, suggesting long-term rather than short-term use as recommended by the guidelines. Although guidelines recommend use of PPIs together with an NSAID, only 25.2% of regular NSAID users reported PPI use. Regular NSAID users were significantly more likely to report use of opioid analgesics (P<.0001) compared with nonregular users. In relation to pain prevalence, regular NSAID users were significantly more likely to report chronic pain (P<.0001), recent pain (P=.0001), and chronic intrusive pain (P<.0001) compared with nonregular users. The findings of this study indicate that NSAID prescribing practices do not align with clinical guidelines for safe use in older people. This difference between the guideline recommendations and what is happening in the real world should be explored further.
Publisher: Wiley
Date: 27-02-2014
DOI: 10.1111/JGS.12693
Abstract: To explore associations between serum 25-hydroxyvitamin D (25(OH)D) levels and a wide range of health conditions, physical performance measures, disability, and mortality in a large epidemiological study to identify an optimum range for 25(OH)D concentrations. Cross-sectional study, with additional prospective data on falls and mortality. Concord Health and Ageing in Men Project, Sydney, Australia. Community-dwelling men aged 70 and older (N = 1,659). Serum 25(OH)D levels, general health status, self-reported diseases, physical performance measures, disability (activities of daily living and instrumental activities of daily living) and falls. Fair, poor, and very poor health self-reported diabetes mellitus hyperglycemia depression muscle weakness poor balance and all-cause mortality were all associated with serum 25(OH)D levels less than 50 nmol/L, even after adjustment for confounding. The findings also suggest that, in older men, for a wide range of health conditions, physical performance measures, disability, falls, and mortality, the optimum range of 25(OH)D is between 50.0 and 74.9 nmol/L, with no additional benefit for 25(OH)D levels of 75.0 nmol/L or greater. Programs aimed at achieving an optimum range of serum 25(OH)D at levels between 50.0 and 74.9 nmol/L may have overall health benefits and such levels are adequate for older men.
Publisher: Wiley
Date: 03-2015
DOI: 10.1111/IMJ.12693
Abstract: Inappropriate polypharmacy and its associated harm pose a significant threat to older patients. The prescribing decisions of physicians greatly influence what other practitioners prescribe. Minimising medication-related harm requires physicians to adopt a systematic approach to the deliberate and judicious deprescribing of potentially inappropriate medicines in at-risk in iduals.
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00023210-200317110-00004
Abstract: A hip fracture epidemic is occurring in developed countries in association with population aging. The increasing number of people with a hip fracture has major implications for clinicians and health service managers. More importantly, a hip fracture is a devastating event in the life of an older person, as it often leads to loss of independence and death. Identification of risk factors for hip fracture is an essential first step towards prevention. The use of psychotropic medications is an established risk factor for hip fracture. The purpose of this article is to systematically review epidemiological studies of the relationship between use of benzodiazepines and risk of hip fracture and, then, to see how the findings of these studies fit with what is known about the pharmacology of benzodiazepines. Eleven primary epidemiological studies were identified. The results of these studies were not consistent however, the inconsistency appeared to be almost entirely explained by research design. The studies that did not show an association between increased hip fracture risk and benzodiazepine use were nearly all hospital-based case-control studies, a type of study that often lacks validity because of the difficulty of finding an appropriate control group. After excluding the hospital-based case-control studies, all but one of the remaining seven studies found that use of benzodiazepines was associated with an increased risk of hip fracture that varied between 50% and 110%. The only higher quality study that did not find an association between benzodiazepine use and hip fracture was also the only study conducted entirely in nursing homes. There was no evidence that the risk of hip fracture differed between short- and long-acting benzodiazepines. People using higher doses of benzodiazepines and those who had recently started using benzodiazepines were at the highest risk of hip fracture. In very old people, there was some preliminary evidence that benzodiazepines that undergo oxidation in the liver may be associated with a higher risk of hip fracture than other benzodiazepines. The epidemiological evidence strongly suggests that the use of benzodiazepines by older people increases their risk of hip fracture by at least 50%. The benefits of benzodiazepines for older people are unclear. Given the high morbidity and mortality of hip fracture, it can be concluded that older people should rarely be prescribed benzodiazepines and that many older people already taking these drugs should have them withdrawn under appropriate supervision.
Publisher: Oxford University Press (OUP)
Date: 30-03-2022
Abstract: Nutritional intake could influence the development of frailty. The aim was to evaluate the associations between dietary iron intakes and changes in dietary iron intakes with frailty. Cross-sectional analyses involved 785 men with Fried frailty phenotype (FP) and 758 men with Rockwood frailty index (FI) data aged 75 years and older at nutrition assessment from the Concord Health and Ageing in Men Project prospective cohort study. Of these, 563 men who were FP robust or prefrail, and 432 men who were FI nonfrail were included in the longitudinal analyses for more than 3 years. Dietary intake was assessed at both timepoints using a validated diet history questionnaire. The dietary calculation was used to derive heme iron and nonheme iron intakes from total iron intakes. The associations were evaluated through binary logistic regression. Incidence of FP frailty was 15.3% (n = 86). In longitudinal analyses, maintaining total iron intakes (medium tertile −2.61–0.81 mg/d), increases in total iron and nonheme iron intakes (high tertiles ≥0.82 mg/d and ≥0.80 mg/d), and changes in nonheme iron intake (1 mg increment) were associated with reduced risks of incident FP frailty (OR: 0.47 [95% confindence interval (CI): 0.24, 0.93, p = .031], OR 0.48 [95% CI: 0.23, 0.99, p = .048], OR 0.41 [95% CI: 0.20, 0.88, p = .022], and OR 0.89 [95% CI: 0.82, 0.98, p = .017]). Maintaining or increases in total dietary iron and increases or changes in dietary nonheme iron intakes more than 3 years were associated with reduced incidence of FP frailty in older men.
Publisher: Oxford University Press (OUP)
Date: 20-08-2019
Abstract: Increased blood levels of branched chain amino acids (BCAAs) have been associated with cardiometabolic risk factors. Here, we studied 918 community-dwelling older men to determine the relationship between BCAAs and other amino acids with cardiometabolic risk factors, major cardiovascular endpoints (MACE), and mortality. BCAAs had robust associations with many adverse metabolic risk factors (increased glucose, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), triglycerides decreased high-density lipoprotein cholesterol). However, paradoxically, participants with lower levels of BCAAs had greater mortality and MACE possibly because increasing age and frailty, both of which were associated with lower BCAA levels, are powerful risk factors for these outcomes in older people. Overall, amino acids that were lowest in frail subjects (BCAAs, α-aminobutyric acid [AABA], histidine, lysine, methionine, threonine, tyrosine) were inversely associated with mortality and MACE. In conclusion, BCAAs are biomarkers for important outcomes in older people including cardiometabolic risk factors, frailty, and mortality. In old age, frailty becomes a dominant risk factor for MACE and mortality.
Publisher: Oxford University Press (OUP)
Date: 22-07-2010
Publisher: Wiley
Date: 12-1999
Publisher: Proceedings of the National Academy of Sciences
Date: 20-08-2013
Abstract: CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A 2A /A 2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A 2A −/− mice were strongly protected against tumor metastasis, indicating that host A 2A receptors enhanced tumor metastasis. A 2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A 2A blockade was due to enhanced NK cell function. Interestingly, A 2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73 + tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A 2A or A 2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A 2A /A 2B receptor antagonists have already entered clinical trials in other therapeutic settings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2003
Publisher: Wiley
Date: 10-2007
Abstract: 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.
Publisher: IEEE
Date: 12-2010
Publisher: Wiley
Date: 10-2007
Abstract: 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.
Publisher: Oxford University Press (OUP)
Date: 22-07-2005
DOI: 10.1093/QJMED/HCI102
Abstract: Activated charcoal (AC) is commonly used for the routine management of oral drug overdose. To determine whether the routine use of activated charcoal has an effect on patient outcomes. Randomized controlled unblinded trial. We recruited all adult patients presenting with an oral overdose at The Canberra Hospital, excluding only transfers, late presenters, those who had ingested drugs not adsorbed by activated charcoal or where administration was contraindicated, and very serious ingestions (at the discretion of the admitting physician). Patients were randomized to either activated charcoal or no decontamination. The trial recruited 327 patients over 16 months. Of 411 presentations, four refused consent, 27 were protocol violations and 53 were excluded from the trial. Only seven were excluded due to the severity of their ingestion. The most common substances ingested were benzodiazepines, paracetamol and selective serotonin reuptake inhibitor antidepressants. More than 80% of patients presented within 4 h following ingestion. There were no differences between AC and no decontamination in terms of length of stay (AC 6.75 h, IQR 4-14 vs. controls 5.5 h, IQR 3-12 p=0.11) or secondary outcomes including vomiting, mortality and intensive care admission. Routine administration of charcoal following oral overdose did not significantly influence length of stay or other patient outcomes following oral drug overdose. There were few adverse events. This does not exclude a role in patients who present shortly after ingestion of highly lethal drugs.
Publisher: Wiley
Date: 05-11-2008
Publisher: Wiley
Date: 10-2007
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 30-12-2016
Publisher: Oxford University Press (OUP)
Date: 21-10-2015
Abstract: There is a strong association between aging, diet, and immunity. The effects of macronutrients and energy intake on splanchnic and hepatic lymphocytes were studied in 15 month old mice. The mice were ad-libitum fed 1 of 25 diets varying in the ratios and amounts of protein, carbohydrate, and fat over their lifetime. Lymphocytes in liver, spleen, Peyers patches, mesenteric lymph nodes, and inguinal lymph nodes were evaluated using flow cytometry. Low protein intake reversed aging changes in splenic CD4 and CD8 T cells, CD4:CD8 T cell ratio, memory/effector CD4 T cells and naïve CD4 T cells. A similar influence of total caloric intake in these ad-libitum fed mice was not apparent. Protein intake also influenced hepatic NK cells and B cells, while protein to carbohydrate ratio influenced hepatic NKT cells. Hepatosteatosis was associated with increased energy and fat intake and changes in hepatic Tregs, effector/memory T, and NK cells. Hepatic NK cells were also associated with body fat, glucose tolerance, and leptin levels while hepatic Tregs were associated with hydrogen peroxide production by hepatic mitochondria. Dietary macronutrients, particularly protein, influence splanchnic lymphocytes in old age, with downstream associations with mitochondrial function, liver pathology, and obesity-related phenotype.
Publisher: Oxford University Press (OUP)
Date: 04-05-2015
Publisher: Wiley
Date: 09-2002
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2003
Publisher: Springer Science and Business Media LLC
Date: 02-2015
Publisher: Oxford University Press (OUP)
Date: 17-03-2022
Abstract: Aging and multimorbidity are associated with inflammation. Polypharmacy is common in older people with multimorbidity. Given the potential for interactions between polypharmacy and inflammation, the relationship between inflammation and polypharmacy were studied in older adults with multimorbidity and in healthy aging mice. A cross-sectional analysis of data from the 5-year wave of the Concord Health and Ageing in Men Project, a population-based study of community-dwelling men aged ≥70 years. Serum concentrations of 27 cytokines were measured using a multiplex immunoassay. Associations between polypharmacy (≥5 medications) and cytokines were evaluated using multivariable linear regression adjusting for age, frailty, comorbidities, and in idual drug classes. Interaction between polypharmacy and Drug Burden Index (DBI―drugs with anticholinergic and sedative effects) was analyzed. Effects of polypharmacy and DBI on serum levels of 23 cytokines were determined in aging male mice treated with chronic polypharmacy or control. Compared to the nonpolypharmacy group (n = 495), CHAMP participants with polypharmacy (n = 409) had significantly higher concentrations of IL-8, IL-6, CCL3, Eotaxin, IL-1ra, IL-1β, IP-10, and lower concentrations of anti-inflammatory cytokine IL-4. In fully-adjusted multivariable models, polypharmacy was positively associated with concentrations of IL-8 and CCL3. There were no significant differences in inflammatory profiles between control and polypharmacy-treated mice. The relationship was not influenced by DBI in men or in mice. Inflammatory markers associated with polypharmacy in older adults were not seen in healthy aged mice administered polypharmacy, and may be related to underlying diseases. The polypharmacy mouse model provides opportunities for mechanistic investigations in translational research.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.CMET.2016.09.001
Abstract: Fibroblast growth factor 21 (FGF21) is the first known endocrine signal activated by protein restriction. Although FGF21 is robustly elevated in low-protein environments, increased FGF21 is also seen in various other contexts such as fasting, overfeeding, ketogenic diets, and high-carbohydrate diets, leaving its nutritional context and physiological role unresolved and controversial. Here, we use the Geometric Framework, a nutritional modeling platform, to help reconcile these apparently conflicting findings in mice confined to one of 25 diets that varied in protein, carbohydrate, and fat content. We show that FGF21 was elevated under low protein intakes and maximally when low protein was coupled with high carbohydrate intakes. Our results explain how elevation of FGF21 occurs both under starvation and hyperphagia, and show that the metabolic outcomes associated with elevated FGF21 depend on the nutritional context, differing according to whether the animal is in a state of under- or overfeeding.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.SMIM.2015.11.003
Abstract: The frontiers of cancer immunotherapy are extending in terms of both the range of cancer types that can potentially be targeted and the types of therapeutics that are in clinical development. The use of adoptive cellular therapy (ACT) and its derivative, chimeric antigen receptor (CAR) T cells, is currently limited to hematological malignancies and immunogenic cancers such as melanoma and renal cell carcinoma. Although ACT utilizing ex vivo expanded tumor-infiltrating lymphocytes (TIL) or engineered CAR/TCR T cells have undergone clinical trials for other solid cancers, their efficacy to date has been limited. This may be due, in part, to the immunosuppressive nature of the tumor microenvironment. The development of novel combination approaches which target the immunosuppressive network engineered by tumors has raised the possibility of using ACT for a broader range of cancers. This review summarizes the potential of such strategies and outlines the clinical relevance of these observations.
Publisher: Elsevier BV
Date: 07-2002
DOI: 10.1016/S0304-3940(02)00398-1
Abstract: Iron homeostasis is altered in Parkinson's disease (PD). The HFE protein is an important regulator of cellular iron homeostasis and variations within this gene can result in iron overload and the disorder known as hereditary haemochromatosis. We studied the Cys282Tyr single nucleotide polymorphism as a genetic risk factor for PD in two distinct and separately collected cohorts of Australian PD patients and controls. In the combined cohort comprising 438 PD patients and 485 control subjects, we revealed an odds ratio for possession of the 282Tyr allele of 0.61 (95% confidence interval, CI=0.42-0.90, P=0.011) from univariate chi-squared and 0.59 (95% CI=0.39-0.90, P=0.014) after logistic regression analyses (correcting for potential confounding factors). These results suggest that possession of the 282Tyr allele may offer some protection against the development of PD.
Publisher: Future Medicine Ltd
Date: 08-2012
DOI: 10.2217/AHE.12.35
Publisher: Wiley
Date: 2006
Publisher: Wiley
Date: 12-01-2016
DOI: 10.1002/NAU.22951
Abstract: To describe the natural history of non-neurogenic overactive bladder (OAB) and urgency incontinence in community-dwelling older men. A representative s le of 1,705 community-dwelling men aged 70 and older in a defined geographic area of Sydney, Australia, had their urinary symptoms assessed using the International Prostate Symptom Scores (IPSS) and the International Consultation of Incontinence Questionnaire (ICIQ) at baseline, 2-year follow-up, and 5-year follow-up. Four hundred and eighty-eight men without neurological diseases or prostate cancer during follow-up, or history of urological treatment at baseline were included in the analysis. Urgency incontinence was defined as leakage of urine occurring more than weekly in the above-defined population. OAB was defined as either urgency or urgency incontinence according to 2002 International Continence Society consensus. Of the men with OAB at baseline, 29% received treatment for OAB or benign prostatic enlargement over 5 years. Of the remaining men, 33% had sustained remission at 2-year and 5-year follow-ups without treatment. Of the men with OAB at 2-year follow-up, remission rate at 5-year follow-up was 53% in men without OAB at baseline and 27% in men with OAB at baseline (P = 0.23). No statistically significant difference was found in baseline characteristics between men with sustained remission and men with persistent symptoms. One in three older men with non-neurogenic OAB had sustained remission of symptoms without medical or surgical interventions. No significant predictor of sustained remission was identified. Neurourol. Urodynam. 36:443-448, 2017. © 2016 Wiley Periodicals, Inc.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.PHRS.2016.12.018
Abstract: The aim of this study was to apply Association Rule and Frequent-Set analysis, and novel means of data visualisation to ascertain patterns of medication use and medication combinations contributing to medication group clusters according to geriatric syndrome status in older adults. Participants were community-dwelling men (aged ≥70 years, n=1686), Sydney, Australia. Medication exposure was categorised at medication class level and data were analysed according to geriatric syndrome status (presence of at least one syndrome including frailty, falls, cognitive impairment and urinary incontinence). Association Rule and Frequent-Set analysis were performed to identify "interesting" patterns of medication combinations that occur together. This analysis involves advanced computer algorithms that investigated all possible combinations of medications in the dataset in order to identify those which are observed more or much less frequently than expected. Frequent-Set Analysis demonstrated one unexpected medication combination, antiulcer and antidiabetic medications (3.5% of participants) in the overall population (n=1687). Frequency of medication combinations was similar in participants with (n=666) and without (n=1020) geriatric syndromes. Among participants with geriatric syndromes, the most frequent combinations included antigout with lipid-lowering agents (5.7%) followed by angiotensin II and diuretics combination (22%). This novel methodology can be used to detect common medication combinations overall by data visualisation, and against specific adverse drug reactions such as geriatric syndromes. This methodology may be a valuable pharmacovigilance approach to monitor large databases for the safety of medications.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2010
DOI: 10.1007/S00198-010-1478-9
Abstract: 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. The aim of this cross-sectional analysis was to identify the factors associated with areal bone mineral density (BMD) and their relative contribution in older men. The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia, involving 1,705 men aged 70-97. Data were collected using questionnaires and clinical assessments. BMD of the hip and spine was measured by dual X-ray absorptiometry. In multivariate regression models, BMD of the hip was associated with body weight and bone loading physical activities, but not independently with age. The positive relationship between higher BMD and recreational activities is attenuated with age. Factors independently associated with lower BMD at the hip were inability to stand from sitting, a history of kidney stones, thyroxine use, and Asian birth and at the spine, chronic obstructive pulmonary disease, paternal fracture history, and thyroxine use. Higher body weight, participation in dancing, tennis or jogging, quadriceps strength, alcohol consumption, and statin use were associated with higher hip BMD, while older age, osteoarthritis, higher body weight, and aspirin use were associated with higher spinal BMD. Maintaining body weight, physical activity, and strength were positively associated with BMD even in very elderly men. Other parameters were also found to influence BMD, and once these were included in multivariate analysis, age was no longer associated with BMD. This suggests that age-related diseases, lifestyle choices, and medications influence BMD rather than age per se.
Publisher: Springer Netherlands
Date: 2010
Publisher: Oxford University Press (OUP)
Date: 24-01-2006
Publisher: Oxford University Press (OUP)
Date: 06-2016
Abstract: The longitudinal association between progressive temporal change in sexual (dys)function and mortality in older men. Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project were assessed at baseline (2005-2007, n = 1,705), 2-years follow-up (n = 1,367), and 5-years follow-up (n = 958). Self-reported sexual function (erectile function and sexual activity) using standardized questions were analyzed by generalized estimating equations to examine the longitudinal prediction of mortality according to change in sexual function across three time-points. Men reported to have erectile dysfunction increased from 64% to 80%, and to be sexually inactive increased from 56% to 59% over the course follow-up. In univariate analyses, erectile dysfunction (hazard ratio: 2.02, 95% confidence interval [CI]: 1.45-2.81) or having no sexual activity (hazard ratio: 2.31, 95% CI: 1.82-2.93) at baseline predicted increased mortality over the subsequent 7 years. Models adjusted for multivariate and major reproductive hormones had negligible impact on mortality prediction, but neither statistically significantly predicted mortality after adjusting for depression. Similarly, change in erectile dysfunction over time was associated with mortality over 7 years in univariate (odds ratio: 1.69, 95% CI: 1.34-2.14) and multivariate analysis, including hormones, but not after adjusting for depression (odds ratio: 1.24, 95% CI: 0.95-1.62). Change in sexual activity was associated with mortality over 7 years in univariate analysis (odds ratio: 2.37, 95% CI: 1.33-4.20) but not after adjusting for age (odds ratio: 1.45, 95% CI: 0.79-2.64). Our analyses suggest sexual dysfunction was not an independent risk factor of, but rather may be a biomarker for, all-cause mortality in older men.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1002/HEP.21378
Abstract: The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node-activated T cells, liver-activated T cells are short-lived, a mechanism that might contribute to the "liver tolerance effect." Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8(+) T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that naïve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating naïve CD8(+) T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion, this study has identified, at the ultrastructural level, a unique type of interaction between naïve T lymphocytes and liver parenchymal cells in vivo. These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.
Publisher: Springer Netherlands
Date: 2010
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/J.EXGER.2003.07.002
Abstract: Age-related changes in the hepatic sinusoid termed pseudocapillarization have been reported in the rat and human and have implications for disease susceptibility in old age. In this study, we investigated whether similar changes occur in the livers of old baboons and thus represent a widespread aging change. Liver tissue from five young baboons (5.4+/-0.5yrs) and five old baboons (21.8+/-0.7yrs) was compared by transmission electron microscopy, scanning electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old baboons (130+/-8 nm versus 186+/-9 nm, P<0.001) and the frequency of endothelial fenestrae decreased, with the porosity declining from 4.2+/-0.5% to 2.4+/-0.4% (P=0.006). The expression of laminin and von Willebrands factor was more extensive in old baboons. Novel perisinusoidal ring-shaped cells, probably fat-engorged stellate cells, were prominent in the old baboons. Pseudocapillarization is a significant age-related change in the baboon liver. Aging in baboons is associated with a novel aging change in the stellate cell not reported in other species. Hepatic pseudocapillarization is a widespread aging liver change found in several species including humans and other non-human primates.
Publisher: Springer New York
Date: 2010
Publisher: Oxford University Press (OUP)
Date: 28-04-2020
Abstract: APOE genotype has been associated with various age-related outcomes including Alzheimer’s disease, frailty, and mortality. In this study, the relationship between health, particularly cognitive function, and APOE was investigated in older men from the Concord Health and Ageing in Men Project (n = 1,616 age 76.9 ± 5.5 years [range 70–97 years] Australia). Baseline characteristics and survival up to 12 years were determined. Frailty was measured using Cardiovascular Health study (CHS) criteria and Rockwood frailty index, and cognition using Mini-Mental State Examination (MMSE) and Addenbrookes Cognitive Examination. APOE ε4 was less common in the oldest men and those born in Mediterranean countries. APOE ε2 was beneficially associated with cholesterol, creatinine, gamma-glutamyl transaminase, glucose, and HDL cholesterol while APOE ε4 was adversely associated with cholesterol and albumin. APOE ε4 was associated with a clinical diagnosis of Alzheimer’s disease when adjusted for age and region of birth (ε4 homozygotes Odds ratio (OR) 7.0 ε4 heterozygotes OR 2.4, p & .05), and APOE ε2 had a small positive association with cognition. On multivariate regression, overall cognitive function in the entire cohort was associated with age, country of birth, education, and frailty (all p & .001). APOE was not associated with frailty or survival. In conclusion, age and region of birth influenced distribution of APOE genotype in older men. Although APOE ε4 was associated with Alzheimer’s disease, overall cognitive function in the cohort was associated more strongly with frailty than APOE genotype.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 28-05-2004
DOI: 10.1124/PR.56.2.4
Publisher: Springer Science and Business Media LLC
Date: 07-02-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 02-03-2015
Abstract: A fundamental tenet of life-history theory is that reproduction and longevity trade off against one another. Experiments on invertebrates show that, rather than competing for limiting resources, reproduction and lifespan are optimized on different dietary macronutrient compositions. In mice, studies have yet to establish the relationship between macronutrient balance, reproduction, and lifespan. We evaluated the effects of macronutrients and energy on lifespan and reproductive function. Indicators of reproductive function (uterine mass, ovarian follicle number, testes mass, epididymal sperm counts) were optimized by high protein (P), low carbohydrate (C) diets whereas lifespan was greatest on low P:C diets. Corpora lutea and estrous cycling were higher in females on lower P:C diets. Macronutrient balance has profound and opposing effects on reproduction and longevity.
Publisher: Wiley
Date: 09-09-2009
DOI: 10.1096/FJ.09-137133
Publisher: Proceedings of the National Academy of Sciences
Date: 20-09-2011
Abstract: 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 naïve 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.
Publisher: Wiley
Date: 21-08-2014
DOI: 10.1111/BCP.12359
Publisher: The Royal Society
Date: 05-2019
Abstract: Protein and calorie restrictions extend median lifespan in many organisms. However, studies suggest that among-in idual variation in the age at death is also affected. Ultimately, both of these outcomes must be caused by effects of nutrition on underlying patterns of age-specific mortality (ASM). Using model life tables , we tested for effects of dietary macronutrients on ASM in mice ( Mus musculus ). High concentrations of protein and fat relative to carbohydrates were associated with low life expectancy and high variation in the age at death, a result caused predominantly by high mortality prior to middle age. A lifelong diet comprising the ratio of macronutrients self-selected by mouse (in early adulthood) was associated with low mortality up until middle age, but higher late-life mortality. This pattern results in reasonably high life expectancy, but very low variation in the age at death. Our analyses also indicate that it may be possible to minimize ASM across life by altering the ratio of dietary protein to carbohydrate in the approach to old age. Mortality in early and middle life was minimized at around one-part protein to two-parts carbohydrate, whereas in later life slightly greater than equal parts protein to carbohydrate reduced mortality.
Publisher: Springer Netherlands
Date: 2010
Publisher: Wiley
Date: 05-04-2007
DOI: 10.1111/J.1472-8206.2007.00473.X
Abstract: 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-in idual 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.
Publisher: The Endocrine Society
Date: 04-2016
DOI: 10.1210/JC.2015-3810
Abstract: Although androgen status decreases with aging in unselected men, the contemporaneous relationship over time between circulating hormones and androgen-sensitive outcomes has not been reported. To investigate the temporal relationships between age-specific androgen status and muscle (mass, strength), hemoglobin, and prostate-specific antigen (PSA). Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005–2007 n = 1705) and at 2-year (n = 1367) and 5-year follow-up (n = 958). At all assessments, serum T, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and serum SHBG, LH, and FSH were measured by immunoassay together with calculation of free T (cFT). Muscle mass, strength of upper (hand grip) and lower (walking speed) limbs, hemoglobin, and prostate size (serum PSA) were measured. Serum hormones showed longitudinal, within-man decreases in serum T (−2.6%/y), DHT (−2.6%/y), E1 (−3.2%/y), and cFT (−2.8%/y) but increases in serum E2 (2.6%/y), SHBG (1.3%/y), LH (1.9%/y), and FSH (1.8%/y). Significant positive correlation was observed between changes in serum T with muscle mass, strength, and hemoglobin but not with PSA across the three time-points. Changes in serum DHT, cFT, and E1 had significant correlation with muscle mass, strength, and hemoglobin, but not with PSA. These extended observational data are consistent with the impact of reduced androgen status on some somatic features of male aging. However, they do not exclude reverse causality or independent effects of aging on both androgen status and androgen-sensitive outcomes.
Publisher: Springer Science and Business Media LLC
Date: 24-08-2015
Publisher: Wiley
Date: 17-02-2016
DOI: 10.1111/FCP.12184
Publisher: BMJ
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 05-12-2012
DOI: 10.1007/S00198-012-2226-0
Abstract: Though bone loss tends to accelerate with age there are modifiable factors that may influence the rate of bone loss even in very old men. The aim of this 2-year longitudinal study was to examine potential predictors of change in total hip bone mineral density (BMD) in older men. The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia. For this study, 1,122 men aged 70-97 years had baseline and follow-up measures of total hip BMD measured with dual X-ray absorptiometry. Data about mobility, muscle strength, balance, medication use, cognition, medical history and lifestyle factors were collected using questionnaires and clinical assessments. Serum 25-hydroxyvitamin D [25(OH)D] was also measured. Multivariate linear regression models were used to assess relationships between baseline predictors and change in BMD. Over a mean of 2.2 years, there was a mean annualised loss of total hip BMD of 0.006 g/cm(2)/year (0.6 %) and hip BMC of 0.14 g/year (0.3 %). Annual BMD loss accelerated with increasing age, from 0.4 % in men aged between 70 and 75 years, to 1.2 % in men aged 85+ years. In multivariate regression models, predictors of faster BMD loss were anti-androgen, thiazolidinedione and loop-diuretic medications, kidney disease, poor dynamic balance, larger hip bone area, older age and lower serum 25(OH)D. Factors associated with attenuated bone loss were walking for exercise and use of beta-blocker medications. Change in BMD was not associated with baseline BMD, smoking, alcohol consumption, BMI, frailty, or osteoarthritis. There was considerable variation in the rate of hip bone loss in older men. Walking, better balance and beta blockers may attenuate the acceleration of BMD loss that occurs with age.
Publisher: Oxford University Press (OUP)
Date: 13-08-2019
Abstract: Weight loss increases fracture risk in older adults. We aimed to determine associations of 2-year body composition trajectories with subsequent falls and fractures in older men. We measured appendicular lean mass (ALM) and total fat mass (FM) by dual-energy X-ray absorptiometry at baseline and Year 2 in 1,326 community-dwelling men aged ≥70 and older. Body composition trajectories were determined from residuals of a linear regression of change in ALM on change in FM (higher values indicate maintenance of ALM over FM), and a categorical variable for change in ALM and FM (did not lose [≥−5% change] versus lost [& −5% change]). Bone mineral density (BMD), hand grip strength, and gait speed were assessed at Years 2 and 5. After Year 2, incident fractures (confirmed by radiographical reports) and falls were recorded for 6.8 years. Compared with men who did not lose ALM or FM, men who did not lose ALM but lost FM, and men who lost both ALM and FM, had reduced falls (−24% and −34%, respectively both p & .05). Men who lost ALM but did not lose FM had increased falls (incidence rate ratio = 1.73 95% CI 1.37–2.18). ALM/FM change residuals were associated with improved lumbar spine BMD (B = 0.007 95% CI 0.002–0.012 g/cm2 per SD increase) and gait speed (0.015 0.001–0.029 m/s), and reduced hip fractures (hazard ratio = 0.68 95% CI 0.47–0.99). Fracture risk may be increased in older men who lose higher ALM relative to FM. Weight loss interventions for obese older men should target maintenance of lean mass.
Publisher: Wiley
Date: 14-05-2015
DOI: 10.1002/JBMR.2493
Abstract: The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2 years follow-up (2007-2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4-monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (β = -0.071), FSH (β = -0.085), LH (β = -0.070), and E1 (β = 0.107) remained significantly associated with BMD loss in multivariate-adjusted models however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171 hip, n = 44 and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging.
Publisher: Oxford University Press (OUP)
Date: 06-03-2019
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/439835
Abstract: Aging is associated with marked changes in the hepatic sinusoid, yet the effect of old age on hepatic stellate cells (HSC) has not been well described. Transmission electron microscopy and immunohistochemistry were used to study the effects of aging on HSC in livers from rats (3-4 mths versus 24–27 mths) and mice (2-3 mths versus 20–22 mths). Desmin-positive HSC doubled in old age in both mice and rats. Alpha-smooth muscle actin- (αSMA-) positive cells did not increase significantly and remained only a small percentage of desmin-positive cells. Electron microscopy revealed that old age is associated with HSC that have a substantial increase in the number of lipid droplets which are larger in diameter. There was also a marked increase of HSC that protruded into the sinusoidal lumen in old mice. In conclusion, old age is associated with hyperplasia of HSC that are not activated and are engorged with lipid droplets.
Publisher: Wiley
Date: 11-03-2016
DOI: 10.1111/AJAG.12310
Abstract: To describe the age at which the geriatric syndromes and frailty become common in community-dwelling men. The Concord Health and Ageing in Men Project involves a population-based s le of 1705 community-dwelling men aged 70 and over from a defined geographic region in Sydney. Data were obtained by physical performance tests, clinical examinations, and questionnaire to determine the prevalence of the following conditions by five-year age group. Poor mobility, recurrent falls, urinary incontinence, dementia and frailty phenotype were all uncommon (less than 10%) in men in their 70s, but the prevalence of each of these conditions exceeded 10% in men aged 85-89. The prevalence of Frailty Index-defined frailty, multimorbidity, polypharmacy and instrumental activities of daily living dependence was constantly high in all age groups. The different health-care needs of the 'old old' aged 85 years and older should be accounted for in health service planning.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2011
DOI: 10.1016/J.PAIN.2010.11.022
Abstract: 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.
Publisher: Wiley
Date: 09-2003
Publisher: The Endocrine Society
Date: 05-2014
DOI: 10.1210/JC.2013-3984
Abstract: Self-rated health and health-related quality of life are inversely associated with increased morbidity and mortality however, the temporal relationship with reproductive hormones is poorly understood. The objective of the study was to examine relationships between reproductive hormones, self-rated health, and quality of life in older men at baseline as well as changes over a 2-year follow-up. One thousand six hundred thirty-seven men aged 70 years and older from the Concord Health and Ageing in Men Project were assessed at baseline and 1316 men returned for the 2-year follow-up. Serum T, dihydrotestosterone, estradiol, and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. Logistic regression and multivariate linear regression models were performed. Self-rated health and health-related quality of life measures (12-Item Short Form Health Survey) were determined. In the cross-sectional baseline data, univariate analyses revealed significant associations between many of the hormones and quality-of-life scores and self-rated health. In a multivariable analysis, the associations between T, E1, and calculated free T and self-rated health remained statistically significant. Compared with men in the highest T quartile, men in the lowest T quartile had an odds ratio of 1.47 (95% confidence interval 1.04-2.06) for reporting fair, poor, or very poor health vs excellent or good health. The findings for E1 and calculated free T were similar. In the longitudinal data, the only significant relationship was that between E1 and self-rated health. Compared with those in the highest E1 quartile, those in the lowest quartile experienced deterioration in self-rated health: adjusted odds ratio of 1.84 (95% confidence interval 1.10-3.06). Low serum T and E1 are associated with poorer self-rated health in older men, whereas lower serum levels of E1 are predictive of subsequent deterioration in self-rated health over time. Therefore, serum E1 is a novel potential risk factor for poor self-rated health in older men that warrants further investigation.
Publisher: American College of Physicians
Date: 02-07-2013
Publisher: S. Karger AG
Date: 1998
DOI: 10.1159/000026185
Abstract: A prevalence study of Parkinson’s disease (PD) was conducted in the rural town of Nambour, Australia. There were 5 cases of PD in a study population of 1207, yielding a crude prevalence ratio of 414 per 100,000 (95% confidence interval 53–775). We performed a separate case-control study involving 224 patients with PD and 310 controls from South East Queensland and Central West New South Wales, to determine which factors increase the risk for PD in Australia. A positive family history of PD was the strongest risk factor for the development of the disease (odds ratio = 3.4 p 0.001). In addition, rural residency was a significant risk factor for PD (odds ratio = 1.8, p 0.001). Hypertension, stroke and well water ingestion were inversely correlated with the development of PD. There was no significant difference between patients and controls for exposure to herbicides and pesticides, head injury, smoking or depression. The high prevalence of PD in Nambour may be explained by rural residency. However, the most significant risk factor for PD was a positive family hisotry. This demonstrates the need for improved understanding of the genetic nature of the disease.
Publisher: Elsevier BV
Date: 09-2010
Publisher: Springer Netherlands
Date: 2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2001
Abstract: Age-related impairment of drug metabolism by the liver is consistent with hepatocyte hypoxia, suggestive of the development of a diffusional barrier to oxygen supply. Because the effects of aging on the diffusional pathway (sinusoidal endothelium and space of Disse) have not been described, we performed comparative studies on the livers of Fischer F344 rats aged 4 to 7, 12 to 15, and 24 to 27 months. Light-microscopic examination revealed no evidence of fibrosis, cirrhosis, or other specific pathology. In contrast, scanning and transmission electron-microscopic examination revealed that aging is associated with pseudocapillarization of the sinusoidal endothelium, indicated by defenestration with reduced porosity, thickening of the endothelium, infrequent development of basal lamina, and only minor collagen deposits in the space of Disse. Furthermore, immunohistochemistry studies showed strong expression of collagen IV, moderate expression of factor VIII-related antigen, and weak expression of collagen I along the sinusoids of livers from old rats (P <.0001). In vitro (31)P magnetic resonance spectroscopy analysis showed that aging is associated with changes in high-energy phosphate and other metabolites, consistent with hepatocyte hypoxia. Aging in the liver is associated with changes in the sinusoidal endothelium and space of Disse that may restrict the availability of oxygen and other substrates.
Publisher: SAGE Publications
Date: 21-01-2011
Abstract: Poloxamer 407 (P407) is a non-ionic detergent that is used widely in pharmaceutical formulations and personal care products. In animals, P407 causes hyperlipidaemia. P407 is taken up by the liver and causes loss of fenestrations in liver sinusoidal endothelial cells (LSEC), which contributes to the pathogenesis of hyperlipidaemia. Here the short-term (1–15 days) effects of P407 on all liver cells were investigated in mice using electron and light microscopy. As expected, P407 was associated with hyperlipidaemia. Kupffer cells became massively engorged with vacuoles and took on a marked honeycomb morphology. LSECs also became engorged with vacuoles and endocytosis was activated. The diameter of lipoproteins in the space of Disse was less than those in the lumen, consistent with a filtering effect of fenestrations. Defenestration of the LSEC was noted. Hepatocyte endocytosis of lipoproteins and P407 particles was also noted however, hepatocyte steatosis was not evident. Hepatic stellate cells did not appear to be abnormal. In conclusion, P407 is taken up by the liver mostly through endocytosis by LSECs and Kupffer cells.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Wiley
Date: 07-08-2012
DOI: 10.1111/J.1465-3362.2012.00496.X
Abstract: To explore the association between psychotropic drug use and alcohol drinking in community-dwelling older Australian men. We conducted a cross-sectional population-based study using baseline data collected between 2005 and 2007 from 1705 participants in the Concord Health and Ageing in Men Project (CHAMP) conducted in Sydney, Australia. All participants were men aged ≥70 years. The prevalence of antidepressant and sedative or anxiolytic drug use was ascertained at clinical examinations and alcohol drinking was self-reported. Logistic regression models were used to compute the unadjusted and adjusted prevalence ratios and 95% confidence intervals for the association between sedative or anxiolytic use and antidepressant use with drinking patterns. In the study s le, 8.0% used an antidepressant, 5.7% used a sedative or anxiolytic, 33.7% were daily drinkers, 13.9% were binge drinkers, 19.2% were heavy drinkers and 11.0% were problem drinkers. Overall, 27.1% of antidepressant users were daily drinkers and 42.7% of sedative or anxiolytic users were daily drinkers. Sedative or anxiolytic use was associated with daily drinking (prevalence ratio = 1.42 95% confidence intervals 1.09-1.76) but not with other drinking patterns. The associations between antidepressant use and alcohol drinking were not statistically significant. Potential psychotropic drug-alcohol interactions were common in older Australian men. Users of sedative or anxiolytic drugs were more likely to engage in daily drinking compared with non-users of sedative or anxiolytic drugs. Clinicians should monitor patients prescribed sedative or anxiolytic drugs for possible adverse events arising from concomitant use with alcohol.
Publisher: Wiley
Date: 25-07-2005
DOI: 10.1111/J.1532-5415.2005.53403.X
Abstract: To determine whether use of atypical antipsychotics (olanzapine and risperidone) is associated with lower risk of falls than use of typical antipsychotics. Prospective cohort study with 1-month follow-up. Residential aged care facilities in Sydney, Australia. Two thousand five people aged 65 to 104 (mean age 86). Medication use at baseline was collected from medical records. Data on potential confounders were collected at interview and physical examination and from medical records. The outcome was accidental falls (one or more). One thousand one hundred seven subjects (55%) used at least one type of psychotropic medication, with 289 (14%) using an antipsychotic. There were 82 olanzapine users, 38 risperidone users, and 181 users of typical antipsychotics. Eleven percent of subjects (n=226) had at least one fall during follow-up. After adjusting for a comprehensive range of falls risk factors, hazard ratios (HRs) for falls were 1.35 (95% confidence interval (CI)=0.87-2.09) for typical antipsychotics, 1.32 (95% CI=0.57-3.06) for risperidone, and 1.74 (95% CI=1.04-2.90) for olanzapine. Antidepressants were also associated with falls (adjusted HR=1.45, 95% CI=1.09-1.93). Despite fewer extrapyramidal side effects, atypical antipsychotic medications are not associated with fewer falls than the older, more-established antipsychotics.
Publisher: Bioscientifica
Date: 28-05-2015
DOI: 10.1530/JOE-15-0173
Abstract: Both lifespan and healthspan are influenced by nutrition, with nutritional interventions proving to be robust across a wide range of species. However, the relationship between nutrition, health and aging is still not fully understood. Caloric restriction is the most studied dietary intervention known to extend life in many organisms, but recently the balance of macronutrients has been shown to play a critical role. In this review, we discuss the current understanding regarding the impact of calories and macronutrient balance in mammalian health and longevity, and highlight the key nutrient-sensing pathways that mediate the effects of nutrition on health and ageing.
Publisher: Oxford University Press (OUP)
Date: 08-05-2013
Abstract: Poor vitamin D status and frailty are common in older people and associated with adverse health outcomes. The aim of this study was to examine the associations between serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels and frailty and components of frailty in older Australian men. Cross-sectional analysis of the Concord Health and Ageing in Men Project, a large epidemiological study conducted in Sydney, Australia, between January 2005 and May 2007. Participants included 1,659 community-dwelling men. Main outcome measurements were frailty (assessed using the Cardiovascular Health Study), frailty criteria comprising five core components: weight loss reduced muscular strength/weakness slow walking speed exhaustion and low activity level, and the separate components of frailty. Covariates included serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels measured by radioimmunoassay, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, income, measures of health, parathyroid hormone, estimated glomerular function. Frailty was present in 9.2% of the s le. Low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were independently associated with frailty and with four of the five components of frailty (except weight loss). 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels were independently associated with frailty in older men. This suggests that there might be a number of different biological mechanisms for how low vitamin D status might contribute to the frailty syndrome. In addition, the possibility that improving vitamin D status may specifically influence the incidence and progression of frailty needs to be explored.
Publisher: Oxford University Press (OUP)
Date: 07-02-2011
Publisher: Wiley
Date: 2003
DOI: 10.1002/PATH.1328
Abstract: Age-related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age-related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post-mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post-mortem s les of human liver, was associated with increased peri-sinusoidal expression of von Willebrand's factor, collagen I, collagen IV, and staining with Masson's trichrome. Electron microscopy revealed significant age-related thickening of the sinusoidal endothelium (young 165 +/- 17 nm, middle age 222 +/- 11 nm, older 289 +/- 9 nm, p < 0.001) with loss of fenestrations (young 7.7 +/- 0.7 per 10 micro m, middle age 3.6 +/- 0.5 per 10 micro m, older 1.5 +/- 0.4 per 10 micro m, p < 0.001), and age-related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility.
Publisher: Oxford University Press (OUP)
Date: 19-03-2010
Abstract: to describe the prevalence and impact on quality of life of urinary incontinence in a population-based cohort of older community-dwelling Australian men. 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. 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. 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. 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.
Publisher: Wiley
Date: 21-01-2010
Publisher: Springer Science and Business Media LLC
Date: 09-02-2013
DOI: 10.1007/S12603-013-0013-Z
Abstract: Inadequate vitamin D status (25-hydroxyvitamin D (25(OH)D) concentrations <50 nmol/L) is an increasingly important public health issue in Australia. The aim of this analysis is to describe 25(OH)D levels in community dwelling men aged ≥70 years in Sydney, Australia, and to determine associations between serum 25(OH)D levels and socioeconomic and lifestyle factors. A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. 1659 non-institutionalised men aged ≥70 years. The cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants included 1659 community dwelling men who were interviewed and had clinical assessments. Main outcome measurements included serum 25(OH)D levels measured in blood s les using a radioimmunoassay kit (DiaSorin Inc., Stillwater, MN). Covariates included age, socioeconomic measures, season of blood s le, physical activity, sun exposure, vitamin D supplement use, cigarette smoking status, alcohol consumption, obesity and measures of health. Prevalence of vitamin D insufficiency was 43.0% highest in winter (55.5%) and spring (53.9%), and was associated with season (winter and spring), low physical activity, avoidance of sun exposure, current smoking and obesity, even after adjustment for confounding factors. Inadequate vitamin D status is highly prevalent among Australian older men and is associated with specific lifestyle factors. These findings emphasize the need to screen and monitor 25(OH)D levels in this population group, despite living in a sunny country such as Australia.
Publisher: Oxford University Press (OUP)
Date: 14-06-2020
Abstract: Age-related changes in the liver sinusoidal endothelium, particularly the reduction in fenestrations, contribute to insulin resistance in old age. Metformin impacts on the aging process and improves insulin resistance. Therefore, the effects of metformin on the liver sinusoidal endothelium were studied. Metformin increased fenestrations in liver sinusoidal endothelial cells isolated from both young and old mice. Mice administered metformin in the diet for 12 months had increased fenestrations and this was associated with lower insulin levels. The effect of metformin on fenestrations was blocked by inhibitors of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, and myosin light chain kinase phosphorylation. Metformin led to increased transgelin expression and structural changes in the actin cytoskeleton but had no effect on lactate production. Metformin also generated fenestration-like structures in SK-Hep1 cells, a liver endothelial cell line, and this was associated with increased ATP, cGMP, and mitochondrial activity. In conclusion, metformin ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways, which might promote insulin sensitivity in the liver, particularly in old age.
Publisher: MyJove Corporation
Date: 30-04-2015
DOI: 10.3791/52698
Publisher: Informa UK Limited
Date: 05-05-2015
Publisher: Wiley
Date: 12-2011
Publisher: Informa UK Limited
Date: 18-11-2016
DOI: 10.1080/07853890.2016.1252053
Abstract: Anticholinergic and sedative medications are associated with acute cognitive impairment, but the long-term impact on change in cognition is unclear. This study investigated the effect of anticholinergic and sedative medications, quantified using the Drug Burden Index (DBI), on change in cognition over time in community-dwelling older men. This was a prospective cohort study of men aged ≥70 years in Sydney, Australia. DBI was assessed at baseline, 2, and 5 years. Cognitive performance was assessed using the Mini-Mental State Exam (MMSE) at each wave. Logistic quantile mixed-effects modelling was used to assess the adjusted effect of DBI on the median MMSE-time profile. Analyses were restricted to men with English-speaking backgrounds (n = 1059, 862, and 611 at baseline, 2, and 5 years). Overall, 292 (27.7%), 258 (29.9%), and 189 (31.3%) men used anticholinergic or sedative medications at baseline, 2, and 5 years. There was a concave relationship between MMSE and time, where higher DBI corresponded to lower MMSE scores (coefficient: -0.161 95% CI: -0.250 to -0.071) but not acceleration of declining MMSE over time. Exposure to anticholinergic and sedative medications is associated with a small impairment in cognitive performance but not decline in cognition over time. KEY MESSAGES Exposure to anticholinergic and sedative medications, quantified using the Drug Burden Index, is associated with small cross-sectional impairments in cognitive performance. There was no evidence that exposure to anticholinergic and sedative medications is associated with accelerating decline in cognitive performance over a 5-year follow-up. Older people taking anticholinergic and sedative medications may derive immediate but small benefits in cognitive performance from clinical medication reviews to minimize or cease prescribing of these medications.
Publisher: S. Karger AG
Date: 20-05-2023
DOI: 10.1159/000524311
Abstract: b i Introduction: /i /b This study aimed to assess the extent to which a single item of self-reported hearing difficulties is associated with future risk of falling among community-dwelling older adults. b i Methods: /i /b We used data from two Australian population-based cohorts: three waves from the PATH Through Life study (PATH i n /i = 2,048, 51% men, age 66.5 ± 1.5 SD years) and three waves from the Concord Health and Ageing in Men Project (CHAMP i n /i = 1,448, 100% men with mean age 77.3 ± 5.3 SD years). Hearing difficulties were recorded on a four-point ordinal scale in PATH and on a dichotomous scale in CHAMP. The number of falls in the past 12 months was reported at each wave in both studies. In CHAMP, incident falls were also ascertained by triannual telephone call cycles for up to four years. Multivariable-adjusted random intercept negative binomial regression models were used to estimate the association between self-reported hearing difficulties and number of falls reported at the following wave or 4-monthly follow-ups. b i Results: /i /b In PATH, self-reported hearing difficulties were associated with a higher rate of falls at follow-up (incidence rate ratio = 1.15, 95% CI = 1.03–1.27 per a one-level increase in self-reported hearing difficulties), after adjusting for sociodemographic characteristics, health behaviours, physical functioning, balance, mental health, medical conditions, and medications. There were no significant associations between hearing difficulties and the rate of falls based on either repeated survey or 4-monthly follow-ups in CHAMP. b i Conclusion: /i /b Though we find mixed results, findings from PATH data indicate an ordinal measure of self-reported hearing loss may be predictive of falls incidence in young-old adults. However, the null findings in the male-only CHAMP preclude firm conclusions of a link between hearing loss and falls risk.
Publisher: Wiley
Date: 24-06-2022
DOI: 10.1111/JOIM.13530
Abstract: Nutrition profoundly influences the risk for many age‐related diseases. Whether nutrition influences human aging biology directly is less clear. Studies in different animal species indicate that reducing food intake (“caloric restriction” [CR]) can increase lifespan and delay the onset of diseases and the biological hallmarks of aging. Obesity has been described as “accelerated aging” and therefore the lifespan and health benefits generated by CR in both aging and obesity may occur via similar mechanisms. Beyond calorie intake, studies based on nutritional geometry have shown that protein intake and the interaction between dietary protein and carbohydrates influence age‐related health and lifespan. Studies where animals are calorically restricted by providing free access to diluted diets have had less impact on lifespan than those studies where animals are given a reduced aliquot of food each day and are fasting between meals. This has drawn attention to the role of fasting in health and aging, and exploration of the health effects of various fasting regimes. Although definitive human clinical trials of nutrition and aging would need to be unfeasibly long and unrealistically controlled, there is good evidence from animal experiments that some nutritional interventions based on CR, manipulating dietary macronutrients, and fasting can influence aging biology and lifespan.
Publisher: Elsevier BV
Date: 02-1992
Publisher: Springer Science and Business Media LLC
Date: 20-06-2012
DOI: 10.1038/CLPT.2012.74
Publisher: S. Karger AG
Date: 2003
DOI: 10.1159/000070408
Abstract: i Background: /i The association between postprandial blood pressure, falls and medications is controversial. i Objective: /i To investigate cardiovascular responses to meals in elderly people together with clinical associations and therapeutic issues. i Methods: /i A cross-sectional observational study of 179 semi-independent older people (age 83.2 ± 7.0 years) in residential care facilities was undertaken. Data on the frequency of falls, medical and medication history and measurement of blood pressure before and after a breakfast meal, and then after standing and walking after the meal were documented. i Results: /i Postprandial hypotension (≧20 mm Hg fall in systolic blood pressure (SBP)) and low absolute SBP (≤115 mm Hg) were common after meals and exacerbated by standing. Risk factors for low postprandial SBP included use of selective serotonin reuptake inhibitors (OR = 4.3, CI 1.4–13.1, p = 0.006), antipsychotic medications (OR = 5.2, CI 1.4–19.2, p = 0.007) and a history of smoking (OR = 4.7, CI 1.5–14.9, p = 0.005). Antihypertensive therapy ameliorated the postprandial decline in blood pressure. The incidence of falls was increased only in the 10% of subjects with low postprandial SBP. i Conclusions: /i Significant adverse cardiovascular change is common after meals in older people and a postprandial SBP of mm Hg was associated with a history of falls. Selective serotonin reuptake inhibitors and antipsychotic medications were associated with low postprandial SBP, which may provide a mechanism for their association with falls. Hypertension was positively and antihypertensive therapy negatively associated with postprandial hypotension.
Publisher: Informa UK Limited
Date: 2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1002/HEP.20937
Abstract: The mechanisms for the association of old age with post-prandial hyperlipidemia and atherosclerosis are not well understood. Post-prandial hyperlipidemia has emerged as a significant risk for atherosclerosis. The liver is the central organ for lipoprotein metabolism. The initial step in the hepatic uptake of post-prandial lipoproteins is their transfer from the hepatic sinusoidal capillary lumen across the hepatic sinusoidal endothelium into the space of Disse. Here, they access hepatocytes for receptor-mediated uptake. We proposed that fenestrations (pores) within the hepatic sinusoidal endothelium filter lipoproteins on the basis of size. Recently we discovered age-related changes in the sinusoidal endothelium (pseudocapillarization), including reduction in the porosity of the endothelium. Using the impulse response technique in perfused rat livers, we found that aging is associated with impaired hepatic transendothelial transfer of chylomicrons with diameters smaller than those of fenestrations. In conclusion, age-related pseudocapillarization of the hepatic sinusoidal endothelium provides a novel mechanism for the association of old age with impaired hepatic lipoprotein metabolism and with atherosclerosis.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.ATHEROSCLEROSIS.2005.12.025
Abstract: Poloxamer 407 is a ubiquitous synthetic surfactant that causes massive hyperlipidemia and atherosclerosis in the rodent. The initial step in hepatic metabolism of lipoproteins is their transfer through 100-200 nm pores (fenestrations) in the liver sinusoidal endothelial cell, prior to receptor-mediated uptake. The 'liver sieve hypothesis' emphasizes the role of these fenestrations in the regulation of lipoprotein disposition. Here we show that P407 causes dramatic defenestration of the liver sinusoidal endothelium in vivo. By 24h after intraperitoneal administration in mice, fenestrations were reduced by approximately 80% coincident with a 10-fold increase in plasma lipids. Moreover impulse-response experiments in the perfused rat liver showed that P407 prevented the passage of small chylomicrons across the liver sinusoidal endothelium. Defenestration was also induced acutely with P407 in isolated liver sinusoidal endothelial cells, indicating this is a direct effect of P407 on fenestrations. The results establish the role of the porosity of the liver sinusoidal endothelial cell as a pivotal yet relatively unrecognised mechanism for hyperlipidemia. Furthermore, the results establish an intriguing mechanism for surfactant-induced hyperlipidemia. Thus the liver sieve is a new and untapped target for the treatment and prevention of hyperlipidemia.
Publisher: Wiley
Date: 2013
DOI: 10.1002/OBY.20007
Abstract: Protein leverage plays a role in driving increased energy intakes that may promote weight gain. The influence of the protein to carbohydrate ratio (P:C) in diets of C57BL/6J mice on total energy intake, fat storage, and thermogenesis was investigated. Male mice (9 weeks old) were provided ad libitum access to one of five isocaloric diets that differed in P:C. Food intake was recorded for 12 weeks. After 16 weeks, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were dissected, weighed, and the expression levels of key metabolic regulators were determined in BAT. In a separate cohort, body surface temperature was measured in response to 25 diets differing in protein, fat, and carbohydrate content. Mice on low P:C diets (9:72 and 17:64) had greater total energy intake and increased WAT and BAT stores. Body surface temperature increased with total energy intake and with protein, fat, and carbohydrate, making similar contributions per kJ ingested. Expression of three key regulators of thermogenesis were downregulated in BAT in mice on the lowest P:C diet. Low-protein diets induced sustained hyperphagia and a generalized expansion of fat stores. Increased body surface temperature on low P:C diets was consistent with diet-induced thermogenesis (DIT) as a means to dissipate excess ingested energy on such diets, although this was not sufficient to prevent development of increased adiposity. Whether BAT was involved in DIT is not clear. Increased BAT mass on low P:C diets might suggest so, but patterns of thermogenic gene expression do not support a role for BAT in DIT, although they might reflect failure of thermogenic function with prolonged exposure to a low P:C diet.
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1016/S0140-6736(98)03453-9
Abstract: Parkinson's disease is thought to be secondary to the presence of neurotoxins, and pesticides have been implicated as possible causative agents. Glutathione transferases (GST) metabolise xenobiotics, including pesticides. Therefore, we investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson's disease. We genotyped by PCR polymorphisms in four GST classes (GSTM1, GSTT1, GSTP1, and GSTZ1) in 95 Parkinson's disease patients and 95 controls. We asked all patients for information about pesticide exposure. The distribution of the GSTP1 genotypes differed significantly between patients and controls who had been exposed to pesticides (controls vs patients: AA 14 [54%] of 26 vs seven [18%] of 39 AB 11 [42%] of 26 vs 22 [56%] of 39 BB 1 [4%] of 26 vs six [15%] of 39 AC 0 vs four [10%] of 39, p=0.009). No association was found with any of the other GST polymorphisms. Pesticide exposure and a positive family history were risk factors for Parkinson's disease. GSTP1-1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides.
Publisher: Wiley
Date: 06-10-2009
Publisher: Wiley
Date: 07-2009
DOI: 10.1111/J.1445-5994.2009.01942.X
Abstract: 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. A cross-sectional study was performed on all interns (n= 191) who attended intern orientation programmes at four NSW hospitals in January 2008. A clinical case scenario that tested prescribing ability and a survey investigating impressions of clinical pharmacology training in medical school were administered to the interns in exam format. Outcome measures were: (i) ability to prescribe medications safely and appropriately for the clinical case scenario and (ii) interns' impressions of their training in clinical pharmacology at medical school. No intern completed all prescribing tasks correctly. No intern charted the patient's usual medications on admission completely correctly, only six wrote an accurate discharge medication list, and none wrote both an accurate discharge medication list and a legal Schedule 8 discharge script. None of the respondents strongly agreed that they felt adequately trained to prescribe medications in their intern year and 84% would have liked to have more training in pharmacology as medical students. Interns about to commence clinical practice in NSW teaching hospitals demonstrated significant deficits in prescribing of regular medications, initiation of new therapies, prescribing of discharge medications, and particularly prescribing of Schedule 8 medications. Most interns recognized these deficits and would have liked more clinical pharmacology training at medical school.
Publisher: Wiley
Date: 20-08-2014
DOI: 10.1002/JBMR.2230
Abstract: The aim of this population-based, prospective, observational study was to examine the relationship between serum levels of 25-hydroxyvitamin D (25OHD) and fracture risk in a cohort of 1662 community-dwelling men aged 70 to 97 years followed for a mean of 4.3 years. Data about mobility, muscle strength, balance, medication use, cognition, medical history, lifestyle factors, renal function, and serum 25OHD were collected at baseline. Data on radiologically verified fractures were collected every 4 months. The relationship between fractures and serum 25OHD levels was analyzed using Cox's proportional hazard regression. We accounted for bone mineral density, falls, physical activity, sun exposure, and season of blood draw, in addition to anthropometric and lifestyle factors, medical history, muscle strength, balance, and medication and supplement use. There were 123 first-incident fragility fractures. The relationship between baseline 25OHD and fracture risk was U-shaped, with increased fracture risk in men with either low or high serum 25OHD levels. In multivariate analysis, the risk of fracture was greatest in men with 25OHD levels in the lowest quintile (25OHD ≤36 nmol/L hazard ratio [HR] = 3.5 95% confidence interval [CI] 1.7-7.0) and in men in the highest quintile (25OHD >72 nmol/L HR = 2.7 95% CI 1.4-5.4) compared with men in the 4th quintile (25OHD ≥60 to ≤72 nmol/L). These associations were not explained by lower BMD, increased physical activity, fall risk, or other lifestyle or anthropomorphic factors. In community-dwelling older men, there appears to be a healthy target range for serum 25OHD concentrations. Thus, serum 25OHD levels too high and too low may be harmful in regard to fracture risk.
Publisher: Springer New York
Date: 2010
Publisher: Wiley
Date: 15-12-2014
Abstract: Although many studies reporting the organ-level biodistribution of nanoparticles (NPs) in animals, very few have addressed the fate of NPs in organs at the cellular level. The liver appears to be the main organ for accumulation of NPs after intravenous injection. In this study, for the first time, the in vivo spatiotemporal disposition of recently developed mercaptosuccinic acid (MSA)-capped cadmium telluride/cadmium sulfide (CdTe/CdS) quantum dots (QDs) is explored in rat liver using multiphoton microscopy (MPM) coupled with fluorescence lifetime imaging (FLIM), with subcellular resolution (∼1 μm). With high fluorescence efficiency and largely improved stability in the biological environment, these QDs show a distinct distribution pattern in the liver compared to organic dyes, rhodamine 123 and fluorescein. After intravenous injection, fluorescent molecules are taken up by hepatocytes and excreted into the bile, while negatively charged QDs are retained in the sinusoids and selectively taken up by sinusoidal cells (Kupffer cells and liver sinusoidal endothelial cells), but not by hepatocytes within 3 h. The results could help design NPs targeting the specific types of liver cells and choose the fluorescent markers for appropriate cellular imaging.
Publisher: Cambridge University Press (CUP)
Date: 12-08-2015
DOI: 10.1017/S0007114515002421
Abstract: Previous research shows that older men tend to have lower nutritional intakes and higher risk of under-nutrition compared with younger men. The objectives of this study were to describe energy and nutrient intakes, assess nutritional risk and investigate factors associated with poor intake of energy and key nutrients in community-dwelling men aged ≥75 years participating in the Concord Health and Ageing in Men Project – a longitudinal cohort study on older men in Sydney, Australia. A total of 794 men (mean age 81·4 years) had a detailed diet history interview, which was carried out by a dietitian. Dietary adequacy was assessed by comparing median intakes with nutrient reference values (NRV): estimated average requirement, adequate intake or upper level of intake. Attainment of NRV of total energy and key nutrients in older age (protein, Fe, Zn, riboflavin, Ca and vitamin D) was incorporated into a ‘key nutrients’ variable dichotomised as ‘good’ (≥5) or ‘poor’ (≤4). Using logistic regression modelling, we examined associations between key nutrients with factors known to affect food intake. Median energy intake was 8728 kJ (P5=5762 kJ, P95=12 303 kJ), and mean BMI was 27·7 ( sd 4·0) kg/m 2 . Men met their NRV for most nutrients. However, only 1 % of men met their NRV for vitamin D, only 19 % for Ca, only 30 % for K and only 33 % for dietary fibre. Multivariate logistic regression analysis showed that only country of birth was significantly associated with poor nutritional intake. Dietary intakes were adequate for most nutrients however, only half of the participants met the NRV of ≥5 key nutrients.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2015
DOI: 10.1158/2326-6066.CIR-14-0211
Abstract: Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti–PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti–PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti–PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor antagonist. The blockade of PD-1 enhanced A2A receptor expression on tumor-infiltrating CD8+ T cells, making them more susceptible to A2A-mediated suppression. Thus, dual blockade of PD-1 and A2A significantly enhanced the expression of IFNγ and Granzyme B by tumor-infiltrating CD8+ T cells and, accordingly, increased growth inhibition of CD73+ tumors and survival of mice. The results of our study indicate that CD73 expression may constitute a potential biomarker for the efficacy of anti–PD-1 mAb in patients with cancer and that the efficacy of anti–PD-1 mAb can be significantly enhanced by A2A antagonists. We have therefore revealed a potentially novel biomarker for the efficacy of anti–PD-1 that warrants further investigation in patients. Because our studies used SYN-115, a drug that has already undergone phase IIb testing in Parkinson disease, our findings have immediate translational relevance for patients with cancer. Cancer Immunol Res 3(5) 506–17. ©2015 AACR.
Publisher: Oxford University Press (OUP)
Date: 24-06-2010
Publisher: Springer Science and Business Media LLC
Date: 12-01-2012
Publisher: Elsevier BV
Date: 04-2005
Publisher: Wiley
Date: 04-09-2011
DOI: 10.1111/J.1741-6612.2011.00564.X
Abstract: To determine adherence, persistence and continuation beyond 6 months with cholinesterase inhibitors in Australians with Alzheimer's disease. Adherence and persistence with cholinesterase inhibitors were assessed by data linkage using the Pharmaceutical Benefits Scheme (PBS) Authority database and other health databases. 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. Persistence and adherence with cholinesterase inhibitors was reasonable once treatment was established. There was an unexpectedly high continuation rate beyond six prescriptions.
Publisher: The Endocrine Society
Date: 08-2011
DOI: 10.1210/JC.2011-0143
Abstract: 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. The objective of the study was to examine, using longitudinal measurements, the relations of serum androgens, estrogens, gonadotropins, and SHBG to the prevalence and progression of frailty in older men. Concord Health and Ageing in Men Project is an observational cohort study of 1705 men (aged 70 yr or older) living in the suburb of Concord, Sydney, Australia. Measurements were obtained at baseline (2005-2007) and 2-yr follow-up (2007-2009). Testosterone (T), dihydrotestosterone, estradiol, and estrone were obtained by liquid chromatography-tandem mass spectrometry, whereas SHBG, LH, and FSH were measured by immunoassay. Subjects from the general community were s led. A total of 1645 subjects constituting a representative s le of community-dwelling men aged 70 yr old or older participated in the study. The frailty syndrome was measured according to the Cardiovascular Health Study (CHS) and Study of Osteoporotic Fractures (SOF) indices. Androgens and estrogens showed significant age-adjusted associations with concurrent frailty. Subjects in the lowest T quintile had 2.2-fold odds of exhibiting greater CHS frailty as compared with the highest T quintile (P < 0.001) results for dihydrotestosterone, estradiol, estrone, and calculated free T were similar, and were unchanged when the SOF frailty index was substituted for the CHS frailty index. A 1 sd, 2-yr decrease in T, calculated free T, or LH was associated with a 1.2- to 1.3-fold increase in the odds of progression (increase in severity) of frailty. The control for comorbid medical conditions did not affect results. Age-related changes in blood androgens and estrogens may contribute to the development or progression of frailty in men.
Publisher: Wiley
Date: 05-2011
DOI: 10.1002/JBMR.286
Abstract: Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross-sectional analysis consisted of 1705 community-dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population-based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (β = 0.12 to 0.14, p < .001), serum calcium (β = 0.11, p = .001), parathyroid hormone (β = 0.09, p = .002), 25-hydroxyvitamin D (β = 0.09, p = .005), and was negatively associated with urinary excretion amino-terminal cross-linked telopeptide of type 1 collagen (β = -0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R(2) = 0.10 to 0.22). In multiple logistic regression analyses, above-median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22-0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23-0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43-0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29-0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men.
Publisher: Springer Science and Business Media LLC
Date: 1998
DOI: 10.2165/00003088-199834050-00003
Abstract: A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations. Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the 'oxygen diffusion barrier' hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion. Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.
Publisher: The Endocrine Society
Date: 05-2016
DOI: 10.1210/JC.2016-1025
Abstract: The dynamic temporal relationship between changes in serum reproductive hormones and mortality in men has not been reported. The objective of the study was to examine the relationship between progressive changes in circulating reproductive hormones over time with all-cause and cause-specific mortality in older men. Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005-2007, n = 1705) and at 2-year (n = 1367) and 5-year follow-up (n = 958). At all three time-points, T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were determined by immunoassay and calculated free T (cFT) was calculated. Mortality was ascertained through the state death registry. Statistical modeling was by general estimating equations with the Poisson regression. Serum T over time (relative risk [RR] per 1 SD decrease in concentration: 1.18, 95% confidence interval [CI] 1.05-1.32), DHT (RR 1.17, 95% CI 1.05-1.32), and E2 (RR 1.46, 95% CI 1.30-1.63) as well as cFT (RR 1.27, 95% CI 1.13-1.41) was associated with all-cause mortality. After adjusting for multiple covariables, the decline in serum T (RR 1.17, 95% CI 1.03-1.32), DHT (RR 1.17, 95% CI 1.03-1.32), and cFT (RR 1.13, 95% CI 1.08-1.19) remained significantly associated with all-cause mortality. Similar relationships were observed for cancer but not cardiovascular mortality. Progressive decline in serum E2 levels remained significantly associated with all-cause (RR 1.49, 95% CI 1.31-1.69), cancer (RR 1.82, 95% CI 1.45-2.28), and cardiovascular (RR 1.37, 95% CI 1.13-1.66) mortality, even after adjustment for covariables. Serum E1, LH, FSH, and SHBG were not associated with all-cause, cancer, or cardiovascular mortality. Dynamic temporal changes in serum T, cFT, DHT, and E2 (but not E1, LH, FSH, and SHBG) in older men are associated with all-cause and cause-specific mortality in distinct patterns.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2013
DOI: 10.1038/JHG.2012.144
Abstract: Cytochrome c oxidase (COX) of the electron transport system is thought to be the rate-limiting step in cellular respiration and is found mutated in numerous human pathologies. Here, we employ quaternary three-dimensional (3-D) modeling to construct a model for human COX. The model was used to predict the functional consequences of amino-acid mutations based on phylogenetic conservation of amino acids together with volume and/or steric perturbations, participation in subunit-subunit interfaces and non-covalent energy loss or incompatibilities. These metrics were combined and interpreted for potential functional impact. A notable strength of the 3-D model is that it can interpret and predict the structural consequences of amino-acid variation in all 13 protein subunits. Importantly, the influence of compensatory changes can also be modeled. We examine mutations listed in the human mutation database Mitomap, and in 100 older men, and compare the results from the 3-D model against the automated MutPred web application tool. In combination, these comparisons suggest that the 3-D model predicts more functionally significant mutations than does MutPred. We conclude that the model has useful functional prediction capability but may need modification as functional data on specific mutations becomes known.
Publisher: The Endocrine Society
Date: 04-2015
DOI: 10.1210/JC.2014-4104
Abstract: It is unclear whether declining sexual function in older men is a cause or consequence of reduced androgen status. Longitudinal associations were examined between reproductive hormones and sexual function in older men. Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (n = 1705) and 2-year follow-up (n = 1367), with a total of 1226 men included in the final analyses. At both visits, serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were measured by immunoassay. Sexual functions (erectile function, sexual activity, and sexual desire) were self-reported via standardized questions. In longitudinal analyses, although baseline hormones (T, DHT, E2, and E1) did not predict decline in sexual function, the decline in serum T (but not DHT, E2, or E1) over 2 years was strongly related to the change in sexual activity and desire (but not erectile function). For each 1-SD decrease in T from baseline to 2-year follow-up, there was a multivariate-adjusted odds ratio of 1.23 (95% confidence interval, 1.12-1.36) for an additional risk of further decline in sexual activity. However, the magnitude of the decrease in serum T was strikingly small (<10%). Similar associations were found for changes over 2 years in serum T and decline in sexual desire, but not for erectile function. We found a consistent association among older men followed over 2 years between the decline in sexual activity and desire, but not in erectile function, with a decrease in serum T. Although these observational findings cannot determine causality, the small magnitude of the decrease in serum T raises the hypothesis that reduced sexual function may reduce serum T rather than the reverse.
Publisher: Wiley
Date: 09-11-2015
DOI: 10.1111/FCP.12157
Publisher: Oxford University Press (OUP)
Date: 24-05-2020
Abstract: Aging is a powerful risk factor for the development of many chronic diseases including dementia. Research based on disease models of dementia have yet to yield effective treatments, therefore it is opportune to consider whether the aging process itself might be a potential therapeutic target for the treatment and prevention of dementia. Numerous cellular and molecular pathways have been implicated in the aging process and compounds that target these processes are being developed to slow aging and delay the onset of age-associated conditions. A few particularly promising therapeutic agents have been shown to influence many of the main hallmarks of aging and increase life span in rodents. Here we discuss the evidence that some of these antiaging compounds may beneficially affect brain aging and thereby lower the risk for dementia.
Publisher: Springer Science and Business Media LLC
Date: 11-2006
DOI: 10.1038/NATURE05354
Publisher: Oxford University Press (OUP)
Date: 07-08-2014
Abstract: Although there is a conflicting evidence for an association between low serum 25-hydroxyvitamin D (25D) levels and pain, the relationship between pain and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25D), has not been investigated. The aim of this study was to examine the associations between serum vitamin D metabolites: 25D and 1,25D with intrusive or chronic pain in community-living men aged ≥70 years. Population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project, a large epidemiological study conducted in Sydney between January 2005 and May 2007. Participants included 1,659 community dwelling men aged ≥70 years, taking part in Concord Health and Ageing in Men Project. Main outcome measurements were symptoms of chronic or intrusive pain. Covariates included 25D and 1,25D, parathyroid hormone, estimated glomerular filtration rate as well as age, country of birth, season of blood collection, body mass index, health conditions, and medication, including nonsteroidal anti-inflammatory drugs and statins. The prevalence of intrusive pain was 22.9% and of chronic pain was 29.7%. Low serum 25D concentrations were associated with intrusive and chronic pain in unadjusted analysis, but after adjustment, the associations were no longer significant. Low 1,25D levels (<62.0 pmol/L) remained independently associated with chronic pain (odds ratio: 1.53 [1.05, 2.21, p = .02]), even after adjustment for a wide range of potential confounders and covariates of clinical significance. Low serum 1,25D concentrations are associated with chronic pain in older men. This raises the question whether vitamin D metabolites may influence pain states, mediated through different biological mechanisms and pathways.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JCLINEPI.2012.02.018
Abstract: 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. 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. 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. 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.
Publisher: Oxford University Press (OUP)
Date: 18-07-2018
Abstract: It is unclear whether older men with osteopenia/osteoporosis and sarcopenia (so-called osteosarcopenia) are at greater risk of falls and fractures than those with either condition alone. One thousand five hundred seventy-five community-dwelling men aged ≥70 years had appendicular lean mass, total hip and lumbar spine bone mineral density determined by dual-energy x-ray absorptiometry, and completed hand grip strength and gait speed tests. Osteopenia/osteoporosis was defined as a T-score at any site ≤-1.0 SD. Sarcopenia was defined using the European Working Group on Sarcopenia algorithm. Participants were contacted every 4 months for 6 ± 2 years to ascertain incident fractures (confirmed by radiographic reports) and for 2 years for incident falls. Prevalence of osteosarcopenia was 8%, while 34% of participants had osteopenia/osteoporosis alone and 7% had sarcopenia alone. Men with osteosarcopenia had significantly increased fall (incidence rate ratio: 1.41 95% confidence interval [CI]: 1.02 to 1.95) and fracture risk (hazard ratio: 1.87 95% CI: 1.07 to 3.26) compared with men with neither osteopenia/osteoporosis nor sarcopenia. There was no statistical interaction between osteopenia/osteoporosis and sarcopenia, and falls and fracture risk were not different for osteosarcopenia compared with either condition alone (all p > .05). Community-dwelling older men with combined osteopenia/osteoporosis and sarcopenia do not have increased falls and fracture risk compared with those with either condition. Further research is required to clarify whether the term "osteosarcopenia" has any meaning above and beyond either term alone and therefore potential clinical utility for falls and fracture prediction.
Publisher: Oxford University Press (OUP)
Date: 14-01-2019
Abstract: The liver endothelium plays a key role in the progression and resolution of liver diseases in young and adult in iduals. However, its role in older people remains unknown. We have herein evaluated the importance of the sinusoidal endothelium in the pathophysiology of acute liver injury, and investigated the applicability of simvastatin, in aged animals. Eighteen-months-old male Wistar rats underwent 60 minutes of partial warm ischemia followed by 2 hours of reperfusion (WIR). A group of aged rats received simvastatin for 3 days before WIR. Endothelial phenotype, parenchymal injury, oxidative and nitrosative stress, and fenestrae dynamics were analyzed. The effects of WIR and simvastatin were investigated in primary LSEC from aged animals. The results of this study demonstrated that WIR significantly damages the liver endothelium and its effects are markedly worse in old animals. WIR-aged livers exhibited reduced vasodilation and sinusoidal capillarization, associated with liver damage and cellular stress. Simvastatin prevented the detrimental effects of WIR in aged livers. In conclusion, the liver sinusoidal endothelium of old animals is highly vulnerable to acute insult, thus targeted protection is especially relevant in preventing liver damage. Simvastatin represents a useful therapeutic strategy in aging.
Publisher: Oxford University Press (OUP)
Date: 21-06-2012
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.TIV.2009.08.018
Abstract: 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.
Publisher: Wiley
Date: 02-2011
Publisher: Medknow
Date: 27-08-2012
DOI: 10.1038/AJA.2012.88
Publisher: Elsevier BV
Date: 2011
DOI: 10.1002/JPS.22235
Publisher: Elsevier BV
Date: 04-1996
Publisher: Informa UK Limited
Date: 08-2017
DOI: 10.2147/CIA.S140581
Publisher: American Association for Cancer Research (AACR)
Date: 14-10-2013
DOI: 10.1158/1078-0432.CCR-13-0458
Abstract: Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression. Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2+ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach. Results: In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8+ T cells following antigen-specific stimulation with PD-L1+ tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2+ tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1+ CD11b+ myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. Conclusion: This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer. Clin Cancer Res 19(20) 5636–46. ©2013 AACR.
Publisher: Oxford University Press (OUP)
Date: 22-10-2014
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000341724
Publisher: American Diabetes Association
Date: 17-07-2014
DOI: 10.2337/DB13-1665
Abstract: The vascular endothelial growth factor (VEGF) family of cytokines are important regulators of angiogenesis that have emerged as important targets for the treatment of obesity. While serum VEGF levels rise during obesity, recent studies using genetic models provide conflicting evidence as to whether VEGF prevents or accelerates metabolic dysfunction during obesity. In the current study, we sought to identify the effects of VEGF-A neutralization on parameters of glucose metabolism and insulin action in a dietary mouse model of obesity. Within only 72 h of administration of the VEGF-A–neutralizing monoclonal antibody B.20-4.1, we observed almost complete reversal of high-fat diet–induced insulin resistance principally due to improved insulin sensitivity in the liver and in adipose tissue. These effects were independent of changes in whole-body adiposity or insulin signaling. These findings show an important and unexpected role for VEGF in liver insulin resistance, opening up a potentially novel therapeutic avenue for obesity-related metabolic disease.
Publisher: BMJ
Date: 15-12-2011
DOI: 10.1136/BMJ.D7679
Publisher: Springer Science and Business Media LLC
Date: 03-2005
Publisher: Elsevier BV
Date: 05-1995
Publisher: Elsevier BV
Date: 11-2021
Publisher: Elsevier BV
Date: 03-2003
Publisher: Springer Science and Business Media LLC
Date: 18-03-2010
DOI: 10.1007/S10522-010-9269-4
Abstract: 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.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 02-08-2021
DOI: 10.1111/BCP.14967
Publisher: Elsevier BV
Date: 04-2013
Publisher: Wiley
Date: 12-08-2014
DOI: 10.1111/JGS.12975
Abstract: To examine the associations between serum 25-hydroxyvitamin D (25OHD) levels and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25OHD), with type 2 diabetes mellitus (DM) in community-living men aged 70 and older. Cross-sectional. A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. Community dwelling men aged 70 and older taking part in CHAMP (N = 1,659). Serum 25OHD and 1,25OHD levels, presence of DM, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, statin use, income, measures of health, depression, activity of daily living disabilities, parathyroid hormone, estimated glomerular filtration rate, phosphate, and calcium. The prevalence of DM was 20.0%. There was a significant association between low 25OHD and 1,25OHD levels and DM that remained after adjustment for a wide range of confounders and covariates of clinical significance such as comorbidity, renal function, calciotropic hormones, and medications. 25OHD and 1,25OHD levels were associated with DM. The independent association between serum 25OHD and 1,25OHD concentrations and DM raises the question of whether each of the two vitamin D metabolites may influence DM through different biological mechanisms and pathways.
Publisher: American Physiological Society
Date: 05-2016
DOI: 10.1152/AJPHEART.00949.2015
Abstract: Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes. Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-06-2013
Abstract: Using gene-expression data from over 6,000 breast cancer patients, we report herein that high CD73 expression is associated with a poor prognosis in triple-negative breast cancers (TNBC). Because anthracycline-based chemotherapy regimens are standard treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy. In TNBC patients treated with anthracycline-only preoperative chemotherapy, high CD73 gene expression was significantly associated with a lower rate of pathological complete response or the disappearance of invasive tumor at surgery. Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
Publisher: Oxford University Press (OUP)
Date: 20-01-2016
Publisher: Informa UK Limited
Date: 2000
Abstract: Herbal medicines may have significant adverse effects which are not suspected or recognized. A 34-year-old female developed severe nausea, vomiting, drowsiness, prolonged QTc, and episodes of nonsustained ventricular tachycardia following self-administration of a herbal remedy, Passiflora incarnata L., at therapeutic doses. The possible association of symptoms with passiflora was not recognized for several days. She required hospital admission for cardiac monitoring and intravenous fluid therapy. Passiflora incarnata was associated with significant adverse effects in this patient. It is important to ask specifically about the use of herbal medicines in patients with undiagnosed illnesses.
Publisher: Wiley
Date: 08-2007
Publisher: Oxford University Press (OUP)
Date: 14-01-2010
Abstract: 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. 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. 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. 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.
Publisher: Wiley
Date: 11-2010
DOI: 10.1111/J.1532-5415.2010.03145.X
Abstract: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men. Cross-sectional study of older men participating in the Concord Health and Ageing in Men Project (CHAMP). Elderly men living in a defined geographical region in Sydney, Australia. One thousand seven hundred five community-dwelling men aged 70 and older who participated in the baseline assessments of CHAMP. Upper and lower extremity strength were measured using dynamometers for grip and quadriceps strength. Appendicular skeletal lean mass was assessed using dual X-ray absorptiometry. Muscle quality was defined as the ratio of strength to mass in upper and lower extremities. For each parameter, subjects in the lowest 20% of the distribution were defined as below normal. Functional limitation was assessed according to self-report and objective lower extremity performance measures. Physical disability was measured according to self-report questionnaire. After adjusting for important confounders, the prevalence ratio (PR) for poor quadriceps strength and self-reported functional limitation was 1.91 (95% confidence interval (CI) = 1.10-2.40) for performance-based functional limitation the PR was 1.81 (95% CI = 1.45-2.24). The adjusted PR for poor grip strength and physical disability in instrumental activities of daily living (IADLs) was 1.37 (95% CI = 1.20-1.56). The adjusted PR for low skeletal lean mass (adjusted for fat mass) and physical disability in basic activities of daily living was 2.08 (95% CI = 1.37-3.15). For muscle quality, the PR for lower extremity specific force and functional limitation and physical disability was stronger than upper extremity specific force. Muscle strength is the single best measure of age-related muscle change and is associated with physical disability in IADLs and functional limitation.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2008
Publisher: Oxford University Press (OUP)
Date: 27-04-2019
Abstract: while both negative and positive impacts of caregiving on health have been reported, findings regarding caregiver's mortality may be biased by the lack of consideration of changes in their health and caregiving status during follow-up. This study examines the impact of caregiving on the risk of death in older men, allowing for caregiving-transition by in iduals and adjusting for changes over time in their health status. data from 1639 men age ≥70 years old from the Concord Health and Ageing in Men Project (CHAMP) were collected between baseline (2005-07), 2-year and 5-year follow-up and linked to death records up to 30 September 2015. A time-varying Cox proportional hazards model was used to examine the risk of death from caregiving between 2005 and 2015, adjusting for baseline education, history of myocardial infarction, congestive heart failure, and risk factors which may change over time (age, income, self-rated overall health, number of morbidities, physical disability, depression and anxiety). the average follow-up was 7.39 years (SD = 2.95) with 495 deaths observed. There was no significant difference in all-cause mortality between caregivers and non-caregivers in the multivariable model (HR: 0.95, 95% CI: 0.67-1.32, P = 0.73). this study addressed the dynamic caregiving role and covariates which has been rarely considered in the literature. While there is concern that when older people take on a caring role their health suffers, we found no difference in mortality between older male caregivers and non-caregivers when we accounted for transitions in their caregiving status.
Publisher: Oxford University Press (OUP)
Date: 10-09-2014
Publisher: Elsevier BV
Date: 11-2001
Publisher: Wiley
Date: 03-11-2017
DOI: 10.1002/JBMR.3016
Abstract: Body composition and muscle function have important implications for falls and fractures in older adults. We aimed to investigate longitudinal associations between sarcopenic obesity and its components with bone mineral density (BMD) and incident falls and fractures in Australian community-dwelling older men. A total of 1486 men aged ≥70 years from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2-year follow-up (2007-2009 n = 1238), and 5-year follow-up (2010-2013 n = 861). At all three time points, measurements included appendicular lean mass (ALM), body fat percentage and total hip BMD, hand-grip strength, and gait speed. Participants were contacted every 4 months for 6.1 ± 2.1 years to ascertain incident falls and fractures, the latter being confirmed by radiographic reports. Sarcopenic obesity was defined using sarcopenia algorithms of the European Working Group on Sarcopenia (EWGSOP) and the Foundation for the National Institutes of Health (FNIH) and total body fat ≥30% of total mass. Sarcopenic obese men did not have significantly different total hip BMD over 5 years compared with non-sarcopenic non-obese men (p > 0.05). EWGSOP-defined sarcopenic obesity at baseline was associated with significantly higher 2-year fall rates (incidence rate ratio [IRR] 1.66 95% confidence interval [CI] 1.16-2.37), as were non-sarcopenic obesity (1.30 1.04-1.62) and sarcopenic non-obesity (1.58 1.14-2.17), compared with non-sarcopenic non-obese. No association with falls was found for sarcopenic obesity using the FNIH definition (1.01 0.63-1.60), but after multivariable adjustment, the FNIH-defined non-sarcopenic obese group had a reduced hazard for any 6-year fracture compared with sarcopenic obese men (hazard ratio 0.44 95% CI 0.23-0.86). In older men, EWGSOP-defined sarcopenic obesity is associated with increased fall rates over 2 years, and FNIH-defined sarcopenic obese men have increased fracture risk over 6 years compared with non-sarcopenic obese men. © 2016 American Society for Bone and Mineral Research.
Publisher: Wiley
Date: 02-2012
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.ARR.2017.03.001
Abstract: Nearly a century of research has shown that nutritional interventions can delay aging and age- related diseases in many animal models and possibly humans. The most robust and widely studied intervention is caloric restriction, while protein restriction and restriction of various amino acids (methionine, tryptophan) have also been shown to delay aging. However, there is still debate over whether the major impact on aging is secondary to caloric intake, protein intake or specific amino acids. Nutritional geometry provides new perspectives on the relationship between nutrition and aging by focusing on calories, macronutrients and their interactions across a landscape of diets, and taking into account compensatory feeding in ad libitum-fed experiments. Nutritional geometry is a state-space modelling approach that explores how animals respond to and balance changes in nutrient availability. Such studies in insects and mice have shown that low protein, high carbohydrate diets are associated with longest lifespan in ad libitum fed animals suggesting that the interaction between macronutrients may be as important as their total intake.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0531-5565(02)00097-9
Abstract: Recently there has been recognition in Australia of the importance of experimental gerontological research. To date, the major areas of research into the biology of ageing have been oxidative stress and mitochondrial dysfunction. Future directions for gerontological research in Australia are likely to place more emphasis on comprehensive studies that integrate basic biological research, with clinical studies and the behavioural and social domains of ageing. Priority will be given to studies incorporating biological markers that are population based and longitudinal. The growing interest in experimental gerontological research complements Australian research strengths in other domains such as disease-based research, social gerontology, population studies and health policy research.
Publisher: Springer Netherlands
Date: 2010
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.EXGER.2016.04.007
Abstract: Considerable progress has been made in understanding both evolutionary and mechanistic aspects of biological aging, although the two areas remain poorly integrated. We suggest that a greater emphasis on ecology can help to remedy this, by focusing on the interface between biological mechanisms and the environments in which they evolved by natural selection. Among the most salient aspects of the environment relevant to aging is nutrition, and yet in the bulk of aging research nutrition is coarsely represented as dietary restriction or caloric restriction, without consideration for how specific components of diet, beyond "energy" (the undifferentiated mix of macronutrients), are driving the observed effects. More recently, it has become clear that specific nutrients (notably amino acids) and interactions among nutrients (i.e., nutritional balance) play important roles in the biology of aging. We show how a method developed in nutritional ecology, called the Geometric Framework for nutrition, can help to understand the nutritional interactions of animals with their environments, by explicitly distinguishing the roles of calories, in idual nutrients and nutrient balance. Central to these models are the active regulatory responses that animals use to mediate between variation in the nutritional environment and fitness-related consequences such as lifespan and reproduction. These homeostatic responses provide a guide for researchers that can help to link the biological mechanisms with evolutionary processes in the context of a multi-dimensional nutritional environment.
Publisher: Oxford University Press (OUP)
Date: 08-12-2016
Abstract: to explore the longitudinal associations between body composition measures, sarcopenic obesity and outcomes of frailty, activities of daily living (ADL) and instrumental ADL (IADL) disability, institutionalisation and mortality. men aged ≥ 70 years (2005-07) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 (n = 1,366) and 5 years (n = 954). The main outcome measures were frailty (adapted Fried criteria), ADL, including personal care and mobility and IADL disability (ability to perform tasks for independent living), institutionalisation and mortality. The Foundation for the National Institutes of Health cut-points were used for low muscle mass: appendicular lean mass (ALM):Body Mass Index (BMI) ratio (ALMBMI) 30% fat. Generalised estimating equations were used to examine the longitudinal associations between the independent variables (obesity alone, low muscle mass and sarcopenic obesity) and frailty, ADL and IADL disability. in unadjusted, age adjusted and fully adjusted analysis, men with low muscle mass showed increased risk of frailty and IADL disability. In fully adjusted analysis, men with sarcopenic obesity had an increased risk of frailty (odds ratio (OR): 2.00 (95% confidence of interval (CI): 1.42, 2.82)) ADL disability (OR: 1.58 (95% CI: 1.12, 2.24)) and IADL disability (OR: 1.36 (95% CI: 1.05, 1.76)). Obesity alone was protective for institutionalisation (OR: 0.51 (95% CI: 0.31, 0.84)) but was not associated with any other outcomes. low muscle mass and sarcopenic obesity were associated with poor functional outcomes, independent of confounders. This would suggest that future trials on frailty and disability prevention should be designed to intervene on both muscle mass and fat mass.
Publisher: Elsevier BV
Date: 05-2002
Publisher: The Endocrine Society
Date: 06-2015
DOI: 10.1210/JC.2015-1016
Abstract: The longitudinal relationship between declining levels of reproductive hormones and cognitive function remains unclear in older men. The objective of this study was to examine the temporal relationship between changes in major reproductive hormone levels and cognitive decline over time. Men age 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) were assessed at baseline (2005-2007 n = 1705), 2-year followup (2007-2009 n = 1367), and 5-year followup (2010-2013 n = 958). At all assessments, T, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Dementia was diagnosed at baseline by clinical assessment and review by a specialist panel. Cognitive function was measured at all three assessments by the Mini Mental State Examination. None of the baseline reproductive hormones predicted cognitive decline in men without dementia over 5 years. However, the change in serum hormones over time was associated with cognitive decline. In univariate analysis, change in all the studied hormones, except for E2, was significantly associated with cognitive decline. However, in multivariate-adjusted models accounting for potential confounders, only change in serum T (β = 0.067), DHT (β = 0.394), calculated free T (β = 0.005), and E1 (β = 0.009) remained significantly associated (P < .05) with cognitive decline. Men who had dementia at baseline had significantly greater decline in serum T levels, but not in other studied hormones, over the 5 years. Our findings show that decline in androgen status is associated with cognitive decline in older men, but the causality of this association requires further elucidation.
Publisher: Elsevier BV
Date: 2003
Abstract: In order to estimate the placental barrier to gas transfer, a novel carbon monoxide (CO) wash-in method was used to estimate the permeability-surface area (PS) product for the transfer of gas across the foetal circulation in the perfused human term placenta. The PS product for CO was 0.0096+/-0.006 ml/s/g or 0.012+/-0.007 ml/s/g using compartmental or Crone-Renkin analysis, respectively. Using this result and a published estimate of the placental capillary surface area, the permeability coefficient to CO across the foetal circulation was found to be approximately 4 x 10(-5)cm/s. This result is compatible with the hypothesis that the foetal circulation of the human placenta imposes a potentially significant barrier to gas transfer.
Publisher: Oxford University Press (OUP)
Date: 05-12-2013
Abstract: chronic knee pain is still considered a fairly benign disease by many, an 'unavoidable' consequence of ageing. This passive acceptance may be unnecessarily exposing older people to disability and serious co-morbidity. The aim of this study was to determine the disease burden associated with chronic knee pain and the role of knee extensor strength as a modifiable risk factor. a longitudinal cohort study with 2-year follow-up conducted among 1,587 community-dwelling men aged 70 years and over, 637 (40%) reported chronic knee pain. Of the 950 (60%) men without knee pain at baseline, 768 (81%) returned for the follow-up assessment with 150 (20%) reporting incident chronic knee pain. knee pain was significantly associated with marked mobility disability [odds ratio (OR) 2.38 95% confidence interval (CI) 1.74-3.29], falls (OR: 1.31 95% CI: 1.01-1.70) and having four or more co-morbidity (OR: 1.63 95% CI: 1.16-2.30) as well as reduced knee extensor strength and mass (dual X-ray absorptiometry). Men with incident knee pain at the 2-year follow-up assessment demonstrated greater increases in these measures of disease burden and greater decreases in muscle strength and mass, compared with those without incident chronic knee pain. Obesity, high co-morbidity burden, back pain, higher levels of physical activity or low knee extensor strength were all significant risk factors for incident knee pain. prevention of chronic knee pain may reduce a considerable burden of mobility disability and increased risk of serious co-morbidity among older men.
Publisher: Oxford University Press (OUP)
Date: 18-07-2012
Publisher: Wiley
Date: 16-02-2017
DOI: 10.1111/AJAG.12376
Abstract: To explore differences between older male caregivers and non-caregivers on health status, health behaviours and well-being, including symptoms of anxiety. Data were collected through self-completed questionnaires and face-to-face interviews with 1705 community living men aged ≥70 in the Concord Health and Ageing in Men Project. Eleven per cent of older men were caregivers, of whom 81.7% were looking after their wives or partners. Older male caregivers did not have worse physical health or more depressive symptoms than non-caregivers, but being a caregiver was associated with increased likelihood of reporting anxiety symptoms (OR: 2.32, 95% CI: 1.39-3.87). Caregivers had similar levels and frequencies of leisure activities but did more housework activities than non-caregivers. Higher anxiety levels were the main adverse health condition in older male caregivers. Strategies to assist minimising anxiety for caregivers should be a target of interventions.
Publisher: Elsevier BV
Date: 2016
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 16-07-2004
DOI: 10.1124/DMD.32.8.794
Abstract: To determine the role of the hepatic sinusoidal endothelium in the hepatic disposition of liposomal doxorubicin, we compared the hepatic pharmacokinetics of doxorubicin hydrochloride and the pegylated, liposomal formulation of doxorubicin (Caelyx). The multiple indicator-dilution technique and electron microscopy were used to study the disposition of doxorubicin and liposomal doxorubicin in the rat liver. Doxorubicin had a volume of distribution 1.56 +/- 0.45 times greater than that of the extracellular marker, sucrose, whereas liposomal doxorubicin had a volume of distribution 0.56 +/- 0.30 times smaller than that of sucrose (P < 0.001). The recovery of doxorubicin was less than that of liposomal doxorubicin (70 +/- 24% versus 94 +/- 17%, P < 0.05). The disposition of liposomal doxorubicin was found to be flow-limited, whereas a permeability-limited sequestration model fitted doxorubicin. The transfer of doxorubicin across the hepatocyte membrane was symmetrical (permeability - surface area product for influx 0.02 +/- 0.01 ml s/g versus 0.03 +/- 0.02 ml s/g for efflux) and consistent with diffusion. Electron microscopy confirmed that liposomes were restricted entirely to the sinusoidal lumen and none were seen in the extracellular space of Disse. Liposomal doxorubicin is restricted to the sinusoidal lumen, presumably secondary to steric exclusion by fenestrations in the sinusoidal endothelium. This provides the mechanism for the longer half-life and reduced hepatic extraction of liposomal doxorubicin compared with doxorubicin. The sinusoidal endothelium and fenestrations within the sinusoidal endothelium have an important role in hepatic pharmacology and are important considerations when designing liposomal preparations.
Publisher: Informa UK Limited
Date: 1999
Publisher: Elsevier BV
Date: 04-2012
Publisher: BMJ
Date: 29-12-2016
DOI: 10.1136/BMJ.I6771
Publisher: Wiley
Date: 20-04-2016
DOI: 10.1111/ACEL.12481
Publisher: Wiley
Date: 05-06-2013
DOI: 10.1111/AJAG.12048
Abstract: To describe the prevalence and correlates of alcohol consumption and tobacco smoking among older Australian men. Self-reported alcohol and tobacco use was assessed among a random s le of community-dwelling men aged ≥70 years living in Sydney (n = 1705) from 2005 to 2007. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with alcohol and tobacco use. The prevalence of heavy/excessive drinking was 19.2%, daily drinking 33.7%, and binge drinking 14.1%. Daily drinking was associated with chronic pain (OR = 1.38, 95% CI: 1.07-1.78). Binge drinking was associated with anxiety (OR = 1.93, 95% CI: 1.05-3.54) and being widowed (OR = 1.74, 95% CI: 1.11-2.73). Six per cent of men were current smokers and 56.7% were former smokers. Former smoking was associated with polypharmacy (OR = 1.47, 95% CI: 1.14-1.91) and each additional comorbid condition (OR = 1.11, 95% CI: 1.03-1.19). Nearly one-fifth of older men drank heavily or excessively. This highlights the need for public health initiatives to reduce alcohol consumption in older people.
Publisher: Wiley
Date: 31-07-2012
DOI: 10.1111/J.1472-8206.2012.01063.X
Abstract: The aim of this cross-sectional study was to investigate the association between sedative load and functional outcomes in community-dwelling older Australian men. A total of 1696 males aged ≥ 70 years, enrolled in the Concord Health and Ageing in Men Project, were studied. Participants underwent assessments during 2005-2007. Sedative load was computed using a published model. Outcomes included activities of daily living (ADL), instrumental activities of daily living (IADL), physical performance measures and a clinical diagnosis of cognitive impairment. Of the participants, 15.3% took medications with sedative properties. After adjusting for age, education, depressive symptoms and comorbidities, participants who took one medication with sedation as a prominent side effect (sedative load = 1) had odds ratio (OR) of 2.15 (95% confidence interval, CI: 1.20-3.85) for ADL disability, compared with participants with sedative load = 0. Participants who took at least one primary sedative or two medications with sedation as a prominent side effect (sedative load ≥ 2) had an OR of 1.55 (95% CI: 1.02-2.35) for IADL disability, compared with participants with sedative load = 0. The mean 6-m walking speed (P = 0.001) and grip strength (P = 0.003) were significantly different between sedative load groups in unadjusted models only. No association between sedative load and poorer performance on balance and chair stands tests or cognitive impairment was observed. Participants with sedative load of one were more likely to report ADL disability, whereas participants with sedative load of ≥2 were more likely to report IADL disability. Higher sedative load was not associated with poorer physical performance or cognitive impairment in older Australian men.
Publisher: Wiley
Date: 06-2005
Publisher: Oxford University Press (OUP)
Date: 04-02-2021
Abstract: Socioeconomic status (SES) has been suggested as a risk factor for falls but the few prospective studies to test this have had mixed results. We evaluated the prospective association between SES and falls in the Concord Health and Ageing in Men Project (CHAMP). CHAMP is a population-based prospective cohort study of men aged ≥70 years in Sydney, Australia. Incident falls were ascertained by triannual telephone calls for up to 4 years. SES was assessed with 4 indicators (education, occupation, source of income, home ownership) and cumulative SES score. We tested for interaction between SES indicators and country of birth and conducted stratified analyses. We evaluated 1624 men (mean age: 77.3 ± 5.4 years). During a mean ± SD follow-up of 42.6 ± 8.7 months, 766 (47%) participants reported ≥1 incident falls. In nonstratified analyses, there were no associations between SES indicators and falls. In stratified analyses, falls rates were higher among Australian-born men with less formal education (incidence rate ratio [IRR] 1.66, 95% confidence interval [CI] 1.16–2.37, compared with those with more education) and those with low occupational position (1.45 1.09–1.93). However, among men born in non-main English-speaking countries the rate of falls was lower among those with low educational level and no associations were evident for occupational position. Lower educational level and occupational position predicted a higher falls rate in Australian-born men the opposite relationship was evident for educational level among migrants born in non-main English-speaking countries. Further studies should test these relationships in different populations and settings and evaluate targeted interventions.
Publisher: Oxford University Press (OUP)
Date: 28-04-2016
Publisher: S. Karger AG
Date: 1999
DOI: 10.1159/000008012
Abstract: The deletion allele (D allele) polymorphism in the angiotensin converting enzyme (ACE) gene is associated with increased levels of the neuropeptide substance P in the basal ganglia and substantia nigra. A reduction of substance P levels in the brain occurs in Parkinson’s disease (PD) and has been implicated in the pathogenesis of the disease. We investigated the hypothesis that the D allele may be protective towards PD by examining the frequency of the ACE (I/D) polymorphism in 178 PD cases (male:female ratio = 1.4) and 192 controls (male:female ratio = 1.5). ACE (I/D) genotype was determined using polymerase chain reaction and 3% agarose gel electrophoresis. Unadjusted chi-square analysis revealed no significant difference between genotype frequencies (χ sup /sup = 3.30, p 0.10) or allele frequencies (χ sup /sup = 2.52, p 0.10) between patient and control groups, although PD patients were less likely to be homozygous (OR = 0.80, 95% CI = 0.49–1.29) or heterozygous (OR = 0.80, 95% CI = 0.59–1.06) for the D allele. A stepwise logistic regression analysis of the ACE deletion and risk factor data confirmed that there was no significant association between the ACE deletion (D allele) polymorphism and PD (OR = 0.62, 95% CI = 0.35–1.10, p = 0.10). This study does not support the hypothesis that the D allele of the ACE gene confers a protective effect with respect to PD.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JAMDA.2015.02.006
Abstract: Sarcopenia is associated with an increased risk of adverse outcomes. The aim of this study was to explore the relationship between severity of sarcopenia and incident activities of daily living (ADL) disability, institutionalization, and all-cause mortality among community-dwelling older men participating in the Concord Health and Ageing in Men Project (CHAMP). Longitudinal analysis of 1705 participants aged 70 years or older at baseline (2005-2007) living in the community in Sydney, Australia. The main outcome measures were incident ADL disability, institutionalization, and mortality. Of the 1705 participants who completed the baseline assessments, a total of 1678 men (mean age 77 years) had complete measures by dual-energy x-ray absorptiometry, to assess sarcopenia in terms of low appendicular lean mass (ALM), using the Foundation for the National Institutes of Health (FNIH) criteria. To differentiate between severity of sarcopenia we used low ALM alone (sarcopenia I), low ALM with weakness (sarcopenia II), and sarcopenia with weakness and poor gait speed (sarcopenia III). Cox proportional hazard models and logistic regression models were used to assess the risk of mortality and institutionalization, and incidence of ADL disability. From baseline to follow-up, 103 (11.3%) men had incident ADL disability, 191 (11.2%) men were institutionalized, and 535 (31.9%) had died. At baseline, 14.2% had sarcopenia I, 5.3% had sarcopenia II, and 3.7% had sarcopenia III. Fully adjusted analysis (adjusted for demographics, lifestyle factors, comorbidities and health conditions, and blood measures) showed that sarcopenia I, II, and III were associated with increased risk of disability, institutionalization, and mortality. Associations between sarcopenia I, II, and III and risk of incident disability were as follows: odds ratio (OR) 2.77 95% confidence interval (CI) 1.30-5.87, OR 3.78 95% CI 1.23-11.64, and OR 4.53 95% CI 0.90-22.72 associations with institutionalization were hazard ratio (HR) 1.96 95% CI 1.14-3.35, HR 2.53 95% CI 1.31-4.90, and HR 2.27 95% CI 1.08-4.80 and with mortality were HR 1.65 95% CI 1.30-2.09, HR 1.50 95% CI 1.08-2.08, and HR 1.69 95% CI 1.17-2.44. This study shows that, in community-dwelling older men, sarcopenia defined by the FNIH criteria is associated with increased risk of incident disability, institutionalization, and mortality.
Publisher: Wiley
Date: 2008
DOI: 10.1002/AR.20661
Abstract: 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.
Publisher: Oxford University Press (OUP)
Date: 24-05-2010
Publisher: Springer Science and Business Media LLC
Date: 18-02-2009
DOI: 10.1038/CLPT.2009.1
Publisher: Oxford University Press (OUP)
Date: 09-03-2020
Abstract: Polypharmacy (use of ≥5 medications) and increasing Drug Burden Index (DBI) score (measure of person’s total exposure to anticholinergic/sedative medications) are associated with impaired physical function in observational studies of older adults. Deprescribing, the supervised withdrawal of medications for which harms outweigh benefits for an in idual, may be a useful intervention. Current knowledge is limited to clinical observational studies that are unable to determine causality. Here, we establish a preclinical model that investigates the effects of chronic polypharmacy, increasing DBI, and deprescribing on global health outcomes in aging. In a longitudinal study, middle-aged (12 months) male C57BL/6J (B6) mice were administered control feed or feed and/or water containing polypharmacy or monotherapy with different DBI scores. At 21 months, each treatment group was sub ided (stratified by frailty at 21 months) to either continue on treatment for life or to have treatment withdrawn (deprescribed). Frailty and physical function were evaluated at 12, 15, 18, and 24 months, and were analyzed using a mixed modeling approach. Polypharmacy with increasing DBI and monotherapy with citalopram caused mice to become frailer, less mobile, and impaired their strength and functional activities. Critically, deprescribing in old age reversed a number of these outcomes. This is the first preclinical study to demonstrate that chronic polypharmacy with increasing DBI augments frailty and impairs function in old age, and that drug withdrawal in old age reversed these outcomes. It was not the number of drugs (polypharmacy) but the type and dose of drugs (DBI) that caused adverse geriatric outcomes.
Publisher: Elsevier BV
Date: 2004
DOI: 10.1016/J.EXGER.2003.09.016
Abstract: Apolipoprotein E (apoE) is involved in hepatic disposition of chylomicron remnants, which is impaired in old age. Isoforms of apoE have been implicated in age-related diseases and possibly the aging process itself. Because the effects of old age on expression and distribution of apoE in the liver have not been reported, we studied the effect of old age on the immunohistochemistry of apoE in the livers of humans and the non-human primate, Papio hamadryas. Overall, old age was not associated with marked changes in the expression of apoE between adult (48+/-19 years) and old (82+/-5 years) humans. However, there was a change in the distribution of apoE staining. The livers of older humans displayed increased hepatocyte cytoplasmic staining and reduced peri-sinusoidal staining. Similar trends were noted in the livers from the baboons. Such findings are suggestive of altered apoE recycling in old age and have implications for age-related dyslipidaemia.
Publisher: Wiley
Date: 19-07-2017
DOI: 10.1111/GER.12282
Abstract: To describe an oral health care programme for older people in Residential Aged Care Facilities (RACFs) to improve access to care and support facilities. Different models of residential care have been proposed, but few have been comprehensive (providing on-site health promotion and service delivery) or sustainable. A partnership model of oral health care, with dental services plus oral health education, was integrated into the community outreach services of a metropolitan hospital department of aged care. The programme provided annual oral health education and training to staff, and on-site dental care to 10 (RACFs). None of the RACFs had received organised education or on-site dental service care prior to the programme. At the completion of the third year of the programme, 607 residents (75% of the total bed capacity for the 10 RACFs) had received an annual oral health assessment, and 271 (46.5%) had received on-site dental care. More than 120 nursing and allied health staff had received education and training in oral health support to residents. Oral cleanliness, the proportion not experiencing dental pain and referral for additional care decreased significantly over the period, but dental caries experience and periodontal conditions remained a concern. Sustainable domiciliary oral health services and oral health education are feasible and practical using a partnership model within the Australian health system. Adaptability, continuity and the use of oral health therapists/dental hygienists in the coordination and management of the programme further contribute to viability.
Publisher: Elsevier BV
Date: 10-1999
Publisher: Wiley
Date: 14-02-2008
DOI: 10.1111/J.1741-6612.2007.00271.X
Abstract: 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.
Publisher: Wiley
Date: 2011
DOI: 10.1016/J.EJPAIN.2010.05.009
Abstract: Back pain is common in older people and is associated with functional disability and poor self-rated health. Older persons are under-represented in back pain research, and research on back pain in older persons from ethnic minorities is particularly sparse. We investigated differences in back pain characteristics, effects and medication use in a population-based s le 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.
Publisher: Springer Science and Business Media LLC
Date: 2008
DOI: 10.2165/0002512-200825120-00004
Abstract: 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 >or=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.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1093/JN/NXY146
Publisher: Wiley
Date: 08-1998
DOI: 10.1046/J.1365-2141.1998.00822.X
Abstract: The role of the MDR1 and MRP genes in drug resistance in patients with chronic lymphocytic leukaemia (CLL)/non-Hodgkin's lymphoma (NHL) is unclear. We hypothesized that any relationship between levels of expression and exposure to P-glycoprotein (P-gp) transportable drugs may become evident by using a measure of gene expression that combined the number of positive cells and the degree of positivity. 68 CLL/NHL patients were analysed using flow cytometry with MDR1 and MRP specific antibodies and were ided into subgroups, untreated (n = 31). treated with non P-gp transportable drugs (n = 26), those treated with low total doses of P-gp transportable drugs (n = 6) and patients treated with high total doses of P-gp transportable drugs (n = 5). The group exposed to high doses of P-gp transportable drugs had higher levels of MDR1 expression when compared to all other groups (P<0.05, ANOVA). A positive correlation between the level of MDR1 expression and the cumulative dose of P-gp transportable drugs was demonstrated (P=0.02). MRP expression was higher in those patients exposed to high doses of P-gp transportable drugs when compared to all other groups (P<0.05. ANOVA), although only a trend towards a linear dose correlation effect could be established (P=0.08). We concluded that MDR1 and MRP are involved in drug resistance but only in patients treated with P-gp transportable drugs.
Publisher: Oxford University Press (OUP)
Date: 23-08-2013
Publisher: Oxford University Press (OUP)
Date: 08-2009
Abstract: 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.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JAMDA.2015.02.014
Abstract: Anemia and frailty are both common in older people and are associated with adverse health outcomes. There have been some cross-sectional studies of anemia and frailty but no longitudinal studies. The objectives of this study were to examine cross-sectional and longitudinal associations between anemia and frailty in older Australian men. A total of 1666 men aged 70 years and older from the Concord Health and Aging in Men Project were assessed at baseline (2005-2007), 1314 men came for the 2-year follow-up between 2007 and 2009, and of those, 917 men returned for the 5-year follow-up between 2012 and 2013. The main outcome measurement was frailty, assessed using the Cardiovascular Health Study method. Anemia was defined as a hemoglobin levels <13.0 g/dL. Covariates included age, income, body mass index, measures of health, estimated glomerular filtration rate, and inflammatory markers (white cell count and albumin). The prevalence of anemia was 14.6% at baseline, 16.2% at 2-year follow-up, and 19.4% at 5-year follow-up. Prevalence of frailty was 9.1% at baseline and 9.7 % at both 2- and 5-year follow-up. Among men aged 70-74 at baseline, prevalence of frailty was 4.5%, but at 5-year follow-up the prevalence was 9.0%. There were significant cross-sectional associations between anemia and frailty in unadjusted [odds ratio, [OR 5.03 (95% confidence interval, CI 3.50, 7.25, P < .0001)] and in fully adjusted analysis [OR 2.90 (95% CI 1.87, 4.51, P < .0001)]. Generalized estimating equations time-lag models were used to examine the longitudinal associations between repeated measurements of hemoglobin and frailty. There were significant associations between measurements of anemia and frailty in unadjusted [OR 2.51 (95% CI 1.58, 4.00, P < .0001] and in fully adjusted analysis (OR 1.80, 95% CI 1.14, 2.85, P = .01). Anemia was associated with frailty in both cross-sectional and longitudinal analyses, and anemia precedes frailty in men who were nonfrail at baseline. Low hemoglobin levels among patients may alert clinicians to the increased risk of frailty.
Publisher: Oxford University Press (OUP)
Date: 02-07-2011
Abstract: 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. this study analysed data from 335 Italian-born and 848 Australian-born men aged 70 years and over participating in the Concord Health and Ageing in Men Project (CHAMP). Prospective falls data were collected by 4 monthly phone calls (mean follow-up time: 26.7 months). Negative binomial regression compared falls incidence rate ratios (IRR) between the two groups of men. there were 37 (11%) Italian-born men and 185 (22%) Australian-born men who had two or more falls during follow-up (P < 0.001). Negative binomial analysis demonstrated that Italian-born men had half the incidence rate of falls compared with Australian-born men (IRR = 0.51, 95% CI = 0.38-0.67). After adjustment for falls risk factors, Italian-born men remained significantly less likely to fall with a 43% lower fall rate (IRR = 0.57, 95% CI = 0.39-0.85). older male Italian-born immigrants are less likely to fall than their Australian-born counterparts. Differences in fall rates between the two groups are not explained by established falls risk factors.
Publisher: Oxford University Press (OUP)
Date: 31-03-2020
Publisher: BMJ
Date: 03-2001
Publisher: Elsevier BV
Date: 06-2003
Publisher: BMJ
Date: 09-09-2013
DOI: 10.1136/BMJ.F5125
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S1353-8020(00)00018-3
Abstract: This study determined the frequencies of a G-to-A transition (S/N167) polymorphism in exon 4 of the parkin gene in Australian Parkinson's disease patients and control subjects. The genotype of each subject was determined using the polymerase chain reaction and restriction-fragment-length-polymorphism analysis. Overall, the A allele was significantly less common in the Parkinson's disease group (1.7%) compared with the control group (3.8%, OR=0.43, 95% CI=0.19-1.00, P<0.05), although the frequency in the young onset Parkinson's disease group (6.6%) was not significantly different to controls. The A allele is less common in Australian Caucasian subjects compared to Japanese Parkinson's disease patients and appears to be under-represented in older-onset Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2007
DOI: 10.1007/S00125-007-0739-4
Abstract: 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. Surgical liver biopsies for electron microscopy and immunohistochemistry were obtained from baboons with long-standing streptozotocin-induced, insulin-treated diabetes mellitus and compared with those from age-matched control animals. There was an increase in the thickness of LSECs (170 +/- 17 vs 123 +/- 10 nm, p < 0.01). Fenestrations in LSECs, as determined by overall porosity, were markedly reduced (1.4 +/- 0.1% vs 2.6 +/- 0.2%, p < 0.01). Increased numbers of stellate cells were seen on electron microscopy, and this finding was corroborated by increased smooth muscle actin expression. Diabetes mellitus was also associated with increased endothelial production of von Willebrand factor and caveolin-1. Diabetes mellitus in the non-human primate is associated with marked changes in LSECs, including a reduction in fenestrations. Such changes provide an additional and novel mechanism for impaired hepatic lipoprotein clearance and post-prandial hyperlipidaemia in diabetes mellitus.
Publisher: Wiley
Date: 12-2001
DOI: 10.1034/J.1600-0773.2001.D01-165.X
Abstract: Ageing and liver disease are associated with ultrastructural changes in the hepatic sinusoid. Because of the possibility that reactive oxygen species could mediate these processes, we examined the effect of acute oxidative stress on the ultrastructure of the intact liver. Rat livers were perfused ex vivo, in situ with hydrogen peroxide via the portal vein. The livers were then fixed and the ultrastructure of the liver tissue examined with transmission and scanning electron microscopy. The effects of hydrogen peroxide were largely confined to the perisinusoidal areas. The sinusoidal endothelial cells became swollen and more porous, with large gaps replacing sieve plates. The space of Disse showed an increase in volume and the density of hepatocyte projections decreased. Kupffer cell activation was noted. Little or no ultrastructural change was observed within the hepatocytes. Oxidative stress delivered via the portal vein dramatically alters the ultrastructure of the perisinusoidal regions of the liver. This process may contribute to the pathogenesis of disease and age-related changes in the liver.
Publisher: Informa UK Limited
Date: 1999
Abstract: The management and toxicokinetics of hydroxychloroquine overdose are poorly described. We report a case of an 18-year-old girl who ingested 20 g of hydroxychloroquine. She developed marked hypokalemia, hypotension, and ventricular tachyarrhythmias but survived with treatment including intubation, adrenaline infusion, high-dose diazepam, and aggressive potassium replacement. Plasma hydroxychloroquine level was 29.40 mumol/L (9.87 mg/L) 2 hours after ingestion and the elimination half-life of hydroxychloroquine was 22 hours. The clinical manifestations of this hydroxychloroquine overdose were similar to those reported for chloroquine overdose and the management principles recommended for chloroquine overdose appeared to be efficacious in this case.
Publisher: Wiley
Date: 25-11-2009
DOI: 10.1111/J.1440-1681.2009.05306.X
Abstract: 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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2012
Publisher: Elsevier BV
Date: 03-2014
Publisher: Oxford University Press (OUP)
Date: 14-03-2017
Publisher: Elsevier BV
Date: 04-2007
Publisher: Oxford University Press (OUP)
Date: 25-10-2010
Abstract: Werner syndrome 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 features of Werner syndrome, including a pro-oxidant status and a shorter mean life span. Here, we show that resveratrol supplementation improved the hyperglycemia and the insulin resistance phenotype in these Wrn mutant mice. In addition, resveratrol reversed liver steatosis, lipid peroxidaton, and the defenestration phenotypes observed in such mice. Resveratrol, however, did not improve the hypertriglyceridemia, inflammatory stress, nor extend the mean life span of these mutant mice. Microarray and biologic pathway enrichment analyses on liver tissues revealed that resveratrol mainly decreased lipidogenesis and increased genes involved in the insulin signaling pathway and the glutathione metabolism in Wrn mutant mice. Finally, resveratrol-treated mutant mice exhibited an increase in the frequency of lymphoma and of several solid tumors. These results indicate that resveratrol supplementation might exert at least metabolic benefits for Werner syndrome patients.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2010
DOI: 10.1007/S00198-010-1332-0
Abstract: 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. Previous studies reported conflicting results regarding the relationship between SES and bone health, specifically in men. The main objective of this study was to investigate associations of SES with bone health in community-dwelling men aged 70 years or over who participated in the baseline phase of the CHAMP Study in Sydney, Australia. The Australian Socioeconomic Index 2006 (AUSEI06) based on the Australian and New Zealand Standard Classification of Occupations was used to determine SES in 1,705 men. Bone mineral density and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry. Bone-related biochemical and hormonal parameters, including markers of bone turnover, parathyroid hormone, and vitamin D, were measured in all men. General linear models adjusted for age, weight, height, and bone area revealed no significant differences across crude AUSEI06 score quintiles for BMC at any skeletal site or for any of the bone-related biochemical measures. However, multivariate regression models revealed that in Australian-born men, marital status was a predictor of higher lumbar BMC (β = 0.07, p = 0.002), higher total body BMC (β = 0.05, p = 0.03), and lower urinary NTX-I levels (β=-0.08, p = 0.03), while living alone was associated with lower BMC at the lumbar spine (β=-0.05, p = 0.04) and higher urinary NTX-I levels (β=0.07, p = 0.04). Marital status was also a predictor of higher total body BMC (β = 0.14, p = 0.003) in immigrants from Eastern and South Eastern Europe. However, in immigrants from Southern Europe, living alone and acculturation were predictors of higher femoral neck BMC (β = 0.11, p = 0.03) and lumbar spine BMC (β = 0.10, p = 0.008), respectively. Although crude occupation-based SES scores were not significantly associated with bone health in older Australian men, specific sub-characteristics of SES, namely, marital status, living circumstances, and acculturation, were predictors of bone health in both Australia-born men and European immigrants.
Publisher: Oxford University Press (OUP)
Date: 15-02-2022
Abstract: There are no established or standardized definitions of aging-related disease. Data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to model the relationship between age and incidence of diseases. Clustering analysis identified 4 groups of noncommunicable diseases: Group A diseases with an exponential increase in incidence with age Group B diseases with an exponential increase in incidence that usually peaked in late life which then declined or plateaued at the oldest ages and Groups C and D diseases with an onset in earlier life and where incidence was stable or decreased in old age. From an epidemiological perspective, Group A diseases are “aging-related diseases” because there is an exponential association between age and incidence, and the slope of the incidence curves remains positive throughout old age. These included the major noncommunicable diseases dementia, stroke, and ischemic heart disease. Whether any of the other diseases are aging-related is uncertain because their incidence either does not change or more often decreases in old age. Only biological studies can determine how the aging process contributes to any of these diseases and this may lead to a reclassification of disease on the basis of whether they are directly caused by or are in continuity with the biological changes of aging. In the absence of this mechanistic data, we propose the term “aging-related disease” should be used with precision based on epidemiological evidence.
Publisher: Oxford University Press (OUP)
Date: 17-04-2020
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.3109/00313021003636469
Abstract: 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. Scanning electron microscopy was used to investigate fenestrations in livers from fasted and fed rats. 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). 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.
Publisher: Oxford University Press (OUP)
Date: 26-05-2017
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/JC.2014-1124
Abstract: The relationship between functional disability and reproductive hormones and whether it is mediated by muscle mass and strength in older men are unclear. The objective of the study was to identify the relationships between hormones and change in functional disability over a 2-year follow-up and to examine whether muscle mass and strength explain any of the observed relationships. A total of 1318 men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at both baseline and 2-year follow-up. T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. Functional disability was measured by basic Activities of Daily Living scale at both time points. Grip and quadricep strength were measured using dynamometers and lean (muscle) mass was determined by dual X-ray absorptiometry. All hormones were significantly associated with functional decline in univariate analyses. Only T, E2, E1, and calculated free T remained associated in multivariate analyses. Men in the lowest T quartile (vs the highest quartile) had an increased risk functional decline (odds ratio 1.96, 95% confidence interval 1.01-3.82). Similar associations were observed in E2, E1, and calculated free T. When muscle variables were added into the multivariate model, the associations between these hormones and functional decline were no longer statistically significant. Low T, E2, and E1 were significantly associated with prospective functional decline over 2 years. This relationship was no longer significant when muscle mass or strength were added, suggesting that the hormonal associations are mediated through their sequential effect on muscle mass and strength.
Publisher: Public Library of Science (PLoS)
Date: 12-08-2016
Publisher: Oxford University Press (OUP)
Date: 18-03-2016
Abstract: The objective of this study is to examine associations between Hb levels and sarcopenia, low muscle strength, functional measures, and activities of daily living (ADL) and instrumental ADL (IADL) disabilities in older Australian men. Men aged 70 years and older (2005-2007) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 years (n = 1,367), and 5 years (n = 958). The main outcome measurements were walking speed, muscle strength, ADL and IADL disabilities, and sarcopenia using the Foundation for the National Institutes of Health criteria (low appendicular lean mass adjusted for body mass index < 0.789 and poor grip strength < 26kg). Analysis was performed using Hb levels as a continuous measure, unadjusted and adjusted by age, income, body mass index, measures of health, estimated glomerular function, inflammatory markers, and medication use. Receiver operating characteristic curve analysis was performed to determine a threshold of Hb for each outcome. In cross-sectional and longitudinal analysis, for every 1g/dL increase in Hb, there was a significant reduction in risk of sarcopenia, slow walking speed, poor grip strength, inability to perform chair stands, and ADL and IADL disabilities in unadjusted, age-adjusted, and multivariate-adjusted analysis. The highest value of the Youden Index for Hb was 14.2g/dL for sarcopenia and grip strength, 14.5g/dL for walking speed, and 14.4g/dL for all other outcomes. Declines in Hb levels over time are associated with poor functional outcomes. The risks and benefits of interventions to increase Hb among older men warrant further investigation to differentiate whether this is an active contributor to age-related debility or a passive biomarker of it.
Publisher: Elsevier BV
Date: 08-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1016/J.JURO.2016.06.085
Abstract: We sought to determine which lower urinary tract symptoms are associated with incident falls in community dwelling older men. The Concord Health and Ageing in Men Project involves a representative s le of community dwelling men 70 years old or older in a defined geographic region in Sydney, New South Wales, Australia. Included in analysis were 1,090 men without neurological diseases, poor mobility or dementia at baseline. Lower urinary tract symptoms were assessed using I-PSS (International Prostate Symptom Score) and incontinence was assessed using ICIQ (International Consultation on Incontinence Questionnaire) at baseline. I-PSS subscores were calculated for storage and voiding symptoms. Incident falls in 1 year were determined by telephone followup every 4 months. I-PSS storage and voiding subscores were associated with falls. Urgency incontinence was associated with falls (adjusted incidence rate ratio 2.57, 95% CI 1.54-4.30). In addition, intermediate to high I-PSS storage subscores without urgency incontinence were associated with falls (adjusted incidence rate ratio 1.72, 95% CI 1.24-2.38). Other types of incontinence and urgency alone without urgency incontinence were not associated with falls. Lower urinary tract storage and voiding symptoms were associated with falls in community dwelling older men. Of the symptoms of overactive bladder urgency incontinence carried a high risk of falls. Storage symptoms also contributed to the fall risk independently of urgency incontinence. Circumstances of falls among men with lower urinary tract symptoms should be explored to understand how lower urinary tract symptoms increase the fall risk and generate hypotheses regarding potential interventions. Furthermore, trials to treat lower urinary tract symptoms in older men should include falls as an end point.
Publisher: Wiley
Date: 04-2002
DOI: 10.1034/J.1600-0773.2002.900406.X
Abstract: Idiopathic Parkinson's disease may be caused by environmental neurotoxins such as pesticides, however the major risk factor is old age. We postulated that the high incidence of Parkinson's disease in older people is secondary to age-related impairment of the hepatic detoxification of xenobiotics. Previously, we have shown that there are significant differences between the hepatic disposition of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and pesticides. Here, we investigated whether there are age-related differences in the hepatic disposition of MPTP and pesticides, putatively associated with the pathogenesis of Parkinson's disease. We measured the hepatic disposition of paraquat, dichlorodiphenyltrichloroethane (DDT), malathion and MPTP using the multiple indicator dilution technique in the perfused livers of Fischer F344 rats aged 3 and 18 months. The recoveries of MPTP, DDT and malathion were increased from the livers of the older rats (by 258%, 253% and 134% compared with young rats, respectively). The hepatic transport of DDT and malathion into hepatocytes was reduced with age suggesting that part of the impaired uptake of neurotoxins may be secondary to an age-related barrier to influx. Ageing may increase risk of Parkinson's disease by altering hepatic detoxification and increasing systemic bioavailability of neurotoxins.
Publisher: Elsevier BV
Date: 12-1997
DOI: 10.1016/S0022-510X(97)00179-2
Abstract: We performed a case-control study to investigate the association of the poor metaboliser genotype of the cytochrome P450 2D6 gene with Parkinson's disease (PD). Genotyping was determined by the polymerase chain reaction followed by digestion with restriction enzymes. The poor metaboliser genotype was more frequent in 112 patients with PD than in 206 matched controls (odds ratio 1.7, 95% CI: 0.94-2.45). A meta-analysis of these results together with ten other published studies gave a pooled odds ratio for the poor metaboliser genotype of 1.47 (95% CI: 1.18-1.96, P=0.01). Thus, the poor metaboliser genotype has a small but highly significant association with PD which would be easily missed in small studies. Research now should focus on the mechanism of this association.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1093/JN/NXZ256
Abstract: The relations between diet, chronic inflammation, and musculoskeletal health are unclear, especially among older men. This study aimed to determine associations of the Dietary Inflammatory Index (DII) with inflammatory biomarkers, musculoskeletal health, and falls risk in community-dwelling older men. The cross-sectional analysis included 794 community-dwelling men, mean age 81.1 ± 4.5 y, who participated in the 5-y follow-up of the Concord Health and Aging in Men Project. Of these, 616 were seen again 3 y later for the longitudinal analysis. Energy-adjusted DII (E-DII) was calculated from a validated diet history questionnaire. Bone mineral density (BMD) was measured using DXA. Twenty-four inflammatory biomarkers were analyzed. Incident falls over 3 y were determined through telephone interviews every 4 mo. Multiple regression, linear mixed effects models, negative binomial regression, and mediation analysis were utilized in this study. A higher E-DII score (indicating a more proinflammatory diet) was associated with higher concentrations of IL-6 (β: 0.028 pg/mL 95% CI: 0.003, 0.053), IL-7 (β: 0.020 pg/mL 95% CI: 0.002, 0.037), and TNF-α (β: 0.027 pg/mL 95% CI: 0.003, 0.051). A higher E-DII score was also associated with lower appendicular lean mass adjusted for BMI (ALMBMI) (β: -0.006 kg/m2 95% CI: -0.010, -0.001). For every unit increase in E-DII (range: -4.91 to +3.66 units), incident falls rates increased by 13% (incidence rate ratio: 1.13 95% CI: 1.05, 1.21) over 3 y. Mediation analysis showed that the association between E-DII and 3-y incident falls was influenced by the concentrations of IL-7 by 24%. There was no association between E-DII and BMD. Consumption of a proinflammatory diet was associated with increased concentrations of IL-6, IL-7, and TNF-α increased falls risk and lower ALMBMI in community-dwelling older men. The association between incident falls and E-DII was partly mediated by concentrations of IL-7.
Publisher: American Society of Hematology
Date: 15-04-2003
Publisher: BMJ
Date: 11-2000
Abstract: A patient with multiple sclerosis is described who was treated for neurological symptoms thought to be a progression of his disease but subsequently found to be caused by lead poisoning secondary to the use of alternative medicine. His clinical signs improved with oral chelation therapy. Neurologists should consider asking about the use of complementary and alternative medicine before simply attributing symptoms and signs to exacerbation of multiple sclerosis.
Publisher: Wiley
Date: 07-2009
Publisher: American Physiological Society
Date: 07-2008
Abstract: 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.
Publisher: Oxford University Press (OUP)
Date: 27-02-2021
Abstract: Type 2 diabetes mellitus (T2DM) increases falls and fracture risk. Our objective was to compare incidence and risk factors for falls and fractures in community-dwelling older men with and without T2DM. A total of 1705 men (471 with T2DM 1234 without T2DM) aged ≥70 years were assessed at baseline. Men were contacted every 4 months for 6.0 ± 2.2 years to ascertain incident falls and fractures, with the latter being confirmed by radiographic reports. Hip fractures were ascertained via data linkage (follow-up: 8.8 ± 3.6 years). Risk factors for falls and fractures included physical activity and function, body composition, medications, and vision measures. Men with T2DM had similar fall (incident rate ratio [IRR]: 0.92 [95% confidence interval {CI}: 0.70, 1.12], n = 1246) and fracture rates (hazard ratio [HR]: 0.86 [95% CI: 0.56, 1.32], n = 1326) compared to men without T2DM after adjustment for significant risk factors. In men with T2DM, depression (IRR: 1.87 [95% CI: 1.05, 3.34], n = 333), sulphonylurea usage (IRR: 2.07 [95% CI: 1.30, 3.27]) and a greater number of prescription medications (IRR: 1.13 [95% CI: 1.03, 1.24]) were independently associated with increased fall rates, and higher total hip bone mineral density was independently associated with lower fracture rates (HR: 0.63 [95% CI: 0.47, 0.86], n = 351). Interaction terms demonstrated that better contrast sensitivity was independently associated with lower fracture rates (HR: 0.14 [95% CI: 0.02, 0.87]) in men with T2DM compared to men without T2DM. Fall and fracture rates were similar in men with and without T2DM after adjusting for significant risk factors. Vision assessments including contrast sensitivity measures may improve fracture prediction in older men with T2DM.
Publisher: Wiley
Date: 2010
Publisher: Wiley
Date: 07-02-2007
Publisher: S. Karger AG
Date: 2001
DOI: 10.1159/000052148
Publisher: Public Library of Science (PLoS)
Date: 24-09-2012
Publisher: SAGE Publications
Date: 12-2001
DOI: 10.1345/APH.1A110
Abstract: To report a case of intracerebral hemorrhage following short-term, concomitant use of celecoxib and clopidogrel. An 86-year-old white woman with a medical history of paroxysmal atrial fibrillation, heart failure, osteoarthritis, peptic ulcer disease, chronic airway limitation, and surgery for carcinoma of the bowel and breast began clopidogrel therapy following a syncopal episode. She also began taking celecoxib for osteoarthritis at the same time. Three weeks later, she presented with headaches and left hemiparesis. Computed tomography scan revealed intracerebral hemorrhage that had not been previously detected. Celecoxib and clopidogrel were discontinued, and she recovered fully. This is the first case describing a possible interaction between celecoxib and clopidogrel. A pharmacokinetic interaction mediated by CYP2C9 is possible. However, the hemorrhage may have been secondary to the effects of either drug alone or concomitant disease. Celecoxib and clopidogrel have favorable risk profiles and, therefore, are prescribed widely among older people. However, clinicians should recognize that there may be an interaction between celecoxib and clopidogrel that increases the risk of hemorrhage in older people.
Publisher: Wiley
Date: 09-1997
Abstract: The presynaptic dopamine transporter in nigral dopaminergic neurons confers susceptibility to the cytotoxic effects of the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Polymorphisms in the dopamine transporter might influence the susceptibility to such toxins. Therefore, we investigated whether a polymorphic region in the 3'-untranslated region of the dopamine-transporter gene is associated with idiopathic Parkinson's disease (PD). The frequency distribution of the alleles was significantly different between the patients (n = 100) and controls (n = 200, p < 0.05). The rare 11-copy allele was more common in the patients (odds ratio = 10.2, 95% confidence interval - 1.2-87.9, p < 0.025). The susceptibility of some people to PD may be conferred by polymorphisms in the dopamine-transporter gene that could lead to increased cellular accumulation of neurotoxic compounds in dopaminergic neurons.
No related grants have been discovered for David Le Couteur.