Parkinson's disease (PD) is the most common neurodegenerative disease of the basal ganglia. Like other adult-onset neurodegenerative disorders, it is without a treatment that forestalls its chronic ...progression. Efforts to develop disease-modifying therapies to date have largely focused on the prevention of degeneration of the neuron soma, with the tacit assumption that such approaches will forestall axon degeneration as well. We herein propose that future efforts to develop neuroprotection for PD may benefit from a shift in focus to the distinct mechanisms that underlie axon degeneration. We review evidence from human post-mortem studies, functional neuroimaging, genetic causes of the disease and neurotoxin models that axon degeneration may be the earliest feature of the disease, and it may therefore be the most appropriate target for early intervention. In addition, we present evidence that the molecular mechanisms of degeneration of axons are separate and distinct from those of neuron soma. Progress is being made in understanding these mechanisms, and they provide possible new targets for therapeutic intervention. We also suggest that the potential for axon re-growth in the adult central nervous system has perhaps been underestimated, and it offers new avenues for neurorestoration. In conclusion, we propose that a new focus on the neurobiology of axons, their molecular pathways of degeneration and growth, will offer novel opportunities for neuroprotection and restoration in the treatment of PD and other neurodegenerative diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
An extensive literature shows that social relationships influence psychological well‐being, but the underlying mechanisms remain unclear. We test predictions about online interactions and well‐being ...made by theories of belongingness, relationship maintenance, relational investment, social support, and social comparison. An opt‐in panel study of 1,910 Facebook users linked self‐reported measures of well‐being to counts of respondents' Facebook activities from server logs. Specific uses of the site were associated with improvements in well‐being: Receiving targeted, composed communication from strong ties was associated with improvements in well‐being while viewing friends' wide‐audience broadcasts and receiving one‐click feedback were not. These results suggest that people derive benefits from online communication, as long it comes from people they care about and has been tailored for them.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
mTOR is a regulator of cell growth and survival, protein synthesis-dependent synaptic plasticity, and autophagic degradation of cellular components. When triggered by mTOR inactivation, ...macroautophagy degrades long-lived proteins and organelles via sequestration into autophagic vacuoles. mTOR further regulates synaptic plasticity, and neurodegeneration occurs when macroautophagy is deficient. It is nevertheless unknown whether macroautophagy modulates presynaptic function. We find that the mTOR inhibitor rapamycin induces formation of autophagic vacuoles in prejunctional dopaminergic axons with associated decreased axonal profile volumes, synaptic vesicle numbers, and evoked dopamine release. Evoked dopamine secretion was enhanced and recovery was accelerated in transgenic mice in which macroautophagy deficiency was restricted to dopaminergic neurons; rapamycin failed to decrease evoked dopamine release in the striatum of these mice. Macroautophagy that follows mTOR inhibition in presynaptic terminals, therefore, rapidly alters presynaptic structure and neurotransmission.
► Macroautophagy can rapidly inhibit neurotransmitter release ► mTOR inhibition rapidly elicits local presynaptic macroautophagy ► Local presynaptic autophagy appears to degrade synaptic vesicles ► Chronic autophagy deficiency increases transmitter release and axon size
When triggered by mTOR inactivation, macroautophagy degrades proteins and organelles via sequestration into autophagic vacuoles. Hernandez et al. demonstrate a role in presynaptic terminals for macroautophagy that follows mTOR inhibition in the rapid alteration of presynaptic structure and neurotransmission.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In spite of tremendous research efforts we have not yet achieved two of our principal therapeutic goals in the treatment of Parkinson's disease (PD), to prevent its onward progression and to provide ...restoration of systems that have already been damaged by the time of diagnosis. There are many possible reasons for our inability to make progress. One possibility is that our efforts thus far may not have been directed towards the appropriate cellular compartments. Up until now research has been largely focused on the loss of neurons in the disease. Thus, neuroprotection approaches have been largely aimed at blocking mechanisms that lead to destruction of the neuronal cell body. Attempts to provide neurorestoration have been almost entirely focused on replacement of neurons. We herein review the evidence that the axonal component of diseased neuronal systems merit more of our attention. Evidence from imaging studies, from postmortem neurochemical studies, and from genetic animal models suggests that the axons of the dopaminergic system are involved predominantly and early in PD. Since the mechanisms of axonal destruction are distinct from those of neuron cell body degeneration, a focus on axonal neurobiology will offer new opportunities for preventing their degeneration. At present these mechanisms remain largely obscure. However, defining them is likely to offer new opportunities for neuroprotection. In relation to neurorestoration, while it has been classically believed that neurons of the adult central nervous system are incapable of new axon growth, recent evidence shows that this is not true for the dopaminergic projection. In conclusion, the neurobiology of axons is likely to offer many new approaches to protective and restorative therapeutics.
Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that ...forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration. ANN NEUROL 2010;67:715–725
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Correspondence to Dr Beth Prusaczyk, Department of Medicine, Division of General Medical Sciences, Washington University School of Medicine in St. Louis, St Louis, MO 63110, USA; ...beth.prusaczyk@wustl.edu Hospitalisation is one of the most vulnerable times in an older adult’s life, associated with increased risks of functional and cognitive decline and death.1 2 These risks are magnified for those with pre-existing cognitive or functional impairment.3 4 In response, the geriatrics research community has tested new care delivery models to improve hospital care for older adults and reduce these negative outcomes. ...given this heterogeneity, interventions tested in a controlled, homogenous sample of patients or care settings may not translate to ‘real-world’ implementation in older adults because, on a practical level, the implementation processes that providers are tasked with conducting (eg, screenings, prescribing, etc) will not be the same every time. If the target is adhering to the aforementioned American Geriatrics Society’s recommendations, a separate track is required. ...the medical complexity and variation among older adult patients means implementation processes may not be as routine as in other populations, which would likely have an impact on implementation success. ...it is not just the heterogeneity and complexity of the population—it’s that geriatric evidence-based interventions themselves are complex.
A substantial portion of child deaths in Africa take place in countries with recent history of armed conflict and political instability. However, the extent to which armed conflict is an important ...cause of child mortality, especially in Africa, remains unknown.
We matched child survival with proximity to armed conflict using information in the Uppsala Conflict Data Program Georeferenced Events Dataset on the location and intensity of armed conflict from 1995 to 2015 together with the location, timing, and survival of infants younger than 1 year (primary outcome) in 35 African countries. We measured the increase in mortality risk for infants exposed to armed conflicts within 50 km in the year of birth and, to study conflicts' extended health risks, up to 250 km away and 10 years before birth. We also examined the effects of conflicts of varying intensity and chronicity (conflicts lasting several years), and effect heterogeneity by residence and sex of the child. We then estimated the number and portion of deaths of infants younger than 1 year related to conflict.
We identified 15 441 armed conflict events that led to 968 444 combat-related deaths and matched these data with 1·99 million births and 133 361 infant deaths (infant mortality of 67 deaths per 1000 births) between 1995 and 2015. A child born within 50 km of an armed conflict had a risk of dying before reaching age 1 year of 5·2 per 1000 births higher than being born in the same region during periods without conflict (95% CI 3·7–6·7; a 7·7% increase above baseline). This increased risk of dying ranged from a 3·0% increase for armed conflicts with one to four deaths to a 26·7% increase for armed conflicts with more than 1000 deaths. We find evidence of increased mortality risk from an armed conflict up to 100 km away, and for 8 years after conflicts, with cumulative increase in infant mortality two to four times higher than the contemporaneous increase. In the entire continent, the number of infant deaths related to conflict from 1995 to 2015 was between 3·2 and 3·6 times the number of direct deaths from armed conflicts.
Armed conflict substantially and persistently increases infant mortality in Africa, with effect sizes on a scale with malnutrition and several times greater than existing estimates of the mortality burden of conflict. The toll of conflict on children, who are presumably not combatants, underscores the indirect toll of conflict on civilian populations, and the importance of developing interventions to address child health in areas of conflict.
The Doris Duke Charitable Foundation, and the Centre for Global Child Health at the Hospital for Sick Children.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Experimental studies of the collision phenomena of submicrometer particles is a developing field. This review examines the range of phenomena that can be observed with new experimental approaches. ...The primary focus is on single-particle impact studies enabled by charge detection mass spectrometry (CDMS) implemented using the Aerosol Impact Spectrometer (AIS) at the University of California, San Diego. The AIS combines electrospray ionization, aerodynamic lens techniques, CDMS, and an electrostatic linear accelerator to study the dynamics of particle impact over a wide range of incident velocities. The AIS has been used for single-particle impact experiments on positively charged particles of diverse composition, including polystyrene latex spheres, tin particles, and ice grains, over a wide range of impact velocities. Detection schemes based on induced charge measurements and time-of-flight mass spectrometry have enabled measurements of the impact inelasticity through the determination of the coefficient of restitution, measurements of the angular distributions of scattered submicrometer particles, and the chemical composition and dissociation of solute molecules in hypervelocity ice grain impacts.
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