Abstract Components of the brain's dopaminergic system, such as dopamine receptors, undergo final maturation in adolescence. Exposure to social stress during human adolescence contributes to ...substance abuse behaviors. We utilized a rat model of adolescent social stress to investigate the neural mechanisms underlying this correlation. Rats exposed to repeated social defeat in adolescence (P35–P39) exhibited increased conditioned place preference (CPP) for amphetamine (1 mg/kg) in adulthood (P70). In contrast, rats experiencing foot-shock during the same developmental period exhibited amphetamine CPP levels similar to non-stressed controls. Our previous experiments suggested adolescent defeat alters dopamine activity in the mesocorticolimbic system. Furthermore, dopamine receptors have been implicated in the expression of amphetamine CPP. Therefore, we hypothesized that alteration to dopamine receptor expression in the mesocorticolimbic system may be associated with to heightened amphetamine CPP of adult rats exposed to adolescence defeat. We measured D1 and D2 dopamine receptor protein content in the medial prefrontal cortex, nucleus accumbens (NAc), and dorsal striatum following either adolescent social defeat or foot-shock stress and then adult amphetamine CPP. In controls, amphetamine CPP training reduced D2 receptor protein content in the NAc core. However, this down-regulation of NAc core D2 receptors was blocked by exposure to social defeat but not foot-shock stress in adolescence. These results suggest social defeat stress in adolescence alters the manner in which later amphetamine exposure down-regulates D2 receptors. Furthermore, persistent alterations to adult D2 receptor expression and amphetamine responses may depend on the type of stress experienced in adolescence.
Abstract
This study investigates whether families navigate educational institutions more successfully if they have a higher knowledge of the pathways in the educational system that are available to ...their children. We also study whether this kind of knowledge mediates secondary effects of social origin, i.e. differences in educational pathways once achievement differences between children are accounted for. The role of parents’ knowledge is consistent with various sociological theories concerning educational inequality. Knowledge can affect families’ ability to make rational choices for education but it can also be understood as a form of cultural capital. We use longitudinal student cohort data from the Netherlands combined with individual-level register data on educational attainment to study the importance of knowledge for short-term outcomes (up- and downward transitions in secondary education as well as track placement) and final educational attainment. Our results show that parents’ knowledge is a significant predictor of educational success net of parents’ education, socio-demographic characteristics, and demonstrated ability. If we apply a stricter test to the measure, however, we can see that knowledge matters for downward transitions and obtaining a tertiary degree but that the effect is negligible for upward transitions and track placement if other mechanisms such as cultural capital and aspirations are considered. Further, we conclude that knowledge matters especially for transitions in the educational system that require a move to a new and unknown school environment such as post-secondary or tertiary education. The study shows that knowledge is one useful avenue to investigate when we are confronted with the question why social disparities in educational decision-making arise.
The atmospheric methane burden is increasing rapidly, contrary to pathways compatible with the goals of the 2015 United Nations Framework Convention on Climate Change Paris Agreement. Urgent action ...is required to bring methane back to a pathway more in line with the Paris goals. Emission reduction from “tractable” (easier to mitigate) anthropogenic sources such as the fossil fuel industries and landfills is being much facilitated by technical advances in the past decade, which have radically improved our ability to locate, identify, quantify, and reduce emissions. Measures to reduce emissions from “intractable” (harder to mitigate) anthropogenic sources such as agriculture and biomass burning have received less attention and are also becoming more feasible, including removal from elevated‐methane ambient air near to sources. The wider effort to use microbiological and dietary intervention to reduce emissions from cattle (and humans) is not addressed in detail in this essentially geophysical review. Though they cannot replace the need to reach “net‐zero” emissions of CO2, significant reductions in the methane burden will ease the timescales needed to reach required CO2 reduction targets for any particular future temperature limit. There is no single magic bullet, but implementation of a wide array of mitigation and emission reduction strategies could substantially cut the global methane burden, at a cost that is relatively low compared to the parallel and necessary measures to reduce CO2, and thereby reduce the atmospheric methane burden back toward pathways consistent with the goals of the Paris Agreement.
Plain Language Summary
Methane is a powerful climate warmer, and the amount of methane in the air is growing rapidly. Reducing human‐caused methane emissions is urgent if the 2015 United Nations Paris Agreement to limit climate warming is to succeed. There is hope, though the problem of methane mitigation is very wide and complex. Much of the task is in finding, identifying, and quantifying emissions. Rapid technical advances are making it much easier to locate and thus cut emissions from fossil fuel industries (gas, coal, and oil). Assessing emissions from landfill and sewage facilities is also becoming easier. In particular, poorly regulated landfills in fast‐growing tropical megacities need attention. Agricultural emissions are less tractable but may also be reduced to some extent, especially by improving manure management. Many methane mitigation options offer cost‐effective approaches to cut global warming and bring the amount of methane in the air back to a pathway that is consistent with the aims of the Paris Agreement.
Key Points
The atmospheric methane burden is rising fast; this growth is an increasing threat to the Paris Agreement of the UN Framework Convention on Climate Change (UNFCCC)
New gas measurement technologies, on the ground and in the air, have greatly improved our ability to locate and quantify emissions and to identify mitigation targets
Emissions can be cut by ending fossil fuel emissions, cutting biomass burning, improving landfills, especially in the tropics, and changing cattle farming practice
Little is known about how the proportions of dependency states have changed between generational cohorts of older people. We aimed to estimate years lived in different dependency states at age 65 ...years in 1991 and 2011, and new projections of future demand for care.
In this population-based study, we compared two Cognitive Function and Ageing Studies (CFAS I and CFAS II) of older people (aged ≥65 years) who were permanently registered with a general practice in three defined geographical areas (Cambridgeshire, Newcastle, and Nottingham; UK). These studies were done two decades apart (1991 and 2011). General practices provided lists of individuals to be contacted and were asked to exclude those who had died or might die over the next month. Baseline interviews were done in the community and care homes. Participants were stratified by age, and interviews occurred only after written informed consent was obtained. Information collected included basic sociodemographics, cognitive status, urinary incontinence, and self-reported ability to do activities of daily living. CFAS I was assigned as the 1991 cohort and CFAS II as the 2011 cohort, and both studies provided prevalence estimates of dependency in four states: high dependency (24-h care), medium dependency (daily care), low dependency (less than daily), and independent. Years in each dependency state were calculated by Sullivan's method. To project future demands for social care, the proportions in each dependency state (by age group and sex) were applied to the 2014 England population projections.
Between 1991 and 2011, there were significant increases in years lived from age 65 years with low dependency (1·7 years 95% CI 1·0–2·4 for men and 2·4 years 1·8–3·1 for women) and increases with high dependency (0·9 years 0·2–1·7 for men and 1·3 years 0·5–2·1 for women). The majority of men's extra years of life were spent independent (36·3%) or with low dependency (36·3%) whereas for women the majority were spent with low dependency (58·0%), and only 4·8% were independent. There were substantial reductions in the proportions with medium and high dependency who lived in care homes, although, if these dependency and care home proportions remain constant in the future, further population ageing will require an extra 71 215 care home places by 2025.
On average older men now spend 2·4 years and women 3·0 years with substantial care needs, and most will live in the community. These findings have considerable implications for families of older people who provide the majority of unpaid care, but the findings also provide valuable new information for governments and care providers planning the resources and funding required for the care of their future ageing populations.
Medical Research Council (G9901400) and (G06010220), with support from the National Institute for Health Research Comprehensive Local research networks in West Anglia and Trent, UK, and Neurodegenerative Disease Research Network in Newcastle, UK.
Wet deposition is the dominant mechanism for removing black carbon (BC) from the atmosphere and is key in determining its atmospheric lifetime, vertical gradient and global transport. Despite the ...importance of BC in the climate system, especially in terms of its ability to modulate the radiative energy budget, there are few quantitative case studies of wet removal in ambient environments. We present a case study of BC wet removal by examining aerosol size distributions and BC coating properties sampled in three Canadian boreal biomass burning plumes, one of which passed through a precipitating cloud. This depleted the majority of the plume's BC mass, and the largest and most coated BC-containing particles were found to be preferentially removed, suggesting that nucleation scavenging was likely the dominant mechanism. Calculated single-scattering albedo (SSA) showed little variation, as a large number of non-BC particles were also present in the precipitation-affected plume. The remaining BC cores were smaller than those observed in previous studies of BC in post-precipitation outflow over Asia, possibly due to the thick coating by hydrophilic compounds associated with the Canadian biomass burning particles. This study provides measurements of BC size, mixing state and removal efficiency to constrain model parameterisations of BC wet removal in biomass burning regions, which will help to reduce uncertainty in radiative forcing calculations.
Abstract The ventral hippocampus modulates anxiety-like behavior in rats, and serotonergic transmission within the hippocampus facilitates adaptation to stress. Chronic amphetamine treatment results ...in anxiety-like behavior in rats and reduced monoamine concentrations in the ventral hippocampus. Since reduced hippocampal serotonergic transmission in response to stress is observed in rats that display high anxiety-like behavior, anxiety states in amphetamine-treated rats may be associated with reduced stress-related serotonergic transmission in the hippocampus. Therefore, using in vivo microdialysis in anesthetized rats, we investigated the effect of corticosterone infused locally into the ventral hippocampus on serotonergic transmission, and the effect of chronic amphetamine pretreatment on corticosteroid receptor protein expression and the corticosterone-induced serotonergic response. Extracellular serotonin in the ventral hippocampus was increased by corticosterone in drug naive rats, and this corticosterone-induced serotonin augmentation was blocked by the glucocorticoid receptor antagonist mifepristone. Furthermore, chronic pretreatment with amphetamine abolished the serotonin response to physiologically relevant corticosterone levels and reduced glucocorticoid receptor protein expression. Together, our results suggest that chronic amphetamine exposure reduces serotonergic neurotransmission, in part via alterations to glucocorticoid receptor-facilitation of serotonin release in the rat ventral hippocampus. Reduced serotonergic activity in the ventral hippocampus may contribute to altered stress responses and adaptive coping following repeated drug exposure.
Background: To compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). Patients and methods: In this randomised, open-label, phase III ...study, patients received cisplatin (80 mg/m2 i.v. day 1) plus oral capecitabine (1000 mg/m2 b.i.d., days 1–14) (XP) or 5-FU (800 mg/m2/day by continuous infusion, days 1–5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). Results: A total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 95% confidence interval (CI) 0.63–1.04, P < 0.001 versus noninferiority margin of 1.25. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64–1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). Conclusions: XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.
Introduction
Microinfarcts, small ischaemic foci common in ageing brain, are associated with dementia and gait dysfunction. We determined their relationship with dementia, mobility and ...cerebrovascular disease in an older population‐representative brain donor cohort. These data on microinfarcts were evaluated in relation to pathological assessments of clinically significant cerebral small vessel disease (SVD).
Methods
Microinfarcts were assessed in the MRC Cognitive Function and Ageing Study (n = 331). Nine brain areas were staged according to the number of areas affected.
Results
36% of brains showed at least 1 microinfarct. Higher cortical microinfarct stage was associated with dementia at death (OR 1.41, 95% CI 1.02; 1.96, P = 0.038), whilst cortical and subcortical microinfarct stages were associated with impaired mobility (OR 1.36, 95% CI 1.05–1.74; P 0.018) and falls (OR 1.96, 95% CI 1.11–3.43; P = 0.02). Adding data on microinfarcts to a definition of SVD, based on white matter lesions (WMLs), lacunes and significant arteriosclerosis, were assessed by comparing area under ROC curve (AUC) with and without microinfarcts. SVD was significantly related to dementia status with or without inclusion of microinfarcts. Modelling potential pathological definitions of SVD to predict dementia or impaired mobility indicated optimal prediction using combined assessment of WMLs, lacunes and microinfarcts.
Conclusion
Cortical (dementia) and subcortical microinfarcts (impaired mobility) are related to diverse clinical outcomes. Optimal pathological assessment of significant SVD in brain ageing is achieved based on WMLs, lacunes and microinfarcts and may not require subjective assessment of the extent and severity of arteriosclerosis.
Microinfarcts are common in the brains of elderly individuals correlating with cognitive impairment, impaired mobility and falls. They should be included in the neuropathological assessment of small vessel disease.
Abstract Astrocyte pathology occurs in association with Alzheimer's disease (AD) and in brain ageing, but is poorly characterised. We sought to define the detailed cellular pathology of astrocytes, ...the extent of population variation and the relationship to Alzheimer-type changes in a population-based cohort. Three staining patterns were associated with GFAP and excitatory amino acid transporter 2 (EAAT2): minimal, moderate or extensive immunoreactivity. GFAP and EAAT2 expression were inversely related ( p = 0.015), with trends to increased expression of GFAP ( p = 0.019) and decreased expression of EAAT2 ( p = ns) with increasing Braak stage. GFAP and EAAT2 correlated incompletely with β-amyloid and tau immunoreactivity. However, gliosis increased with increasing burden of neuritic ( p = 0.011), but not diffuse ( p = ns), plaques. Double-staining revealed distinct subsets of astrocytes; GFAP+ EAAT− , GFAP− EAAT+ , or GFAP+ EAAT+ . In contrast to the variation in GFAP and EAAT2, levels of EAAT1 and S100B showed consistent staining patterns. Alzheimer-type pathology only partially explains the variation in gliosis and astrocyte functional markers, suggesting that other factors contribute to the population variance in astrocyte pathology.
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