Advances in a wide range of biological, behavioral, and social sciences are expanding our understanding of how early environmental influences (the ecology) and genetic predispositions (the biologic ...program) affect learning capacities, adaptive behaviors, lifelong physical and mental health, and adult productivity. A supporting technical report from the American Academy of Pediatrics (AAP) presents an integrated ecobiodevelopmental framework to assist in translating these dramatic advances in developmental science into improved health across the life span. Pediatricians are now armed with new information about the adverse effects of toxic stress on brain development, as well as a deeper understanding of the early life origins of many adult diseases. As trusted authorities in child health and development, pediatric providers must now complement the early identification of developmental concerns with a greater focus on those interventions and community investments that reduce external threats to healthy brain growth. To this end, AAP endorses a developing leadership role for the entire pediatric community-one that mobilizes the scientific expertise of both basic and clinical researchers, the family-centered care of the pediatric medical home, and the public influence of AAP and its state chapters-to catalyze fundamental change in early childhood policy and services. AAP is committed to leveraging science to inform the development of innovative strategies to reduce the precipitants of toxic stress in young children and to mitigate their negative effects on the course of development and health across the life span.
Bone defects represent a challenging clinical problem as they can lead to non-union.
models are well suited to study bone regeneration under varying conditions by linking both cellular and systems ...scales. This paper presents an
micro-multiphysics agent-based (micro-MPA) model for bone regeneration following an osteotomy. The model includes vasculature, bone, and immune cells, as well as their interaction with the local environment. The model was calibrated by time-lapsed micro-computed tomography data of femoral osteotomies in C57Bl/6J mice, and the differences between predicted bone volume fractions and the longitudinal
measurements were quantitatively evaluated using root mean square error (RMSE). The model performed well in simulating bone regeneration across the osteotomy gap, with no difference (5.5% RMSE,
= 0.68) between the
and
groups for the 5-week healing period - from the inflammatory phase to the remodelling phase - in the volume spanning the osteotomy gap. Overall, the proposed micro-MPA model was able to simulate the influence of the local mechanical environment on bone regeneration, and both this environment and cytokine concentrations were found to be key factors in promoting bone regeneration. Further, the validated model matched clinical observations that larger gap sizes correlate with worse healing outcomes and ultimately simulated non-union. This model could help design and guide future experimental studies in bone repair, by identifying which are the most critical
experiments to perform.
Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably,
models are regarded as powerful tools to further understand the ...signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA)
model of trabecular bone remodeling using longitudinal
data from the sixth caudal vertebra (CV6) of PolgA
mice, a mouse model of premature aging. Our
model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells' behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of five mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4 weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.
Preclinical studies suggest that exposure to general anaesthesia (GA) could cause neurodegeneration consistent with Alzheimer's disease (AD) pathology. Brain magnetic resonance imaging (MRI) is ...useful to study structural brain changes. We tested the hypothesis that exposure to surgery with GA (surgery/GA) is associated with greater cortical thinning and increased frequency of white matter lesions.
This is a cross-sectional analysis of 70–91-yr-old participants enrolled in the Mayo Clinic Study of Aging who had baseline MRI. The thickness of selected cortical regions, the volume of white matter hyperintensities, and the frequency of cortical infarctions were compared in participants who were and were not exposed to surgery/GA within 20 yr before the first MRI obtained after enrolment.
Of 1410 participants with MRI scans, 932 were exposed to surgery/GA before scanning. In adjusted analyses, cortical thickness in regions vulnerable to AD was significantly less in those exposed to surgery/GA in the prior 20 yr (difference −0.023 mm, 95% confidence interval (CI) −0.041 to −0.005, P=0.014). Those with surgery in the prior 20 yr were more likely to have ‘abnormal thickness’ compared with those without surgery (odds ratio=1.45, 95% CI 1.10–1.90, P=0.009). Exposure was not associated with white matter hyperintensities or the presence of brain infarcts.
This study suggests that exposure of older adults to surgical anaesthesia is associated with thinning in cortical regions implicated in AD. The pathogenesis and mechanisms driving these neurodegenerative changes, and the potential clinical significance of these findings, require further study.
Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and ...brain neurodegeneration.
Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression.
Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change -0.003 mm 95% confidence interval (CI) -0.005 to -0.001, p = .002), but not amyloid accumulation (0.003 95% CI -0.001 to 0.006, p = .107), or WMH increase (0.011 cm3 95% CI -0.001 to 0.023, p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (-0.004 mm 95% CI -0.008 to -0.001, p = .014); amyloid accumulation (0.010, 95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565).
Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.
To investigate the association between episodes of critical care hospitalizations and delirium with structural brain changes in older adults.
We included Mayo Clinic Study of Aging participants ...≥60 years old at the time of study enrollment (October 29, 2004, through September 11, 2017) with available brain MRI and ‘amyloid’ positron emission tomography (PET) scans. We tested the hypothesis that a) intensive care unit (ICU) admission is associated with greater cortical thinning and atrophy in entorhinal cortex, inferior temporal cortex, middle temporal cortex, and fusiform cortex (Alzheimer’'s disease-signature regions); b) atrophy in hippocampus and corpus callosum; c) delirium accelerates these changes; and d) ICU admission is not associated with increased deposition of cortical amyloid.
ICU admission was associated with cortical thinning in temporal, frontal, and parietal cortices, and decreases in hippocampal/corpus callosum volumes, but not Alzheimer’'s disease-signature regions. For hippocampal volume, and 10 of 14 cortical thickness measurements, the change following ICU admission was significantly more pronounced for those who experienced delirium. ICU admission was not associated with an increased amyloid burden.
Critical care hospitalization is associated with accelerated brain atrophy in selected brain regions, without increases in amyloid deposition, suggesting a pathogenesis based on neurodegeneration unrelated to Alzheimer’'s pathway.
•Cortical thinning is accelerated after critical illness in older adults•This thinning occurs in regions other than those affected by Alzheimer's disease•Increased deposition of brain amyloid is not present in these patients.•Delirium during hospitalization further accelerates cortical thinning•Neurodegeneration after critical illness is distinct from Alzheimer's disease pathology
Commercial human MR scanners are optimised for proton imaging, containing sophisticated prescan algorithms with setting parameters such as RF transmit gain and power. These are not optimal for ...X-nuclear application and are challenging to apply to hyperpolarised experiments, where the non-renewable magnetisation signal changes during the experiment. We hypothesised that, despite the complex and inherently nonlinear electrodynamic physics underlying coil loading and spatial variation, simple linear regression would be sufficient to accurately predict X-nuclear transmit gain based on concomitantly acquired data from the proton body coil. We collected data across 156 scan visits at two sites as part of ongoing studies investigating sodium, hyperpolarised carbon, and hyperpolarised xenon. We demonstrate that simple linear regression is able to accurately predict sodium, carbon, or xenon transmit gain as a function of position and proton gain, with variation that is less than the intrasubject variability. In conclusion, sites running multinuclear studies may be able to remove the time-consuming need to separately acquire X-nuclear reference power calibration, inferring it from the proton instead.
Objectives: There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to ...identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. Data sources: For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. Data extraction: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. Data synthesis: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. Conclusions: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.
Among New World monkeys, there is a remarkable correlation between multiple aspects of social behavior and their expression of an oxytocin (OT) variant with proline at the eighth position (Pro8OT) ...vs. the common mammalian OT ligand that has leucine at position 8 (Leu8OT). In light of evidence for OT involvement in normative and dysfunctional social behavior, a better understanding of the impact of OT ligand variation on receptor binding and signaling could provide insights into the pharmacological modulation of sociality. We previously showed that binding and calcium signaling at oxytocin receptors (OTRs) from four primate species were not different for Leu8 vs. Pro8 (Taylor JH et al., J Pharmacol Exp Ther, 367:101–107, 2018). OT also binds and activates vasopressin V1a receptors (V1aRs), whose preferred ligand is the closely related nonapeptide hormone arginine vasopressin (AVP). Thus the binding and signaling of Leu8OT and Pro8OT at V1aRs from Leu8OT‐ vs. Pro8OT‐expressing species was examined. V1aRs from marmoset (a Pro8OT species), macaque (a Leu8OT species), and human (a Leu8OT species) were expressed in CHO cells. Competition binding assays with intact cells on ice were performed using 125I‐OVTA. IC50 values in nM for Leu8OT, Pro8OT, and arginine vasopressin (AVP), respectively, were 220, 150, and 0.78 for marmoset; 28, 21, and 1.1 for macaque; and 16, 8, and 0.63 for human. Pro8OT thus has a slightly higher affinity than Leu8OT at all three receptors. Both OT isoforms exhibited about 20‐fold lower affinity than AVP for the macaque and human V1aRs but a nearly 200‐fold lower affinity for the marmoset V1aR. Calcium signaling downstream of V1aRs was assessed with FlexStation‐II assays. EC50 values in nM for Leu8OT, Pro8OT, and AVP, respectively, were 8.4, 6.7, and 0.06 for marmoset; 21, 10, and 0.03 for macaque; and 145, 110, and 2.1 for human. Thus the potency for Pro8OT is slightly higher than for Leu8OT, and the potencies for both OT isoforms are 50–100 times lower than for AVP, at all three V1aRs. These signaling potency differences are similar to the binding affinity differences for the OT isoforms at each receptor. The maximal calcium response to Leu8OT was about 80% of that for Pro8OT and AVP at the marmoset and macaque receptors; in contrast, the maximal Leu8OT and Pro8OT responses were only about 20% of the response to AVP for the human receptor, indicating that both OT isoforms are relatively weak partial agonists for the human V1aR. This difference in partial agonism at human V1aRs compared to marmoset and macaque V1aRs for both OT isoforms is intriguing. However, neither differences in V1aR ligand binding or calcium signaling provide an obvious explanation for the different behaviors of Pro8OT‐ versus Leu8OT‐expressing species, similar to our previous data showing minimal differences between the OT isoforms for binding and signaling at OTRs. Differential signaling to other downstream responses merits further investigation.
Support or Funding Information
Supported by NIH grant 1‐R01‐HD089147 to JAF.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
An excess incidence of brain cancer in farmers has been noted in several studies. The National Institute for Occupational Safety and Health developed the Upper Midwest Health Study (UMHS) as a ...case-control study of intracranial gliomas and pesticide uses among rural residents. Previous studies of UMHS participants, using "ever-never" exposure to farm pesticides and analyzing men and women separately, found no positive association of farm pesticide exposure and glioma risks. The primary objective was to determine if quantitatively estimated exposure of pesticide applicators was associated with an increased risk of glioma in male and female participants.
The study included 798 histologically confirmed primary intracranial glioma cases (45 % with proxy respondents) and 1,175 population-based controls, all adult (age 18-80) non-metropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. The analyses used quantitatively estimated exposure from questionnaire responses evaluated by an experienced industrial hygienist with 25 years of work on farm pesticide analyses. Odds ratios (ORs) and 95 % confidence intervals (CIs) using unconditional logistic regression modeling were calculated adjusting for frequency-matching variables (10-year age group and sex), and for age and education (a surrogate for socioeconomic status). Analyses were separately conducted with or without proxy respondents.
No significant positive associations with glioma were observed with cumulative years or estimated lifetime cumulative exposure of farm pesticide use. There was, a significant inverse association for phenoxy pesticide used on the farm (OR 0.96 per 10 g-years of cumulative exposure, CI 0.93-0.99). No significant findings were observed when proxy respondents were excluded. Non-farm occupational applicators of any pesticide had decreased glioma risk: OR 0.72, CI 0.52-0.99. Similarly, house and garden pesticide applicators had a decreased risk of glioma: OR 0.79, CI 0.66-0.93, with statistically significant inverse associations for use of 2,4-D, arsenates, organophosphates, and phenoxys.
These results are consistent with our previous findings for UMHS of reported farm pesticide exposure and support a lack of positive association between pesticides and glioma.
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