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Background Experiencing loneliness can be distressing and increasing evidence indicates that being lonely is associated with poor physical and mental health outcomes. Cross-sectional studies have demonstrated that people with disability have increased risk of experiencing loneliness compared to people without disability. However, we do not know if these inequalities have changed over time. This study investigated the prevalence of loneliness for people with disability in Australia annually from 2003 to 2020 to examine whether disability-related inequalities in loneliness have changed over time, and disaggregated results for subgroups of people with disability by age group, sex, and disability group. Methods We used annual data (2003–2020) from the Household, Income and Labour Dynamics in Australia Survey. Loneliness was measured by a single question assessing the subjective experience of loneliness. For each wave, we calculated population-weighted age-standardised estimates of the proportion of people experiencing loneliness for people with and without disability. We then calculated the absolute and relative inequalities in loneliness between people with and without disability for each wave. Analyses were stratified by 10-year age groups, sex, and disability group (sensory or speech, physical, intellectual or learning, psychological, brain injury or stroke, other). Results From 2003 to 2020, the prevalence of loneliness was greater for people with disability, such that people with disability were 1.5 to 1.9 times more likely to experience loneliness than people without disability. While the prevalence of loneliness decreased for people without disability between 2003 and 2020, the prevalence of loneliness did not decrease for people with disability during this period. Inequalities in loneliness were more substantial for people with intellectual or learning disabilities, psychological disability, and brain injury or stroke. Conclusion This study confirms that people with disability have increased risk of loneliness compared to people without disability. We add to the existing evidence by demonstrating that disability-related inequalities in loneliness have persisted for two decades in Australia without improvement. Our findings indicate that addressing inequalities in loneliness for people with disability is a critical public health concern given that loneliness is associated with a wide range of poor health outcomes. [ABSTRACT FROM AUTHOR]

Objective: Cross-sectional studies have demonstrated that people with disability have substantial inequalities in mental health compared to people without disability. However, it is not known if these inequalities have changed over time. This study compared the mental health of people with and without disability annually from 2003 to 2020 to investigate time trends in disability-related mental health inequalities. Methods: We use annual data (2003–2020) of the Household, Income and Labour Dynamics in Australia Survey. Mental health was measured using the five-item Mental Health Inventory. For each wave, we calculated population-weighted age-standardised estimates of mean Mental Health Inventory scores for people with and without disability and calculated the mean difference in Mental Health Inventory score to determine inequalities. Analyses were stratified by age, sex and disability group (sensory or speech, physical, intellectual or learning, psychological, brain injury or stroke, other). Results: From 2003 to 2020, people with disability had worse mental health than people without disability, with average Mental Health Inventory scores 9.8 to 12.1 points lower than for people without disability. For both people with and without disability, Mental Health Inventory scores decreased, indicating worsening mental health, reaching the lowest point for both groups in 2020. For some subpopulations, including young females and people with intellectual disability, brain injury or stroke, mental health inequalities worsened. Conclusion: This paper confirms that people with disability experience worse mental health than people without disability. We add to previous findings by demonstrating that disability-related inequalities in mental health have been sustained for a long period and are worsening in some subpopulations. [ABSTRACT FROM AUTHOR]

Background: Loneliness is a significant public health concern due to its detrimental impact on health and wellbeing. Despite people with disability reporting higher levels of loneliness than the general population, there has been little research into how this is affecting their health and wellbeing. In light of this, the aim of our study was to scope both the existing evidence about the health and wellbeing outcomes associated with loneliness for people with disability, as well as the conceptual frameworks and measures utilised in this field of research. Methods: To conduct this scoping review, we followed the methodology outlined by JBI and searched MEDLINE, Scopus, Informit, Embase, and Web of Science for peer-reviewed, English-language articles published between 1 January 2000 and 8 February 2023. Two independent reviewers completed screening, full-text review and data extraction, with consensus sought at each stage. Data were analysed using content analysis and presented both numerically and narratively. Results: Out of the initial 1602 publications identified in the scoping review, only nine were included after duplicate removal, title and abstract screening, and full-text review. This limited number of studies, with the earliest study one published in 2015, represents a key finding. Eight of the nine studies were quantitative, and all were conducted in high income countries. Most of these studies utilised a version of the University of Los Angles Loneliness Scale to measure loneliness and addressed specific impairment groups. Notably, most of the studies identified associations between loneliness and health and wellbeing outcomes for people with disability. Conclusions: This scoping review highlights the current scarcity of studies examining the effect that loneliness has on the health and wellbeing outcomes of people with disability. As most of the reviewed studies relied on loneliness measures designed for individuals without disability, they potentially overlook the unique life experiences of people with disability. Given that loneliness is an international public health concern, it is imperative that people with disability are not left behind or overlooked in efforts to address the impact of loneliness on health and wellbeing. [ABSTRACT FROM AUTHOR]

Objective. Over the past decade, various programs and reforms have targeted the issue of people aged ,65 years living in 'permanent' residential aged care (PRAC). As context for ongoing policy discourse, the aim of this study was to evaluate trends in rates of young people entering and leaving PRAC from 2008 to 2018. Methods. Counts of people aged ,65 years entering, remaining in and exiting PRAC were obtained from the National Aged Care Data Clearinghouse. Age standardisation was used to control for changes in the age and size of the Australian population. Annual age-standardised rates of admissions (subtracting transfers) and exits to the community were calculated. Linear regression models tested for a sustained increase or decrease in age-standardised rates nationally and within state and age subgroups. Results. Notwithstanding year-to-year variation, neither admissions (subtracting transfers) nor exits to the community showed statistically significant increasing or decreasing trends in the national age-standardised rates. Admission rates varied by age and state. Conclusions. Many more young people are admitted to PRAC each year than return to community living, with no sustained change between 2008 and 2018 at the national level. Age standardisation is crucial for evaluating systemic population-level change regarding younger people in PRAC. [ABSTRACT FROM AUTHOR]

Large inequalities in health and well-being exist between people with and without disability, in part due to poor socio-economic circumstances, and potentially also related to societal factors including issues associated with accessibility and participation. To better understand the contribution of societal factors, we used a unique longitudinal survey of disability in Great Britain to quantify the extent to which barriers to participation contribute to poorer health and well-being. We used data from 2354 individuals who participated in three waves of the Life Opportunities Survey between 2009 and 2014 and compared five health and well-being outcomes (self-rated health, anxiousness, life satisfaction, life worth, happiness) between adults who acquired an impairment and those who remained disability-free. Causal mediation analysis was conducted to quantify how much of the effect of disability acquisition on each outcome was explained by barriers to participation in employment, economic life, transport, community, leisure and civic activities, social contact, and accessibility. People who recently acquired a disability had poorer health and well-being compared to people with no disability. Barriers to participation explained 15% of inequalities in self-rated health, 28% for anxiousness, 32% for life satisfaction, 37% for life worth, and 70% for happiness. A substantial proportion of the inequalities in health and well-being experienced by people with recently acquired disability were socially produced, driven by barriers to participation in different life domains. Furthermore, there was evidence that barriers to participation mediated the effect of well-being measured to a greater extent than the more clinically aligned measures, self-reported health and anxiousness. These findings highlight modifiable factors amenable to public health interventions that could lead to substantial improvements in health and well-being for people with disability. • Inequalities in health and well-being exist between people with and without disability. • Existing evidence suggest inequalities are in part driven by socio-economic factors. • The contribution of upstream societal barriers is not understood. • Barriers to participation mediated a substantial proportion of the inequalities. • Proportion mediated was larger for well-being compared to clinically aligned measures. [ABSTRACT FROM AUTHOR]

Iron and zinc are essential for normal brain function, yet the mechanisms used by astrocytes to scavenge non-transferrin-bound iron (NTBI) and zinc are not well understood. Ischaemic stroke, traumatic brain injury and Alzheimer’s disease are associated with perturbations in the metabolism of NTBI and zinc, suggesting that these two metals may collectively contribute to pathology. The present study has investigated the accumulation of NTBI and zinc by rat primary astrocyte cultures. It was found that astrocytes express mRNA for both divalent metal transporter 1 (DMT1) and Zip14, indicating the potential for these transporters to contribute to the accumulation of NTBI and zinc by these cells. Astrocytes were found to accumulate iron from ferric chloride in a time- and dose-dependent manner, and the rate of accumulation was strongly stimulated by co-incubation with zinc acetate. In addition, cultured astrocytes rapidly accumulated zinc from zinc acetate, and this accumulation was stimulated by co-incubation with ferric chloride. Because a synergistic stimulation of iron and zinc accumulation is inconsistent with the known properties of DMT1 and Zip14, the present results suggest that additional mechanisms assist astrocytes to scavenge iron and zinc when they are present together in the extracellular compartment. These mechanisms may be involved in disorders that involve elevations in the extracellular concentrations of these metal ions. [ABSTRACT FROM AUTHOR]

Alterations in iron metabolism or oxidative damage in response to hypoxic incidents have been examined following re-oxygenation of the hypoxic tissue. To understand the consequences of decreased tissue oxygen on iron load, metal-catalyzed redox activity and oxidative modifications in isolation from re-oxygenation, the present study exposed mice to either normoxia, or mild hypoxia (380 Torr; ∼10% normobaric oxygen) where the tissue was not allowed to re-oxygenate prior to examination. Brain, liver and skeletal muscle were examined for Fe3+ load, metal-catalyzed redox activity and oxidative modifications to proteins (Nε-(carboxymethyl)lysine), lipids (4-hydroxynonenal pyrrole) and nucleic acids (8-hydroxyguanosine). Hypoxia induced a 43% increase in the iron content of the liver (P < 0.001) as determined by ICP-MS and a 3.8-fold increase in Fe3+ load (P < 0.001) as determined by Perl's stain. There was a corresponding 2-fold increase in metal-catalyzed redox activity (P < 0.01) in the liver, but no change in the expression of oxidative markers. In contrast, non-significant increases in Fe3+ and metal-catalyzed redox activity were observed in the cerebral cortex, and molecular and granular layers of the hippocampus and cerebellum. Interestingly, hypoxia significantly decreased oxidative modifications to proteins and lipids, but not nucleic acids in most brain regions examined. In addition, hypoxia did not alter the Fe content of skeletal muscle, or the contents of Zn, Cu, Ni or Mn in liver, skeletal muscle, cerebral cortex or hippocampus. Together, these results indicate that there is a tighter regulation of iron metabolism in the brain than the liver, which limits the redistribution of Fe3+ following hypoxia. [ABSTRACT FROM AUTHOR]

Abstract: The release of zinc (Zn) from glutamatergic synapses contributes to the neuropathology of ischemia, traumatic brain injury, and stroke. Astrocytes surround glutamatergic synapses and are vulnerable to the toxicity of Zn, which impairs their antioxidative glutathione (GSH) system and elevates the production of reactive oxygen species (ROS). It is not known whether one or both of these actions are the primary cause of Zn-induced cell death in astrocytes. Using primary rat astrocyte cultures we have examined whether Zn-mediated impairment of GSH redox cycling is the main source of its toxicity. Zn acetate at concentrations of 100 μM or greater were found to inactivate glutathione reductase (GR) via an NADPH-dependent mechanism, while concentrations of 150 μM and above caused substantial cell death. Furthermore, Zn increased the ratio of GSSG:GSH in astrocytes, increased their export of GSSG, slowed their clearance of exogenous H2O2, and promoted the intracellular production of ROS. In contrast, the GR inhibitor, carmustine, did not induce cell death, cause the production of ROS, or alter the GSH thiol redox balance. Taken together these results indicate that Zn toxicity in astrocytes is primarily associated with the generation of intracellular ROS, rather than the inhibition of GR. [Copyright &y& Elsevier]

The underlying pathological cause of Alzheimer' s disease has been postulated to be an excess of amyloid-β (Aβ) which aggregates into toxic fibrillar deposits within the extracellular space of the brain, thereby disrupting neuronal and synaptic function and eventually leading to neuronal degeneration and dementia. As a result, therapeutic strategies have been developed that are designed to remove Aβ from the brain. Caution needs to be exercised concerning such strategies because, in addition to its presence in neuritic plaques, Aβ has a widespread distribution through the brain and body, even in cognitively normal individuals. Evidence indicates that instead of being a toxic peptide, soluble Aβ serves a variety of physiological functions, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens. These physiological functions must be taken into account when strategies are developed to reduce Aβ load in Alzheimer' s disease. Ideally, such strategies should target forms of Aβ that are not bioavailable, such as fibrillar Aβ, or forms that are regarded to be overexpressed in Alzheimer' s disease (such as oligomers) while leaving normal soluble Aβ1-40 and Aβ1-42 intact. At present none of the available therapeutic strategies appears to have such selectivity. Until these technical limitations and the uncertainties regarding the effect of depletion of Aβ from the brain are resolved, it would not be prudent to begin further clinical trials. [ABSTRACT FROM AUTHOR]

Recent clinical and neuropathological data show that the AN 1792 vaccine enhanced the production of Aβ antibodies in the sera of Alzheimer’s disease (AD) patients, but it appears to have been ineffective at stimulating the removal of Aβ deposits from the brain or at slowing the rate of cognitive decline. The 19 cases of meningoencephalitis were not linked in an obvious way to serum antibody titre, but they may have been linked to infiltration of the brain by antibodies and/or T-cells. Brain imaging indicated that oedema associated with the neuroinflammation did not reflect the typical distribution of neuritic plaques in AD. These outcomes were not anticipated by experiments on transgenic mice because compared to humans, these mice have less genetic variability, and their plaques have a different chemical composition, making them far more soluble and easier to remove. Furthermore, the consequences of vaccination are different. Vaccination of transgenic mice removes superfluous human Aβ while leaving endogenous mouse Aβ intact, whereas in humans the immune response is directed against an endogenous target that occurs naturally and is present in healthy brain tissue. The most important lesson to be learned from the AN 1792 trials is that new strategies for treating AD should not be tested on humans until they have been extensively tested on non-murine species. [Copyright &y& Elsevier]

Describes a therapeutic approach being developed for the treatment of Alzheimer's disease (AD). Deliberate induction of an autoimmune response to amyloid-beta peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD; Cause of the neuroinflammation in the AN-1792 trials.

The ‘amyloid hypothesis’ has guided research into Alzheimer’s disease (AD) for more than a decade. A detailed review of the relevant data led us to conclude that some data, particularly those from transgenic mice, are inconsistent with the predictions of the amyloid hypothesis. Instead, most data are consistent with the notion that amyloid-β (Aβ) peptide is neuroprotective. The majority of commentators agreed with our analysis but some were unwilling to abandon the amyloid hypothesis until the outcome of anti-Aβ therapeutic trials puts the matter beyond debate. All acknowledged that we had highlighted flaws in the amyloid hypothesis which must be addressed. To stimulate a critical reappraisal of the amyloid hypothesis we have proposed the ‘bioflocculant hypothesis’ which posits that Aβ serves to bind neurotoxic solutes (pathogens, proteins and metal ions) so that they can be phagocytosed and prevented from causing further damage. The hypothesis makes clear predictions that are readily falsifiable, and it has already gained credibility by predicting the recent negative outcome of Aβ vaccination trials in humans. [Copyright &y& Elsevier]

Research into Alzheimer’s disease (AD) has been guided by the view that deposits of fibrillar amyloid-β peptide (Aβ) are neurotoxic and are largely responsible for the neurodegeneration that accompanies the disease. This ‘amyloid hypothesis’ has claimed support from a wide range of molecular, genetic and animal studies. We critically review these observations and highlight inconsistencies between the predictions of the amyloid hypothesis and the published data. We show that the data provide equal support for a ‘bioflocculant hypothesis’, which posits that Aβ is normally produced to bind neurotoxic solutes (such as metal ions), while the precipitation of Aβ into plaques may be an efficient means of presenting these toxins to phagocytes. We conclude that if the deposition of Aβ represents a physiological response to injury then therapeutic treatments aimed at reducing the availability of Aβ may hasten the disease process and associated cognitive decline in AD. [Copyright &y& Elsevier]

Iron-mediated oxidative stress occurs in a wide variety of neurological disorders. The present study has investigated whether melatonin can alter the proportion of neurons that die in the 24 h period following 1.0 μl intracortical injections of 1.0 mM ferric ammonium citrate (FAC) or 0.9% saline. Rats which received systemic infusions of melatonin (5 mg/kg body weight per day) displayed a 40% reduction (P=0.019) in the proportion of neurons killed by FAC. By contrast, reduction of endogenous melatonin by continuous light exposure did not significantly affect the extent of neuronal death. Furthermore, elevated or reduced melatonin levels did not alter the number of neurons killed by saline injections. We conclude that pharmacological concentrations of melatonin protect neurons against iron-induced injury. [Copyright &y& Elsevier]

Background: Loneliness can have a detrimental impact on health, yet little is known about the association between disability and loneliness. Methods: Secondary analysis of three waves of data collected between 2017 and 2020 by the UK's annual household panel study, Understanding Society. Direct age-standardisation was used to compare the prevalence of loneliness at each wave and the persistence of loneliness across all three waves for participants with/without disabilities aged 16–65 years. Transitional probabilities for the stability of loneliness, the stability of non-loneliness, the onset of loneliness and the offset of loneliness between consecutive waves were also estimated. Results: At each wave, the prevalence of loneliness was significantly higher among respondents with disabilities than respondents without disabilities; these inequalities persisted with no evidence of change over time. The prevalence of persistent loneliness was 46% for respondents with disabilities compared with 22% for respondents without disabilities. Risk factors for the likelihood of persistent loneliness included disability, financial stress, not living as a couple, living in rented accommodation, being female and not being employed. The probability of the onset and stability of loneliness between successive waves were markedly higher for people with disabilities compared with people without disabilities. Conclusion: Adults with disabilities were more likely to experience loneliness, become lonely and remain lonely over time than their peers. Policies and interventions aimed at reducing loneliness should ensure that they are accessible and effective for people with disabilities. Further research is needed to explore the health outcomes of persistent loneliness among people with/without disabilities. [ABSTRACT FROM AUTHOR]

Focuses on the request of the authors to Elan Pharmaceuticals to publish the details of the trial of the treatment of Alzheimer's disease. Release of Elan of details of their medical condition; Withdrawal of Elan of AN-1792 vaccine from human trials; Lack of obligation of Elan to report the results of the AN-1792 trials.

Abstract: The concentrations of non-transferrin-bound iron are elevated in the brain during pathological conditions such as stroke and Alzheimer''s disease. Astrocytes are specialised for sequestering this iron, however little is known about the mechanisms involved. Carboxylates, such as citrate, have been reported to facilitate iron uptake by intestinal cells. Citrate binds iron and limits its redox activity. The presence of high citrate concentrations in the interstitial fluid of the brain suggests that citrate may be an important ligand for iron transport by astrocytes. This study investigates whether iron accumulation by cultured rat astrocytes is facilitated by citrate or other carboxylates. Contrary to expectations, citrate, tartrate and malate were found to block iron accumulation in a concentration-dependent manner; α-ketoglutarate had limited effects, while fumarate, succinate and glutarate had no effect. This blockade was not due to an inhibition of ferric reductase activity. Instead, it appeared to be related to the capacity of these carboxylates to bind iron, since phosphate, which also binds iron, diminished the capacity of citrate, tartrate and malate to block the cellular accumulation of iron. These findings raise the possibility that citrate may have therapeutic potential in the management of neurodegenerative conditions that involve cellular iron overload. [Copyright &y& Elsevier]

Abstract: Following hemorrhagic stroke, red blood cells lyse and release neurotoxic hemin into the interstitial space. The present study investigates whether neurons can accumulate and metabolize hemin. We demonstrate that cultured neurons express the heme carrier protein 1 (HCP1), and that this transporter appears to contribute to the time- and concentration-dependent accumulation of hemin by neurons. Although exposure of neurons to hemin stimulates the synthesis of the iron storage protein ferritin, approximately 80% of the hemin accumulated by neurons remains intact. Within 24h of incubation, substantial neurotoxicity was observed that was not attenuated by the cell permeable, selective ferrous iron chelator, 1,10-phenanthroline. These results demonstrate that while neurons efficiently accumulate hemin they slowly degrade it, and they support the conclusion that intact hemin is more neurotoxic than the iron released from the breakdown of hemin. Further investigations are required to determine the basis of this neurotoxicity. [Copyright &y& Elsevier]

Abstract: In epilepsy, traumatic brain injury, and ischemic stroke, toxic levels of zinc released from neurons contribute to the brain damage associated with these disorders. Zinc causes oxidative stress by increasing the generation of reactive oxygen species and by inhibiting glutathione reductase (GR). This study investigated whether naturally occurring amino acids can protect cultured mouse astrocytes from zinc. Astrocytes incubated for 24h with 33μM zinc acetate in a minimal medium displayed a loss of GR activity, a depletion of total glutathione, and a loss of total antioxidant capacity. These changes were accompanied by extensive cell death. Four amino acids (200μM L-histidine, 201μM L-cystine, 4mM L-glutamine, 798μM L-threonine), which are a subset of the 15 present in Dulbecco''s modified Eagle medium, were found to collectively prevent zinc toxicity. Histidine was the most protective, followed by cystine, glutamine, and threonine. It is proposed that each of these amino acids protects against different aspects of zinc toxicity by chelating zinc, by serving as precursors for glutathione, or by converting to tricarboxylic acid cycle intermediates. It is possible that these 4 amino acids contribute in vivo to the protection of brain cells from the toxic effects of zinc. [Copyright &y& Elsevier]

Hemorrhagic stroke is a common cause of permanent brain damage, with a significant amount of the damage occurring in the weeks following a stroke. This secondary damage is partly due to the toxic effects of hemin, a breakdown product of hemoglobin. The serum proteins hemopexin and albumin can bind hemin, but these natural defenses are insufficient to cope with the extremely high amounts of hemin (10 mM) that can potentially be liberated from hemoglobin in a hematoma. The present review discusses how hemin gets into brain cells, and examines the multiple routes through which hemin can be toxic. These include the release of redox-active iron, the depletion of cellular stores of NADPH and glutathione, the production of superoxide and hydroxyl radicals, and the peroxidation of membrane lipids. Important gaps are revealed in contemporary knowledge about the metabolism of hemin by brain cells, particularly regarding how hemin interacts with hydrogen peroxide. Strategies currently being developed for the reduction of hemin toxicity after hemorrhagic stroke include chelation therapy, antioxidant therapy and the modulation of heme oxygenase activity. Future strategies may be directed at preventing the uptake of hemin into brain cells to limit the opportunity for toxic interactions. [ABSTRACT FROM AUTHOR]