To investigate the role of the pro-inflammatory cytokine interleukin-1β (IL-1β) in postoperative cognitive dysfunction (POCD) in aged rats, we used laparotomy to mimic human abdominal surgery in ...adult (3 months) and aged (24 months) F344/BN rats. We demonstrated that memory consolidation of the hippocampal-dependent contextual fear-conditioning task is significantly impaired in aged but not young rats 4 d after surgery. Hippocampal-independent auditory-cued fear memory was not disrupted by laparotomy in either age group. The hippocampal-dependent memory impairment was paralleled by elevations of IL-1β in the hippocampus of aged animals 1 and 4 d after surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline after a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112 μg) at the time of surgery was sufficient to block both the behavioral deficit and the neuroinflammatory response. Injecting the same dose of IL-1RA peripherally failed to have a protective effect. These data provide strong support for the specific role of central, not peripheral, IL-1β in POCD. Furthermore, the long-lasting presence of IL-1RA in the brain (4 d) compared with in the blood (<24 h) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.
Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators within the brain, and recruitment of peripheral immune cells. ...Interestingly, memory deficits have been observed following many inflammatory states including infection, traumatic brain injury (TBI), normal aging, and Alzheimer's disease (AD). Prostaglandins (PGs), a class of lipid mediators which can have inflammatory actions, are upregulated by these inflammatory challenges and can impair memory. In this paper, we critically review the success of nonsteroidal anti-inflammatory drugs, which prevent the formation of PGs, in preventing neuroinflammation-induced memory deficits following lipopolysaccharide injection, TBI, aging, and experimental models of AD in rodents and propose a mechanism by which PGs could disrupt memory formation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract We previously reported that aging F344XBN rats are more vulnerable to disruptions of memory consolidation processes following an injection of Escherichia coli than are young rats. ...Furthermore, this disruption was specific to hippocampal-dependent memory. In the present study we examined the time course of the proinflammatory cytokine IL-1 β in young and old rats following a peripheral injection of E. coli . Compared to young rats, aging rats treated with E. coli showed an exaggerated and prolonged up-regulation of IL-1 β protein in the hippocampus, but not in hypothalamus, parietal cortex, prefrontal cortex, serum or spleen. Aging rats showed greater hippocampal IL-1 β protein levels than their young counterparts 4 h after E. coli , and these levels remained significantly elevated for 8 but not 14 days after E. coli . In a second experiment, aging rats exhibited anterograde memory consolidation impairments 4 and 8 days after an E. coli injection, but not after 14 days. A third experiment revealed that following an E. coli injection, bacterial clearance from the spleen and peritoneum was not impaired in aged rats, suggesting that elevations in hippocampal IL-1 β were not mediated by impaired clearance in the periphery in aging rats. These data suggest that the exaggerated and prolonged elevation of IL-1 β, specifically in the hippocampus, may be responsible for hippocampal-dependent memory impairments observed in aging rats following a bacterial infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
INTRODUCTION:The contraceptive implant is highly effective and safe for adolescents yet under-used by this population. Provision of the contraceptive implant should be within the scope of practice of ...primary care providers who care for teenagers, including pediatricians and family physicians. This study aims to assess the attitudes, knowledge, and provision of the contraceptive implant by pediatric and family medicine residents.
METHODS:Researchers emailed a web-based survey to program directors or coordinators for 204 pediatric and 498 family medicine programs, with a request to forward the survey to residents in each program. Responses were recorded, and relationships between participants’ demographics, knowledge, and experience regarding contraceptive implants were assessed using chi-squared analyses.
RESULTS:Among 665 participants, 81.2% recommended the contraceptive implant to adolescents, yet 73.2% had never inserted an implant in this population. 68.5% had received lectures and 52.0% had received hands-on training regarding contraceptive implants. Compared to pediatric residents, more family medicine residents had received lectures (80.1% vs 49.0%, P<.00001) and hands-on training (77.8% vs 19.2%, P<.00001). More family medicine residents had placed one or more implants than pediatric residents (40.5% vs 9.2%, P<.00001). Most participants correctly answered three knowledge-based questions about the contraceptive implant (66.0%, 72.5%, 85.6% correct). Reported setbacks to provision of contraceptive implants included lack of training or experience, lack of patient interest, and lack of implant availability at clinical sites.
CONCLUSION:The provision of contraceptive implants for adolescents by primary care residents is low, particularly among pediatric residents. Primary care residency programs should focus more on contraceptive implant training.
•DARPA's programs foster multi-disciplinary collaborations.•DARPA's BCI programs span four major challenges: detect, emulate, restore, & improve.•Aims: restore function after injury; improve ...performance of healthy individuals.
The Defense Advanced Research Projects Agency (DARPA) has funded innovative scientific research and technology developments in the field of brain–computer interfaces (BCI) since the 1970s. This review highlights some of DARPA's major advances in the field of BCI, particularly those made in recent years. Two broad categories of DARPA programs are presented with respect to the ultimate goals of supporting the nation's warfighters: (1) BCI efforts aimed at restoring neural and/or behavioral function, and (2) BCI efforts aimed at improving human training and performance. The programs discussed are synergistic and complementary to one another, and, moreover, promote interdisciplinary collaborations among researchers, engineers, and clinicians. Finally, this review includes a summary of some of the remaining challenges for the field of BCI, as well as the goals of new DARPA efforts in this domain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Highlights ► Sustained IL-1β expression reduces adult hippocampal neurogenesis and shifts cellular fate towards astroglia; this reduction is not alleviated by voluntary running.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Neuroinflammatory conditions such as traumatic brain injury, aging, Alzheimer’s disease, and Down syndrome are often associated with cognitive dysfunction. Much research has targeted ...inflammation as a causative mediator of these deficits, although the diverse cellular and molecular changes that accompany these disorders obscure the link between inflammation and impaired memory. Therefore, we used a transgenic mouse model with a dormant human IL-1β excisional activation transgene to direct overexpression of IL-1β with temporal and regional control. Two weeks of hippocampal IL-1β overexpression impaired long-term contextual and spatial memory in both male and female mice, while hippocampal-independent and short-term memory remained intact. Human IL-1β overexpression activated glia, elevated murine IL-1β protein and PGE2 levels, and increased pro-inflammatory cytokine and chemokine mRNAs specifically within the hippocampus, while having no detectable effect on inflammatory mRNAs in the liver. Sustained neuroinflammation also reduced basal and conditioning-induced levels of the plasticity-related gene Arc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective: To determine if the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) improves functional impairment, psychiatric symptoms, and sleep and circadian functioning. ...Method: Adults diagnosed with serious mental illness (SMI) and sleep and circadian dysfunction (N = 121) were randomly allocated to TranS-C plus usual care (TranS-C + UC; n = 61; 8 individual weekly sessions) or 6 months of Usual Care followed by Delayed Treatment with TranS-C (UC-DT; n = 60). Schizophrenia (45%) and anxiety disorders (47%) were common. Blind assessments were conducted pre-treatment, post-treatment, and 6 months later (6FU). The latter two were the post-randomization points of interest. The location was Alameda County Behavioral Health Care Services (ACBHCS), a Community Mental Health Center (CMHC) in California. Results: For the primary outcomes, relative to UC-DT, TranS-C + UC was associated with reduction in functional impairment (b = −3.18, p = 0.025, d = −0.58), general psychiatric symptoms (b = −5.88, p = 0.001, d = −0.64), sleep disturbance (b = −5.55, p < .0001, d = −0.96), and sleep-related impairment (b = −9.14, p < .0001, d = −0.81) from pre-treatment to post-treatment. These effects were maintained to 6-month follow-up (6FU; d = −0.42 to −0.82), except functional impairment (d = −0.37). For the secondary outcomes, relative to UC-DT, TranS-C + UC was associated with improvement in sleep efficiency and on the Sleep Health Composite score from pre-treatment to 6FU. TranS-C + UC was also associated with reduced total wake time and wake time variability from pre-treatment to post-treatment, as well as reduced hallucinations and delusions, bedtime variability, and actigraphy measured waking activity count variability from pre-treatment to 6FU. Conclusions: A novel transdiagnostic treatment, delivered within a CMHC setting, improves selected measures of functioning, symptoms of comorbid disorders, and sleep and circadian outcomes.
What is the public health significance of this article?
This study suggests that the Transdiagnostic Intervention for Sleep and Circadian Dysfunction is an effective treatment for a range of sleep and circadian problems across a range of mental illnesses. This study confirms prior research indicating that improving sleep is associated with improvement in mental health symptoms, including psychotic symptoms.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Space missions beyond the protection of Earth's magnetosphere expose astronauts to an environment that contains ionizing proton radiation. The hazards that proton radiation pose to normal tissues, ...such as the central nervous system (CNS), are not fully understood, although it has been shown that proton radiation affects the neurogenic environment, killing neural precursors and altering behavior. To determine the time and dose-response characteristics of the CNS to whole-body proton irradiation, C57BL/6J mice were exposed to 1 GeV/n proton radiation at doses of 0–200 cGy and behavioral, physiological and immunohistochemical end points were analyzed over a range of time points (48 h–12 months) postirradiation. These experiments revealed that proton radiation exposure leads to: 1. an acute decrease in cell division within the dentate gyrus of the hippocampus, with significant differences detected at doses as low as 10 cGy; 2. a persistent effect on proliferation in the subgranular zone, at 1 month postirradiation; 3. a decrease in neurogenesis at doses as low as 50 cGy, at 3 months postirradiation; and 4. a decrease in hippocampal ICAM-1 immunoreactivity at doses as low as 10 cGy, at 1 month postirradiation. The data presented contribute to our understanding of biological responses to whole-body proton radiation and may help reduce uncertainty in the assessment of health risks to astronauts. These findings may also be relevant to clinical proton beam therapy.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim ...is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes.
Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years.
Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h;
=0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%;
<0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14;
=0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (
=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%.
Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate.
URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.
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