Haem Iron Intake Is Associated with Increased Major Adverse Cardiovascular Events, All-Cause Mortality, Congestive Cardiac Failure, and Coronary Revascularisation in Older Men: The Concord Health and Ageing in Men Project.

BACKGROUND: Nutritional intake can influence major adverse cardiovascular events (MACE). Dietary iron is found in two forms: haem-iron (HI) only found in animal sources and non-haem iron (NHI) present mostly in plant sources. OBJECTIVE: We evaluated the associations between dietary iron intakes with MACE and iron status biomarkers. DESIGN: Prospective cohort study. SETTING: The Concord Health and Ageing in Men Project, Sydney, Australia. PARTICIPANTS: 539 community-dwelling older Australian men aged 75 years and older. METHODS: Men underwent nutritional assessment using a validated diet history questionnaire. Entries were converted to food groups and nutrients. The dietary calculation was used to derive HI and NHI intakes from total iron intakes. Analyses of iron intakes with iron status biomarkers were conducted using linear regression, and with MACE and individual endpoints were conducted using Cox regression. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality. RESULTS: At a median of 5.3 (4.6 - 6.3) years follow-up, the incidences were: 31.2% (n = 168) five-point MACE, 17.8% (n = 96) four-point MACE excluding all-cause mortality, 20.1% (n = 111) all-cause mortality, 11.3% (n = 61) CCF, and 3.1% (n = 15) coronary revascularisation. In adjusted analyses, higher HI intake (per 1mg increment) was associated with increased five-point MACE (HR: 1.45 [95% CI: 1.16, 1.80, P = .001]), four-point MACE excluding all-cause mortality (HR: 1.64 [95% CI: 1.26, 2.15, P <.001]), all-cause mortality (HR: 1.51 [95% CI: 1.15, 1.99, P = .003]), CCF (HR: 2.08 [95% CI: 1.45, 2.98, P <.001]), and coronary revascularisation (HR: 1.89 [95% CI: 1.15, 3.10, P = .012]). Compared with the bottom tertile of NHI intake, the middle tertile of NHI intake was associated with reduced risk of all-cause mortality (HR: 0.56 [95% CI: 0.33, 0.96, P = .035]). Total iron intake was not associated with MACE and individual endpoints. Dietary iron intakes were not associated with serum iron and haemoglobin. CONCLUSION: Higher haem iron intake was independently associated with increased risks of five-point MACE, four-point MACE excluding all-cause mortality, all-cause mortality, CCF, and coronary revascularisation in older men over 5 years.

Iterative Development of Clinician Guides to Support Deprescribing Decisions and Communication for Older Patients in Hospital: A Novel Methodology.

BACKGROUND/OBJECTIVES: Medication review is an important component of the management of older hospital patients. Deprescribing (supervised withdrawal of inappropriate medicines) is one outcome of review. This study aimed to iteratively develop and test the usability of deprescribing guides, which support multidisciplinary clinicians to reduce inappropriate polypharmacy in older inpatients. METHODS: Deprescribing guides for hospital clinicians were developed using a novel mixed-methods, ten-step process. Iterative development and usability testing were applied. This included content development through review of the literature; expert consensus through five rounds of feedback using a modified Delphi approach; and usability testing by 16 multidisciplinary hospital clinicians on hypothetical clinical scenarios involving observations, semi-structured interviews, and administration of the System Usability Scale. RESULTS: This novel process was used to develop deprescribing guides that facilitate implementation of evidence on deprescribing in routine hospital care. The guides present evidence-based information in a format that aligns with workflows of multidisciplinary hospital clinicians. The guides were adapted for various clinical roles to navigate efficiently to suit differing workflow needs. Guides include unique communication support in the form of "preferred language". Clinicians can use the "preferred language" to apply the evidence to the individual patient and relay decisions between health providers and with patients/carers. The total System Usability Scale score was 80.6 ± 2.0 (mean ± standard error of the mean), indicating excellent usability. Guides have been developed using consistent format for nine medication classes that are common targets for deprescribing and are publicly available. CONCLUSION: This study demonstrates a novel approach to the development and implementation of evidence-based recommendations that support deprescribing in routine hospital care.

Circulating Sex Steroid Measurements of Men by Mass Spectrometry Are Highly Reproducible after Prolonged Frozen Storage.

Long-term studies investigating hormone-dependent cancers and reproductive health often require prolonged frozen storage of serum which assumes that the steroid molecules and measurements are stable over that time. Previous studies of reproducibility of circulating steroids have relied upon flawed historical rather than contemporaneous controls. We measured serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) in 150 randomly selected serum samples by liquid chromatography-mass spectrometry (LC-MS) from men 70 years or older (mean age 77 years) in the CHAMP study. The original measurements in 2009 were repeated 10 years later using the identical serum aliquot (having undergone 2-4 freeze-thaw cycles in the interim) in 2019 together with another never-thawed aliquot of the same serum sample. The results of all three sets of measurements were evaluated by Passing-Bablok regression and Bland-Altman difference analysis. Serum androgens (T, DHT) and estrogens (E2, E1) measured by LC-MS display excellent reproducibility when stored for 10 years at -80 C without thawing. Serum T and DHT displayed high level of reproducibility across all three sets of measurements. Multiple freeze-thaw cycles over those storage conditions do not significantly affect serum T, DHT and E1 concentrations but produce a modest increase (21%) in serum E2 measurements.

Oral health behaviours of older Australian men: the Concord Health and Ageing in Men Project.

BACKGROUND: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of older Australian men. The aim of this paper is to describe the oral health behaviours and dental service use of CHAMP participants and explore associations between oral health behaviours with and general health status. METHOD: Information collected related to socio-demographics, general health, oral health service-use and oral health behaviours. Key general health conditions were ascertained from the health questionnaire and included physical capacity and cognitive status. RESULTS: Fifty-seven percent of the men reported visiting a dental provider at least once or more a year and 56.7% did so for a "dental check-up". Of those with some natural teeth, 59.3% claimed to brush their teeth at least twice or more a day. Most men (96%) used a standard fluoride toothpaste. Few participants used dental floss, tooth picks or mouth-rinses to supplement oral hygiene. Cognitive status and self-rated general health were associated with dental visiting patterns and toothbrushing behaviour. CONCLUSIONS: Most older men in CHAMP perform favourable oral health behaviours. Smoking behaviour is associated with less favourable dental visiting patterns, and cognitive status with toothbrushing behaviour.

Suicidal emperipolesis: a process leading to cell-in-cell structures, T cell clearance and immune homeostasis.

"Suicidal emperipolesis" is one of the most recently reported processes leading to cell-in-cell structures that promote cell death. This process was discovered in studies investigating the fate of autoreactive CD8 T cells activated within the liver. Recently, we reported that activated T cells invaded hepatocytes, formed transient cell-in-cell structures, and were rapidly degraded within endosomal/lysosomal compartments by a non-apoptotic pathway. Importantly, pharmacological inhibition of this process caused intrahepatic accumulation of tissue-reactive T cells and breach of immune tolerance. The characterization of the molecular mechanisms of suicidal emperipolesis is still in its infancy, but initial studies suggest this phenomenon is distinct from other reported cell-in-cell structures. As opposed to the formation of other cell-in-cell structures, suicidal emperipolesis takes place in a non-malignant environment, and without obvious pathology. It is therefore the first cell-in-cell structure described to have a role in maintaining homeostasis in normal physiology in higher organisms. T cell emperipolesis within hepatocytes has also been observed by pathologists in a range of chronic human liver pathologies. As T cell-in-hepatocyte structures resulting from suicidal emperipolesis are very transiently observed in normal physiology, their accumulation during liver disease would suggest that severe tissue injury is promoted by, or associated with, defective T cell clearance. In this review, we compare "suicidal emperipolesis" to other processes leading to cell-in-cell structures, and consider its potential biological roles in maintaining immune homeostasis and tolerance in the context of the hepatic environment.

Physicians need to take the lead in deprescribing.

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 individuals.

Vitamin D status among older community dwelling men living in a sunny country and associations with lifestyle factors: the Concord Health and Ageing in Men Project, Sydney, Australia.

OBJECTIVES: 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. DESIGN: A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007. PARTICIPANTS: 1659 non-institutionalised men aged ≥70 years. METHODS: 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 samples using a radioimmunoassay kit (DiaSorin Inc., Stillwater, MN). Covariates included age, socioeconomic measures, season of blood sample, physical activity, sun exposure, vitamin D supplement use, cigarette smoking status, alcohol consumption, obesity and measures of health. RESULTS: 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. CONCLUSION: 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.

Predictors of the rate of BMD loss in older men: findings from the CHAMP study.

UNLABELLED: 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. INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

High-risk prescribing and incidence of frailty among older community-dwelling men.

Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ≥70 years of age. High-risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes.

AIMS/HYPOTHESIS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Carbon monoxide wash-in method to determine gas transfer in vascular beds: application to rat hindlimb.

The vascular barrier to gas transfer is an important physiological parameter; however, no readily applicable technique exists to quantitate the process. A simple technique to measure the permeability-surface area (PS) product for gas transfer in vascular beds is proposed using wash in of carbon monoxide (CO) and Crone-Renkin analysis. Wash-in experiments were performed on the perfused hindlimbs of male Wistar rats (n = 15) by using CO as a surrogate marker for oxygen and technetium-99m-labeled albumin as the vascular marker. The use of CO and erythrocyte-free perfusate and the collection of outflow samples into tubes preloaded with erythrocytes obviated the need for an anaerobic collection device or consideration of Hb binding in the analysis. The PS product for CO was determined from the early extraction as 0.013 +/- 0.006 ml. s(-1). g(-1). Compartmental analysis revealed that the fractional recovery of CO was 0.45 +/- 0.14 and the volume of distribution was 2.31 +/- 0.76 ml/g. This technique detected a small measurable barrier to the transfer of CO across the hindlimb vasculature and is potentially applicable to other vascular beds in health and disease.

Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists.

The extensive use of selective histamine H2 receptor antagonists provides a unique opportunity to describe very rare adverse drug reactions. Although mild elevation of serum creatinine level following the administration of cimetidine is relatively common, acute interstitial nephritis (AIN) is a rare hypersensitivity reaction. There have been 25 published reports of AIN associated with H2 antagonist therapy and we also identified 16 cases from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. AIN was reported most commonly following cimetidine administration. AIN was supported by renal biopsy in 28 patients and by rechallenge in 6. H2 antagonist-induced AIN was more commonly reported in men older than 50 years. In the majority of cases the onset was within 2 weeks of initiation of therapy (1 day to 11 months). The clinical manifestations were nonspecific including sterile pyuria, elevated erythrocyte sedimentation rate, fatigue, proteinuria and leucocytosis whereas rash, arthralgia and flank pain were rarely reported. There were 170 cases of hepatotoxicity following H2 antagonist administration reported to ADRAC. These were more common following ranitidine and included cholestatic, hepatocellular and mixed reactions. Hepatotoxicity was proven following liver biopsy in several cases published in the literature and in 15 cases reported to ADRAC. Hepatotoxicity recurred upon rechallenge in 6 cases. Generally, renal and hepatic adverse effects resolved quickly after cessation of H2 antagonist therapy and did not require specific treatment. Nephrotoxicity and hepatotoxicity following administration of an H2 antagonist is rare and a high index of suspicion is necessary for early detection. Now that many H2 antagonists are available over the counter, awareness of these conditions and early detection with cessation of H2 antagonist therapy would appear paramount.

Intracerebral hemorrhage following possible interaction between celecoxib and clopidogrel.

OBJECTIVE: To report a case of intracerebral hemorrhage following short-term, concomitant use of celecoxib and clopidogrel. CASE SUMMARY: 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. DISCUSSION: 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. CONCLUSIONS: 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.

Hepatic disposition of neurotoxins and pesticides.

The hepatic disposition of pesticides and neurotoxins may influence susceptibility to Parkinson's disease. Therefore we examined the behaviour of paraquat, dichlorodiphenyltrichloroethane (DDT), malathion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in perfused rat liver using the multiple indicator-dilution technique. The values for the recovery of paraquat, DDT, malathion and MPTP were 1.05+/-0.12, 0.32+/-0.01, 0.11+/-0.02 and 0.02+/-0.01, respectively. The volumes of distribution were 0.28+/-0.13, 0.69+/-0.12, 3.30+/-0.58 and 5.10+/-6.00 ml/g, respectively. The permeability-surface area products suggest that transport of DDT and MPTP across cell membranes is by simple diffusion. However, there may be a specific influx mechanism for malathion and a specific efflux mechanism for paraquat. There is considerable variability in the hepatic disposition of putative neurotoxins such as MPTP and pesticides. Factors that influence the hepatic disposition of neurotoxins may alter susceptibility to neurotoxic diseases however the effects will be diverse.

31P and 1H NMR spectroscopic studies of liver extracts of carbon tetrachloride-treated rats.

NMR spectroscopy was used to examine hepatic metabolism in cirrhosis with a particular focus on markers of functional cellular hypoxia. (31)P and (1)H NMR spectra were obtained from liver extracts from control rats and from rats with carbon tetrachloride-induced cirrhosis. A decrease of 34% in total phosphorus content was observed in cirrhotic rats, parallelling a reduction of 40% in hepatocyte mass as determined by morphometric analysis. Hypoxia appeared to be present in cirrhotic rats, as evidenced by increased inorganic phosphate levels, decreased ATP levels, decreased ATP:ADP ratios (1.72 +/- 0.40 vs 2.48 +/- 0.50, p < 0.01), and increased inorganic phosphate:ATP ratios (2.77 +/- 0.48 vs 1.62 +/- 0.24, p < 0.00001). When expressed as a percentage of the total phosphorus content, higher levels of phosphoethanolamine and lower levels of NAD and glycerophosphoethanolamine were detected in cirrhotic rats. Cirrhotic rats also had increased phosphomonoester:phosphodiester ratios (5.73 +/- 2.88 vs 2.53 +/- 0.52, p < 0.01). These findings are indicative of extensive changes in cellular metabolism in the cirrhotic liver, with many findings attributable to the presence of intracellular hypoxia.

Pesticides and Parkinson's disease.

Epidemiological studies and case reports provide evidence for an association between Parkinson's disease and past exposure to pesticides. Susceptibility to the effects of pesticides and other putative neurotoxins depends on variability in xenobiotic metabolism possibly generated by genetic polymorphisms, aging and variation in exposure to environmental agents including pesticides. The simplest mechanistic hypothesis for the association of pesticides with Parkinson's disease is that pesticides or their metabolites are directly toxic to mitochondria, although modulation of xenobiotic metabolism by pesticides provides an adjunct or alternative hypothesis.

Parkinson's disease, pesticides, and glutathione transferase polymorphisms.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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.

Hepatic intracellular pH during the prereplicative period following partial hepatectomy.

To investigate the hypothesis that the regenerating liver undergoes intracellular alkalinization during the prereplicative period, we measured intracellular pH (pHi) after partial hepatectomy in the rat. pHi was studied in livers from female Wistar rats perfused in situ with buffer containing HCO3-/CO2. The multiple indicator-dilution technique was used to determine pHi from the distribution volume of dimethyloxazolidine-2,4-dione (DMO). Perfusion conditions influenced pHi. There was a curvilinear relationship between pHi and flow rate and a linear relationship between pHi and temperature. Under equivalent perfusion conditions there were no significant differences between pHi in normal livers (7.27 +/- 0.02) and that following partial hepatectomy (7.27 +/- 0.03 at 0 h, 7.27 +/- 0.04 at 4 h, 7.28 +/- 0.03 at 8 h, and 7.31 +/- 0.02 at 24 h) or sham surgery (7.27 +/- 0.04 at 4 h, 7.33 +/- 0.08 at 24 h). Therefore intracellular alkalinization does not occur following partial hepatectomy and is unlikely to be a signal for regeneration.