APOE genotype and sex affect microglial interactions with plaques in Alzheimer's disease mice.

Microglia affect Alzheimer's disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E (APOE) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across APOE3 and APOE4 genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male APOE3 mice with significant reductions in coverage observed with both APOE4 genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which APOE4 genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male APOE3 mice and reduced by APOE4 genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with APOE4 genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with APOE4 genotype and female sex.

Prenatal and early life exposure to air pollution induced hippocampal vascular leakage and impaired neurogenesis in association with behavioral deficits.

Exposure to traffic-related air pollution (TRAP) is associated with a range of neurodevelopmental disorders in human populations. In rodent models, prenatal TRAP exposure increased depressive behaviors and increased brain microglial activity. To identify cellular mechanisms, we examined adult neurogenesis and the blood-brain barrier (BBB) in relation to cognition and motivated behaviors in rats that were exposed to a nano-sized TRAP subfraction from gestation into adulthood. At age 5 months, exposed male rats had 70% fewer newly generated neurons in the dentate gyrus (DG) of the hippocampus. Microglia were activated in DG and CA1 subfields (35% more Iba1). The BBB was altered, with a 75% decrease of the tight junction protein ZO-1 in the CA1 layer, and twofold more iron deposits, a marker of microhemorrhages. The exposed rats had impaired contextual memory (novel object in context), reduced food-seeking behavior, and increased depressive behaviors (forced swim). Deficits of de novo neurogenesis were inversely correlated with depressive behavior, whereas increased microbleeds were inversely correlated with deficits in contextual memory. These findings give the first evidence that prenatal and early life exposure to TRAP impairs adult hippocampal neurogenesis and increases microbleeds in association with behavioral deficits.

Comment on "The plateau of human mortality: Demography of longevity pioneers".

Barbi et al (Reports, 29 June 2018, p. 1459) reported that human mortality rate reached a "plateau" after the age of 105, suggesting there may be no limit to human longevity. We show, using their data, that potential lifespans cannot increase much beyond the current 122 years unless future biomedical advances alter the intrinsic rate of human aging.

From control to causation: Validating a 'complex systems model' of running-related injury development and prevention.

INTRODUCTION: There is a need for an ecological and complex systems approach for better understanding the development and prevention of running-related injury (RRI). In a previous article, we proposed a prototype model of the Australian recreational distance running system which was based on the Systems Theoretic Accident Mapping and Processes (STAMP) method. That model included the influence of political, organisational, managerial, and sociocultural determinants alongside individual-level factors in relation to RRI development. The purpose of this study was to validate that prototype model by drawing on the expertise of both systems thinking and distance running experts. MATERIALS AND METHODS: This study used a modified Delphi technique involving a series of online surveys (December 2016- March 2017). The initial survey was divided into four sections containing a total of seven questions pertaining to different features associated with the prototype model. Consensus in opinion about the validity of the prototype model was reached when the number of experts who agreed or disagreed with survey statement was ≥75% of the total number of respondents. RESULTS: A total of two Delphi rounds was needed to validate the prototype model. Out of a total of 51 experts who were initially contacted, 50.9% (n = 26) completed the first round of the Delphi, and 92.3% (n = 24) of those in the first round participated in the second. Most of the 24 full participants considered themselves to be a running expert (66.7%), and approximately a third indicated their expertise as a systems thinker (33.3%). After the second round, 91.7% of the experts agreed that the prototype model was a valid description of the Australian distance running system. CONCLUSION: This is the first study to formally examine the development and prevention of RRI from an ecological and complex systems perspective. The validated model of the Australian distance running system facilitates theoretical advancement in terms of identifying practical system-wide opportunities for the implementation of sustainable RRI prevention interventions. This 'big picture' perspective represents the first step required when thinking about the range of contributory causal factors that affect other system elements, as well as runners' behaviours in relation to RRI risk.

Developing a contributing factor classification scheme for Rasmussen's AcciMap: Reliability and validity evaluation.

One factor potentially limiting the uptake of Rasmussen's (1997) Accimap method by practitioners is the lack of a contributing factor classification scheme to guide accident analyses. This article evaluates the intra- and inter-rater reliability and criterion-referenced validity of a classification scheme developed to support the use of Accimap by led outdoor activity (LOA) practitioners. The classification scheme has two levels: the system level describes the actors, artefacts and activity context in terms of 14 codes; the descriptor level breaks the system level codes down into 107 specific contributing factors. The study involved 11 LOA practitioners using the scheme on two separate occasions to code a pre-determined list of contributing factors identified from four incident reports. Criterion-referenced validity was assessed by comparing the codes selected by LOA practitioners to those selected by the method creators. Mean intra-rater reliability scores at the system (M = 83.6%) and descriptor (M = 74%) levels were acceptable. Mean inter-rater reliability scores were not consistently acceptable for both coding attempts at the system level (MT1 = 68.8%; MT2 = 73.9%), and were poor at the descriptor level (MT1 = 58.5%; MT2 = 64.1%). Mean criterion referenced validity scores at the system level were acceptable (MT1 = 73.9%; MT2 = 75.3%). However, they were not consistently acceptable at the descriptor level (MT1 = 67.6%; MT2 = 70.8%). Overall, the results indicate that the classification scheme does not currently satisfy reliability and validity requirements, and that further work is required. The implications for the design and development of contributing factors classification schemes are discussed.

A framework for the etiology of running-related injuries.

The etiology of running-related injury is important to consider as the effectiveness of a given running-related injury prevention intervention is dependent on whether etiologic factors are readily modifiable and consistent with a biologically plausible causal mechanism. Therefore, the purpose of the present article was to present an evidence-informed conceptual framework outlining the multifactorial nature of running-related injury etiology. In the framework, four mutually exclusive parts are presented: (a) Structure-specific capacity when entering a running session; (b) structure-specific cumulative load per running session; (c) reduction in the structure-specific capacity during a running session; and (d) exceeding the structure-specific capacity. The framework can then be used to inform the design of future running-related injury prevention studies, including the formation of research questions and hypotheses, as well as the monitoring of participation-related and non-participation-related exposures. In addition, future research applications should focus on addressing how changes in one or more exposures influence the risk of running-related injury. This necessitates the investigation of how different factors affect the structure-specific load and/or the load capacity, and the dose-response relationship between running participation and injury risk. Ultimately, this direction allows researchers to move beyond traditional risk factor identification to produce research findings that are not only reliably reported in terms of the observed cause-effect association, but also translatable in practice.

Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.

Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/-/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral ß-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aß deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aß oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aß production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.

The use and modification of injury prevention exercises by professional youth soccer teams.

The efficacy of injury prevention exercise programs (IPEPs) for amateur youth soccer has been established, but little is known about their adaptability to other soccer populations. This study aimed to assess the use of individual injury prevention exercises by professional youth soccer teams, against the industry-standard, FIFA 11+ program. Four teams' chosen IPEPs were observed across one season and documented on a standardized form. The use of each FIFA 11+ exercise was coded as "performed", "performed modified" or "not performed". The proportion of the 160 observed sessions containing each individual exercise was calculated. Staff provided reasons for their use and modification of FIFA 11+ exercises. On average, individual FIFA 11+ exercises were conducted in original form in 12% of the sessions (range 0-33%), and in modified form in 28% of sessions (range 2-62%). The five most frequently observed exercises, in either original or modified form, were "bench" (72%), "squats" (69%), "running straight" (68%), "single-leg stance" (66%), and "sideways bench" (64%). Staff modified exercises to add variation, progression, and individualization, and to align with specific training formats and goals. Professional youth soccer teams often use injury prevention exercises similar to those in the FIFA 11+, but tailor them considerably to fit their implementation context.

Preterm infant body composition cannot be accurately determined by weight and length.

BACKGROUND: Body composition is a key metric for assessing nutrition in preterm infants. In many neonatal intensive care units body composition is estimated using anthropometric indices which mathematically combine body weight and length. However, the accuracy of these indices is unknown in preterm infants. In contrast, air-displacement plethysmography (ADP) has been shown to accurately measure neonatal fat mass, but it is not widely available. OBJECTIVE: The aim was to determine which anthropometric index is most correlated to infant fat mass, as determined by ADP. DESIGN: We performed a retrospective observational study, comparing ADP-determined percent body fat at 366 time points for 239 preterm infants (born <32 weeks), with simultaneous weight and length measurements. Non-linear regression was performed to determine the best fit anthropometric index to the body fat percentage as determined by ADP. Our non-linear regression model, % fat = AxwtαxLß, is the generalization of the most common anthropometric indices (BMI, ponderal index, etc.). RESULTS: The best-fit regression formula most closely matched the formula for BMI. However, the regression explained only 51% of variability seen in body fat percentage at post-menstrual age <50 weeks, and 16% of variation seen at 50 weeks or greater. CONCLUSION: Even optimal formulas relating weight and length to body fat percentage predict only a fraction of the variation seen in body composition, especially beyond 50 weeks. BMI was the anthropometric index most predictive of body fat percentage, but still has limited accuracy.

Rust on the Brain from Microbleeds and Its Relevance to Alzheimer Studies: Invited Commentary on Cacciottolo Neurobiology of Aging, 2016.

Cerebral microbleeds (MB) and small vessel disease (SVD) with congophilic arterial angiopathy (CAA) are increasingly recognized as a variable factor in AD cognitive impairments. This commentary on our recent report on sex-ApoE interactions in MBs published this February, briefly explores three aspects of MBs that could not be fully discussed therein: I, A possible gap between the prevalence of MBs as detected by MRI and post mortem analysis; II, The role of hemoglobin-degradation products in amyloid-attributed neurodegenerative changes; and III, Possible assessment of MB by cerebrospinal fluid (CSF) assays for iron-related markers to better screen patient subgroups for AD interventions.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for primary prevention of osteoarthritis by joint injury prevention in sport and recreation.

The risk of post-traumatic osteoarthritis (PTOA) substantially increases following joint injury. Research efforts should focus on investigating the efficacy of preventative strategies in high quality randomized controlled trials (RCT). The objective of these OARSI RCT recommendations is to inform the design, conduct and analytical approaches to RCTs evaluating the preventative effect of joint injury prevention strategies. Recommendations regarding the design, conduct, and reporting of RCTs evaluating injury prevention interventions were established based on the consensus of nine researchers internationally with expertise in epidemiology, injury prevention and/or osteoarthritis (OA). Input and resultant consensus was established through teleconference, face to face and email correspondence over a 1 year period. Recommendations for injury prevention RCTs include context specific considerations regarding the research question, research design, study participants, randomization, baseline characteristics, intervention, outcome measurement, analysis, implementation, cost evaluation, reporting and future considerations including the impact on development of PTOA. Methodological recommendations for injury prevention RCTs are critical to informing evidence-based practice and policy decisions in health care, public health and the community. Recommendations regarding the interpretation and conduct of injury prevention RCTs will inform the highest level of evidence in the field. These recommendations will facilitate between study comparisons to inform best practice in injury prevention that will have the greatest public health impact.

The incidence and burden of hospital-treated sports-related injury in people aged 15+ years in Victoria, Australia, 2004-2010: a future epidemic of osteoarthritis?

OBJECTIVES: Previous sports injury is a known risk factor for subsequent osteoarthritis (OA), but population-based rates of sports injury are unknown. The aims of this study were to: (1) describe the trends in the population incidence and burden of all hospital-treated sports injury in Victoria, Australia in adults aged 15+ years; (2) determine the incidence of lower limb and knee injuries; and (3) quantify their population health burden as average direct hospital costs per injury and lengths of stay. METHODS: Health sector data relating to adults aged 15+ years, for 2004-2010 inclusive, was extracted from the Victorian Admitted Episodes Dataset (VAED) and Victorian Emergency Minimum Dataset (VEMD). Data relating to sports injuries were identified using activity codes in each dataset Trends in injury frequency and rates were determined, and economic burden was calculated. RESULTS: The overall annual rate of hospital treated sports injuries increased by 24% (P = 0.001), and lower limb injuries by 26% (P = 0.001) over the 7 years. The associated accumulated economic burden was $265 million for all sports injuries and $110 million for lower limb injuries over the 7-years. CONCLUSIONS: The findings of this study show a significant increase in sports injuries in the state of Victoria, Australia over a 7-year period. As previous sports injury is a risk factor for the development of OA, the future incidence of OA will escalate, placing an even greater burden on health care systems. Population-wide preventative strategies that reduce the risk of sports injury are urgently required in order to reduce the future burden of OA.

Injury surveillance in community sport: Can we obtain valid data from sports trainers?

A lack of available injury data on community sports participants has hampered the development of informed preventive strategies for the broad-base of sports participation. In community sports settings, sports trainers or first-aiders are well-placed to carry out injury surveillance, but few studies have evaluated their ability to do so. The aim of this study was to investigate the reporting rate and completeness of sports trainers' injury records and agreement between sports trainers' and players' reports of injury in community Australian football. Throughout the football season, one sports trainer from each of four clubs recorded players' injuries. To validate these data, we collected self-reported injury data from players via short message service (SMS). In total, 210 discrete injuries were recorded for 139 players, 21% by sports trainers only, 59% by players via SMS only, and 21% by both. Completeness of injury records ranged from 95% to 100%. Agreement between sports trainers and players ranged from K = 0.32 (95% confidence interval: 0.27, 0.37) for date of return to football to K = 1.00 for activity when injured. Injury data collected by sports trainers may be of adequate quality for providing an understanding of the profile of injuries. However, data are likely to underestimate injury rates and should be interpreted with caution.

Changes in muscle activation following balance and technique training and a season of Australian football.

OBJECTIVES: Determine if balance and technique training implemented adjunct to 1001 male Australian football players' training influenced the activation/strength of the muscles crossing the knee during pre-planned and unplanned sidestepping. DESIGN: Randomized Control Trial. METHODS: Each Australian football player participated in either 28 weeks of balance and technique training or 'sham' training. Twenty-eight Australian football players (balance and technique training, n=12; 'sham' training, n=16) completed biomechanical testing pre-to-post training. Peak knee moments and directed co-contraction ratios in three degrees of freedom, as well as total muscle activation were calculated during pre-planned and unplanned sidestepping. RESULTS: No significant differences in muscle activation/strength were observed between the 'sham' training and balance and technique training groups. Following a season of Australian football, knee extensor (p=0.023) and semimembranosus (p=0.006) muscle activation increased during both pre-planned sidestepping and unplanned sidestepping. Following a season of Australian football, total muscle activation was 30% lower and peak valgus knee moments 80% greater (p=0.022) during unplanned sidestepping when compared with pre-planned sidestepping. CONCLUSIONS: When implemented in a community level training environment, balance and technique training was not effective in changing the activation of the muscles crossing the knee during sidestepping. Following a season of Australian football, players are better able to support both frontal and sagittal plane knee moments. When compared to pre-planned sidestepping, Australian football players may be at increased risk of anterior cruciate ligament injury during unplanned sidestepping in the latter half of an Australian football season.

Pgrmc1: new roles in the microglial mediation of progesterone-antagonism of estradiol-dependent neurite sprouting and in microglial activation.

Pgrmc1 (progesterone receptor membrane component 1) is a multifunctional 22 kDa protein with heme-binding and P450-activating capacity which was recognized under different names for roles in cell motility during neural development and in cancer, and apoptosis. Pgrmc1 expression in microglia was recently shown by the present authors to mediate estrogen-progesterone interactions during axonal sprouting and to mediate microglial activation itself. We also discuss other functions of Pgramc1 in the nervous system and its possible relationship to the 18 kDa sigma-2 receptor (S2R).

Progesterone antagonism of neurite outgrowth depends on microglial activation via Pgrmc1/S2R.

Neuronal plasticity is regulated by the ovarian steroids estradiol (E2) and progesterone (P4) in many normal brain functions, as well as in acute response to injury and chronic neurodegenerative disease. In a female rat model of axotomy, the E2-dependent compensatory neuronal sprouting is antagonized by P4. To resolve complex glial-neuronal cell interactions, we used the "wounding-in-a-dish" model of neurons cocultured with astrocytes or mixed glia (microglia to astrocytes, 1:3). Although both astrocytes and mixed glia supported E2-enhanced neurite outgrowth, P4 antagonized E2-induced neurite outgrowth only with mixed glia, but not astrocytes alone. We now show that P4-E2 antagonism of neurite outgrowth is mediated by microglial expression of progesterone receptor (Pgr) membrane component 1 (Pgrmc1)/S2R, a putative nonclassical Pgr mediator with multiple functions. The P4-E2 antagonism of neurite outgrowth was restored by add-back of microglia to astrocyte-neuron cocultures. Because microglia do not express the classical Pgr, we examined the role of Pgrmc1, which is expressed in microglia in vitro and in vivo. Knockdown by siRNA-Pgrmc1 in microglia before add-back to astrocyte-neuron cocultures suppressed the P4-E2 antagonism of neurite outgrowth. Conditioned media from microglia restored the P4-E2 activity, but only if microglia were activated by lipopolysaccharide or by wounding. Moreover, the microglial activation was blocked by Pgmrc1-siRNA knockdown. These findings explain why nonwounded cultures without microglial activation lack P4 antagonism of E2-induced neurite outgrowth. We suggest that microglial activation may influence brain responses to exogenous P4, which is a prospective therapy in traumatic brain injury.

Refeeding syndrome in very-low-birth-weight intrauterine growth-restricted neonates.

OBJECTIVE: Determine the incidence of refeeding syndrome, defined by the presence of hypophosphatemia in very-low-birth-weight (VLBW) infants with intrauterine growth restriction (IUGR) compared with those without IUGR. STUDY DESIGN: In this retrospective cohort study, VLBW infants admitted over a 10-year period (271 IUGR and 1982 non-IUGR) were evaluated for specific electrolyte abnormalities in the first postnatal week. RESULT: IUGR infants were significantly more likely to have hypophosphatemia (41% vs 8.9%, relative risk (95% confidence interval: 7.25 (5.45, 9.65)) and severe hypophosphatemia (11.4% vs 1%, 12.06 (6.82, 21.33)) in the first postnatal week. The incidence of hypophosphatemia was significantly associated with the presence of maternal preeclampsia in all VLBW infants (odds ratio (OR): 2.58 (1.96, 3.40)) when controlling for birth weight and gestational age. CONCLUSION: Refeeding syndrome occurs in VLBW infants with IUGR and born to mothers with preeclampsia. Close monitoring of electrolytes, especially phosphorus, is warranted in this population.

An anterior cruciate ligament injury prevention framework: incorporating the recent evidence.

Anterior cruciate ligament (ACL) injury rates have increased by ∼50% over the last 10 years. These figures suggest that ACL focused research has not been effective in reducing injury rates among community level athletes. Training protocols designed to reduce ACL injury rates have been both effective (n = 3) and ineffective (n = 7). Although a rationale for the use of exercise to reduce ACL injuries is established, the mechanisms by which they act are relatively unknown. This article provides an injury prevention framework specific to noncontact ACL injuries and the design of prophylactic training protocols. It is also apparent that feedback within this framework is needed to determine how biomechanically relevant risk factors like peak joint loading and muscular support are influenced following training. It is by identifying these links that more effective ACL injury prevention training programs can be developed, and, in turn, lead to reduced ACL injury rates in the future.

Design optimization of liquid-phase flow patterns for microfabricated lung on a chip.

Microreactors experience significant deviations from plug flow due to the no-slip boundary condition at the walls of the chamber. The development of stagnation zones leads to widening of the residence time distribution at the outlet of the reactor. A hybrid design optimization process that combines modeling and experiments has been utilized to minimize the width of the residence time distribution in a microreactor. The process was used to optimize the design of a microfluidic system for an in vitro model of the lung alveolus. Circular chambers to accommodate commercial membrane supported cell constructs are a particularly challenging geometry in which to achieve a uniform residence time distribution. Iterative computational fluid dynamics (CFD) simulations were performed to optimize the microfluidic structures for two different types of chambers. The residence time distributions of the optimized chambers were significantly narrower than those of non-optimized chambers, indicating that the final chambers better approximate plug flow. Qualitative and quantitative visualization experiments with dye indicators demonstrated that the CFD results accurately predicted the residence time distributions within the bioreactors. The results demonstrate that such a hybrid optimization process can be used to design microreactors that approximate plug flow for in vitro tissue engineered systems. This technique has broad application for optimization of microfluidic body-on-a-chip systems for drug and toxin studies.

Early cohort mortality predicts the rate of aging in the cohort: a historical analysis.

Early environmental influences on later-life health and mortality are well recognized in the doubling of life expectancy since 1800. To further define these relationships, we analyzed the associations between early-life mortality and both the estimated mortality level at age 40 and the exponential acceleration in mortality rates with age characterized by the Gompertz model. Using mortality data from 630 cohorts born throughout the 19th and early 20th century in nine European countries, we developed a multilevel model that accounts for cohort and period effects in later-life mortality. We show that early-life mortality, which is linked to exposure to infection and poor nutrition, predicts both the estimated cohort mortality level at age 40 and the subsequent Gompertz rate of mortality acceleration during aging. After controlling for effects of country and period, the model accounts for the majority of variance in the Gompertz parameters (about 90% of variation in the estimated level of mortality at age 40 and about 78% of variation in the Gompertz slope). The gains in cohort survival to older ages are entirely due to large declines in adult mortality level, because the rates of mortality acceleration at older ages became faster. These findings apply to cohorts born in both the 19th century and the early 20th century. This analysis defines new links in the developmental origins of adult health and disease in which effects of early-life circumstances, such as exposure to infections or poor nutrition, persist into mid-adulthood and remain evident in the cohort mortality rates from ages 40 to 90.