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The space radiation environment consists of multiple species of charged particles, including 28Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select pertinent brain regions were dissected for lipidomic analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Levels of the dendritic marker MAP2 in the cortex were higher in irradiated than sham-irradiated mice at middle age, which might be part of a compensatory response. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.

Objective:To describe a pilot project infection prevention and control (IPC) assessment conducted in skilled nursing facilities (SNFs) in New York State (NYS) during a pivotal 2-week period when the region became the nation’s epicenter for coronavirus disease 2019 (COVID-19).Design:A telephone and video assessment of IPC measures in SNFs at high risk or experiencing COVID-19 activity.Participants:SNFs in 14 New York counties, including New York City.Intervention:A 3-component remote IPC assessment: (1) screening tool; (2) telephone IPC checklist; and (3) COVID-19 video IPC assessment (ie, “COVIDeo”).Results:In total, 92 SNFs completed the IPC screening tool and checklist: 52 (57%) were conducted as part COVID-19 investigations, and 40 (43%) were proactive prevention-based assessments. Among the 40 proactive assessments, 14 (35%) identified suspected or confirmed COVID-19 cases. COVIDeo was performed in 26 (28%) of 92 assessments and provided observations that other tools would have missed: personal protective equipment (PPE) that was not easily accessible, redundant, or improperly donned, doffed, or stored and specific challenges implementing IPC in specialty populations. The IPC assessments took ∼1 hour each and reached an estimated 4 times as many SNFs as on-site visits in a similar time frame.Conclusions:Remote IPC assessments by telephone and video were timely and feasible methods of assessing the extent to which IPC interventions had been implemented in a vulnerable setting and to disseminate real-time recommendations. Remote assessments are now being implemented across New York State and in various healthcare facility types. Similar methods have been adapted nationally by the Centers for Disease Control and Prevention.

The overall aim of this contribution to the 'Second Bill Morgan Memorial Special Issue' is to provide a high-level review of a recent report developed by a Committee for the National Council on Radiation Protection and Measurements (NCRP) titled 'Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment'. It derives from previous NCRP Reports and Commentaries that provide the case for integrating data from radiation biology studies (available and proposed) with epidemiological studies (also available and proposed) to develop Biologically-Based Dose-Response (BBDR) models. In this review, it is proposed for such models to leverage the adverse outcome pathways (AOP) and key events (KE) approach for better characterizing radiation-induced cancers and circulatory disease (as the example for a noncancer outcome). The review discusses the current state of knowledge of mechanisms of carcinogenesis, with an emphasis on radiation-induced cancers, and a similar discussion for circulatory disease. The types of the various informative BBDR models are presented along with a proposed generalized BBDR model for cancer and a more speculative one for circulatory disease. The way forward is presented in a comprehensive discussion of the research needs to address the goal of enhancing health risk assessment of exposures to low doses of radiation. The use of an AOP/KE approach for developing a mechanistic framework for BBDR models of radiation-induced cancer and circulatory disease is considered to be a viable one based upon current knowledge of the mechanisms of formation of these adverse health outcomes and the available technical capabilities and computational advances. The way forward for enhancing low-dose radiation risk estimates will require there to be a tight integration of epidemiology data and radiation biology information to meet the goals of relevance and sensitivity of the adverse health outcomes required for overall health risk assessment at low doses and dose rates.

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24-hr internal rhythms are set to precisely 24 hr daily by exposure to the sun. However, the prevalence of night-time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post-stroke anxiety-like behaviour. Overall, dLAN amplified pro-inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery.

Evidence suggests that pediatric traumatic brain injury (TBI) may be causally related to alcohol misuse later in life; however, the nature and extent of the association has not been well described. This study examined the relationship between pediatric TBI and adult alcohol misuse in a population sample ≥20 years of age. We sought to determine (1) whether first self-reported incidence of TBI with loss of consciousness (LOC) before the age of 20 increased the risk for alcohol misuse later in life; and (2) whether sex, injury severity, and age at time of injury modified the association. We found a greater likelihood of binge but not heavy drinking for those whose first self-reported TBI with LOC occurred before the age of 20 when compared with those whose first self-reported TBI with LOC occurred later in life (28.5% vs. 20.4%

Anthracyclines are one of the most widely used and effective chemotherapies in oncology, but their most important side effect is the cumulative, dose-related cardiotoxicity leading to congestive heart failure in ~5% of individuals. Methodology and pharmacogenetic studies for predicting which individuals are at high risk and subsequently the development of targeted and individualized cardioprotective plans are beginning to make progress. Here, we review current putative risk genes and variants, the strength of evidence for each genetic association and the interaction between risk genes, in the context of known clinical risk factors and potential novel cardioprotective strategies.

During space missions, astronauts experience acute and chronic low-dose-rate radiation exposures. Given the clear gap of knowledge regarding such exposures, we assessed the effects acute and chronic exposure to a mixed field of neutrons and photons and single or fractionated simulated galactic cosmic ray exposure (GCRsim) on behavioral and cognitive performance in mice. In addition, we assessed the effects of an aspirin-containing diet in the presence and absence of chronic exposure to a mixed field of neutrons and photons. In C3H male mice, there were effects of acute radiation exposure on activity levels in the open field containing objects. In addition, there were radiation-aspirin interactions for effects of chronic radiation exposure on activity levels and measures of anxiety in the open field, and on activity levels in the open field containing objects. There were also detrimental effects of aspirin and chronic radiation exposure on the ability of mice to distinguish the familiar and novel object. Finally, there were effects of acute GCRsim on activity levels in the open field containing objects. Activity levels were lower in GCRsim than sham-irradiated mice. Thus, acute and chronic irradiation to a mixture of neutrons and photons and acute and fractionated GCRsim have differential effects on behavioral and cognitive performance of C3H mice. Within the limitations of our study design, aspirin does not appear to be a suitable countermeasure for effects of chronic exposure to space radiation on cognitive performance.

High-charge, high-energy ion particle (HZE) radiations are extraterrestrial in origin and characterized by high linear energy transfer (high-LET), which causes more severe cell damage than low-LET radiations like γ-rays or photons. High-LET radiation poses potential cancer risks for astronauts on deep space missions, but the studies of its carcinogenic effects have relied heavily on animal models. It remains uncertain whether such data are applicable to human disease. Here, we used genomics approaches to directly compare high-LET radiation-induced, low-LET radiation-induced and spontaneous hepatocellular carcinoma (HCC) in mice with a human HCC cohort from The Cancer Genome Atlas (TCGA). We identified common molecular pathways between mouse and human HCC and discovered a subset of orthologous genes (mR-HCC) that associated high-LET radiation-induced mouse HCC with a subgroup (mrHCC2) of the TCGA cohort. The mrHCC2 TCGA cohort was more enriched with tumor-suppressing immune cells and showed a better prognostic outcome than other patient subgroups.

Physician-prescribed rest after traumatic brain injury (TBI) is both commonplace and an increasingly scrutinized approach to TBI treatment. Although this practice remains a standard of patient care for TBI, research of patient outcomes reveals little to no benefit of prescribed rest after TBI, and in some cases prolonged rest has been shown to interfere with patient well-being. In direct contrast to the clinical advice regarding physical activity after TBI, animal models of brain injury consistently indicate that exercise is neuroprotective and promotes recovery. Here, we assessed the effect of low and moderate intensity treadmill exercise on functional outcome and hippocampal neural proliferation after brain injury. Using the controlled cortical impact (CCI) mouse model of TBI, we show that 10 days of moderate intensity treadmill exercise initiated after CCI reduces anxiety-like behavior, improves hippocampus-dependent spatial memory, and promotes hippocampal proliferation and newborn neuronal survival. Pathophysiological measures including lesion volume and axon degeneration were not altered by exercise. Taken together, these data reveal that carefully titrated physical activity may be a safe and effective approach to promoting recovery after brain injury.

Purpose. Estimating the cancer risk associated with interplanetary travel is complicated by the lack of data for human exposure to high atomic number, high-energy (HZE) radiation encountered in space. Therefore, human exposure data from low linear energy transfer (low-LET) γ-ray radiation is used in cancer risk models with the critical assumption that HZE and γ-ray radiation have comparable biological effects, including the induction of the same spectrum of tumors with similar lethality. Recently this assumption has been challenged by several reports indicating that HZE radiation might produce more aggressive tumors. The goal of this research is to test the hypothesis that high-LET HZE radiation induced tumors are more aggressive than those that arise spontaneously or from exposure to low-LET γ-rays. Materials & methods. The FVB/N-Tg(MMTV-PyMT) and (DBAxFVB)F1-Tg(MMTV-PyMT) murine models of mammary cancer and the C3H-Tg(Afp-mCherry) and C3B6F1-Tg(Afp-mCherry) liver cancer models were used to determine the impact of exposure to 0.2 Gy of HZE 300 MeV/n silicon ions in comparison to 3 Gy of γ-rays and no radiation. Various measures of tumor aggressiveness including latency, size, pathological grade, prognostic biomarkers, metastasis, and survival were assessed. Results. For both mammary cancer models, there was no significant change in the latency of mammary tumors or in the number or size of pulmonary metastasis in silicon-irradiated mice compared to their sham-irradiated controls. For the C3H-Tg and C3B6-Tg liver cancer models, we did observe an increase in the incidence of liver cancer in irradiated mice, but no differences in measures of aggressiveness, including tumor size, grade, metastasis, or overall survival. Conclusion. The principle finding of our study is that tumors in the HZE-irradiated mice were not more aggressive than those arising from exposure to low-LET γ-rays or spontaneously. Thus, we conclude that enhanced aggressiveness does not appear to be a uniform characteristic of all tumors in HZE-irradiated animals.

Dr. William Francis Morgan, known as Bill to many of his friends and colleagues, passed away on 13 November 2015, at the age of 62 years (Hamada et al. 2016, 2017). To commemorate the first anniver...

Background Diphtheria, a life-threatening respiratory disease, is caused mainly by toxin-producing strains of Corynebacterium diphtheriae, while nontoxigenic corynebacteria (eg, Corynebacterium pseudodiphtheriticum) rarely causes diphtheria-like illness. Recently, global diphtheria outbreaks have resulted from breakdown of health care infrastructures, particularly in countries experiencing political conflict. This report summarizes a laboratory and epidemiological investigation of a diphtheria outbreak among forcibly displaced Myanmar nationals in Bangladesh. Methods Specimens and clinical information were collected from patients presenting at diphtheria treatment centers. Swabs were tested for toxin gene (tox)-bearing C. diphtheriae by real-time polymerase chain reaction (RT-PCR) and culture. The isolation of another Corynebacterium species prompted further laboratory investigation. Results Among 382 patients, 153 (40%) tested tox positive for C. diphtheriae by RT-PCR; 31 (20%) PCR-positive swabs were culture confirmed. RT-PCR revealed 78% (298/382) of patients tested positive for C. pseudodiphtheriticum. Of patients positive for only C. diphtheriae, 63% (17/27) had severe disease compared to 55% (69/126) positive for both Corynebacterium species, and 38% (66/172) for only C. pseudodiphtheriticum. Conclusions We report confirmation of a diphtheria outbreak and identification of a cocirculating Corynebacterium species. The high proportion of C. pseudodiphtheriticum codetection may explain why many suspected patients testing negative for C. diphtheriae presented with diphtheria-like symptoms.

Traumatic brain injuries (TBI) are a significant public health problem costing billions of dollars in healthcare costs and lost productivity while simultaneously reducing the quality of life for both patients and caregivers. Substance abuse is closely interconnected with TBI, as intoxicated individuals are at a greater risk of suffering brain injuries, and TBI may serve as a risk factor for the subsequent development of substance use disorders. There are also prominent sex differences in the etiology, epidemiology, and consequences of TBI. For instance, men are more likely to be injured on sporting fields or in auto accidents, while women are disproportionately likely to suffer TBI associated with intimate partner violence. Moreover, while men are much more likely to suffer TBI during late adolescence-young adulthood, sex differences in the incidence of TBI are much less prominent during other developmental epochs. Further, there are prominent sex differences in substance abuse biology; for example, while more men meet diagnostic criteria for substance abuse disorders, women tend to advance from casual use to addiction more quickly. In this paper, we will discuss the emerging clinical and preclinical evidence that these sex differences in TBI and substance abuse interact and may be prominent determinates of long-term outcomes.

Background During August 2017–January 2018, more than 700,000 forcibly displaced Rohingyas crossed into Cox’s Bazar, Bangladesh. In response to measles and diphtheria cases, first documented in September and November 2017, respectively, vaccination campaigns targeting children 6 years were not assessed. In MSs, measles seroprotection was similarly high among 1- to 6-year-olds and 7- to 14-year-olds (91% [95% CI 86%–94%] and 99% [95% CI 96%–100%], respectively, p < 0.001). Rubella and diphtheria seroprotection in MSs were significantly lower among 1- to 6-year-olds (84% [95% CI 79%–88%] and 63% [95% CI 56%–70%]) compared to 7- to 14-year-olds (96% [95% CI 90%–98%] and 77% [95% CI 69%–84%]) (p < 0.001). Tetanus seroprevalence was similar among 1- to 6-year-olds and 7- to 14-year-olds (76% [95% CI 69%–81%] and 84% [95% CI 77%–89%], respectively; p = 0.07). Vaccination campaign coverage was consistent with seroprotection in both camps. However, nonresponse, the main limitation of the study, may have biased the seroprotection and campaign coverage results. Conclusions In this study, we observed that despite multiple vaccination campaigns, immunity gaps exist among children in MSs, particularly for diphtheria, which requires serial vaccinations to achieve maximum protection. Therefore, an additional tetanus-diphtheria campaign may be warranted in MSs to address these remaining immunity gaps. Rapid scale-up and strengthening of routine immunization services to reach children and to deliver missed doses to older children is also critically needed to close immunity gaps and prevent future outbreaks., In a cross-sectional study, Leora R. Feldstein and colleagues investigate vaccination coverage and seroprevalence among forcibly-displaced Rohingya children in Cox’s Bazar, Bangladesh in 2018., Author summary Why was this study done? Rohingyas living in camps and makeshift settlements (MSs) are at risk of outbreaks of vaccine-preventable diseases (VPDs). Ongoing outbreaks of measles and diphtheria, despite vaccination campaigns, suggest gaps in immunity for some children. We conducted this survey among Rohingya children to better understand these immunity gaps and risk for ongoing and future outbreaks of VPDs. What did the researchers do and find? We conducted a cross-sectional serologic and vaccine coverage survey in 2 camps in April and May 2018. The youngest children living in the MSs, who are more recent arrivals from Myanmar, had low levels of seroprotection for rubella (84% of children), diphtheria (63%), and tetanus (76%). Seroprotection for the youngest children living in Nayapara registered camp was high for measles, rubella, diphtheria, and tetanus (91%–98% of children). What do these findings mean? These findings suggest that despite vaccination campaigns, immunity gaps remain for VPDs, especially among children who are more recent arrivals from Myanmar and now live in MSs. Remaining immunity gaps may increase the risk of outbreaks of VPDs. An additional diphtheria-tetanus containing vaccine (DTCV) campaign may be beneficial to address the very low seroprotection levels identified among children living in the MSs. Rapid scale-up of routine immunization services is necessary to close remaining immunity gaps among children and those that have missed campaign opportunities. Nonresponse, the main limitation of this study, may have biased the seroprotection and campaign coverage results.

Meningococcal disease is a rare, but serious, bacterial infection that progresses rapidly and can be life-threatening, even with prompt antibiotic treatment. Men who have sex with men (MSM) have previously been reported to be at increased risk for meningococcal disease compared with other men, and recent outbreaks of serogroup C meningococcal disease among MSM have occurred (1). However, the epidemiology of meningococcal disease among MSM in the United States is not well described, in part, because information about MSM has not historically been collected as part of routine meningococcal disease surveillance. To better characterize and identify risk factors for meningococcal disease in general, supplementary data and isolates have been collected since 2015 through enhanced meningococcal disease surveillance activities. During 2015-2016, 271 cases of meningococcal disease in men aged ≥18 years were reported to the National Notifiable Diseases Surveillance System (NNDSS) in 45 states participating in this enhanced surveillance. Forty-eight (17.7%) cases were in men identified as MSM, including 17 (37.8%) with human immunodeficiency virus (HIV) infection. Among MSM, 39 (84.8%) cases were caused by Neisseria meningitidis serogroup C, whereas this serogroup was responsible for only 16.4% of cases among men who were not known to be MSM (non-MSM). Despite improvements in surveillance, MSM likely remain underascertained among men with meningococcal disease. Improved surveillance data are needed to understand the prevalence of and risk for meningococcal disease among MSM and inform policy and prevention strategies. Vaccination with quadrivalent meningococcal conjugate (MenACWY) vaccine is recommended for the control of meningococcal disease outbreaks caused by serogroups A, C, W, or Y, including during outbreaks among MSM; in addition, all persons aged ≥2 months with HIV infection should receive MenACWY vaccine because of the increased risk for meningococcal disease.

Alcohol use is a well characterized risk factor for traumatic brain injury (TBI); however, emerging clinical and experimental research suggests that TBI may also be an independent risk factor for the development of alcohol use disorders. In particular, TBIs incurred early in life predict the development of problem alcohol use and increase vulnerability to neuroinflammation as a consequence of alcohol use. Critically, the neuroinflammatory response to alcohol, mediated in large part by microglia, may also function as a driver of further alcohol use. Here, we tested the hypothesis that TBI increases alcohol consumption through microglia-mediated neuroinflammation. Mice were injured as juveniles and alcohol consumption and preference were assessed in a free-choice voluntary drinking paradigm in adolescence. TBI increased alcohol consumption; however, treatment with minocycline, an inhibitor of microglial activation, reduced alcohol intake in TBI mice to sham levels. Moreover, a single injection of ethanol (2 g/kg) significantly increased microglial activation in the nucleus accumbens and microglial expression of the proinflammatory cytokine IL-1β in TBI, but not sham or minocycline-treated, mice. Our data implicate TBI-induced microglial activation as a possible mechanism for the development of alcohol use disorders.

Recent studies have reported that TBI is an independent risk factor for subsequent stroke. Here, we tested the hypothesis that TBI would exacerbate experimental stroke outcomes via alternations in neuroimmune and neurometabolic function. We performed a mild closed-head TBI and then one week later induced an experimental stroke in adult male mice. Mice that had previously experienced TBI exhibited larger infarcts, greater functional deficits, and more pronounced neuroinflammatory responses to stroke. We hypothesized that impairments in central metabolic physiology mediated poorer outcomes after TBI. To test this, we treated mice with the insulin sensitizing drug pioglitazone (Pio) after TBI. Pio prevented the exacerbation of ischemic outcomes induced by TBI and also blocked the induction of insulin insensitivity by TBI. However, tissue respiratory function was not improved by Pio. Finally, TBI altered microvascular responses including promoting vascular accumulation of serum proteins and significantly impairing blood flow during the reperfusion period after stroke, both of which were reversed by treatment with Pio. Thus, TBI appears to exacerbate ischemic outcomes by impairing metabolic and microvascular physiology. These data have important implications because TBI patients experience strokes at greater rates than individuals without a history of head injury, but these data suggest that those strokes may also cause greater tissue damage and functional impairments in that population.

SUMMARYWe determined the prevalence of anti-hepatitis B surface antibodies (anti-HBs) among children and adolescents vaccinated for hepatitis B virus in infancy as part of the routine vaccination programme. A representative serum sample of the Israeli population age 0–19 was tested. In a separate pilot study, a booster dose of hepatitis B vaccine was administered to 31 candidates for national service, who were fully vaccinated in infancy and tested negative for hepatitis B surface antibodies at age 17–19 years and anti-HBs antibodies were assessed 8 weeks later. Of the 1273 samples tested, 631 (49·6%) were positive to anti-HBs antibodies. Seropositivity rates were 89·5% among infants aged 6–12 months and declined significantly with age to 20·7% at age 19 years. No differences in seropositivity rates were observed between Jews and Arabs, males and females and those born in Israel and in other countries. Seroconversion rate among the 31 individuals who received a booster dose was 90·3% (95% CI: 75·1–96·6%). We recommend a booster dose for healthcare personnel before starting to work at the health care facility.

Background: Activation of p53 is one of major pathways by which DNA damaging agents (DDA) such as radiation and chemotherapy cause toxicity in normal tissues and it induces a cascade of events that eventually leads to cell senescence or cell death. We have reported that a brief pretreatment with low dose arsenic (LDA), by temporarily and reversibly downregulating p53 at the time of treatment with DDA, reduces the normal tissue toxicity without compromising tumor response to treatment. This protective effect is selective to normal tissues, as it requires functional p53. Though not every cancer cell has detectable p53 mutations, essentially every cancer cell has dysfunctional p53. Therefore most cancer cells will not be protected by this strategy. Genomic instability and inability to repair DNA damage from DDA in the hematopoietic stem cells have been attributed to the development of therapy-induced myelodysplastic syndrome (tMDS) and acute myeloid leukemia (AML). We have also been studying the effect of LDA on the genome in the setting of cancer therapy. We have reported that LDA pretreatment significantly reduces radiation-induced DNA double strand breaks (DSBs) and apoptosis in normal cells both in-vitro and in-vivo. Persistent DNA damage such as DSBs can trigger genomic instability and can be prevented by proper DNA repair. Our previous work using comet assay to quantify DNA damage after radiation has indicated that DNA repair capacity is enhanced by LDA pretreatment. A role for LDA in maintaining genomic integrity has been implicated in our in-vitro studies, where we found that LDA protected telomeres from enhanced erosion by DDA in Concanavalin A-activated normal human lymphocytes, and that LDA reduced spontaneous and radiation-induced mutations in mouse embryonic stem cells. Yet, whether this p53 downregulation-based strategy helps genome maintenance during cancer treatment using DDA has not been investigated in-vivo. CBA/Ca mice have 15-25% incidence of AML after 3 Gy of total body ionizing radiation (IR). About 95% of mice that develop radiation-induced AML (rAML) have a deletion on chromosome 2 encompassing the PU.1 gene. Since PU.1 deletion is a critical contributor to and a useful surrogate marker for leukemogenesis in the murine rAML model, we tested a hypothesis whether pretreatment with LDA before IR helps maintain genomic integrity by evaluating bone marrow cells for PU.1 gene deletion. Method: One hundred twenty mice were randomized into four groups: PBS+sham IR (control), LDA+sham IR, PBS+IR and LDA+IR. Prior to sham or 3 Gy of IR, CBA/Ca mice were injected with either PBS or LDA intraperitoneally at the dose of 0.4mg/kg for 3 days. At 7, 30 and 180 days after radiation, bone marrow cells were collected from femurs and fixed with Carnoy's Fixative. To assess the effect of LDA on PU.1 gene deletion, fluorescence in-situ hybridization (FISH) assay was performed. An ATTO550 labeled PU.1 probe was designed and used to detect deletions that occur in 2qE1 and involve the PU.1 gene locus, as well as two 6-FAM labeled probes for centromere and telomere respectively. Four to five hundred cells were analyzed for each mouse. Statistical significance was determined from a two-way analysis of variance in log units using SAS Version 9.4. Result: We successfully established the FISH assay that can specifically detect the PU.1 gene not only in metaphase cells but also in interphase cells. As shown in the figure, mice in the LDA+IR group have significantly fewer bone marrow cells exhibiting PU.1 gene deletion compared with PBS+IR group at all three time points examined (Day 7: 2±1.2% vs 3.7±2.6%, P=0.047; Day 30: 1.9±1.1% vs 3.2±1.9%, P=0.040; Day 180: 2.8±1.0% vs 5.6±3.5%, P=0.014). LDA treatment alone has a negligible effect on PU.1 loss as compared to the control group. Conclusion: Our result suggests that LDA pretreatment protects genomic integrity following IR treatment in-vivo. As the development of rAML is a multi-step process, the impact of LDA pretreatment on the actual incidence of secondary malignancy needs further validation in animal models. The genome-protective effect of LDA that we have revealed supports its potential use as a strategy to reduce the development of radiation-induced secondary malignances such as MDS and AML. Disclosures Ha: Protectum Oncology: Current Employment, Current equity holder in private company.

Shared QTL for sporadic and γ-ray– and HZE ion–induced tumors supports use of the current NASA space radiation cancer risk model., Cancer risk from galactic cosmic radiation exposure is considered a potential “showstopper” for a manned mission to Mars. Calculating the actual risks confronted by spaceflight crews is complicated by our limited understanding of the carcinogenic effects of high-charge, high-energy (HZE) ions, a radiation type for which no human exposure data exist. Using a mouse model of genetic diversity, we find that the histotype spectrum of HZE ion–induced tumors is similar to the spectra of spontaneous and γ-ray–induced tumors and that the genomic loci controlling susceptibilities overlap between groups for some tumor types. Where it occurs, this overlap indicates shared tumorigenesis mechanisms regardless of the type of radiation exposure and supports the use of human epidemiological data from γ-ray exposures to predict cancer risks from galactic cosmic rays.

Traumatic brain injury (TBI) is closely interrelated with alcohol use disorders. This is mediated, in part, by the large number of individuals who are intoxicated at the time of their injuries. However, there is also evidence, both preclinically and epidemiologically that TBI, particularly when it occurs early in life can increase the incidence of alcohol use disorders later on. This is extremely important because drinking after TBI has been associated with much poorer long-term outcomes as compared to individuals who do not drink. However, for a number of reasons including potential confounders and a relatively long time between injury and onset of drinking it has been difficult to definitively assign causality. Here, we utilize a framework derived from the toxicology literature to determine whether a causal relationship between pediatric TBI and subsequent alcohol abuse is evident. In order for there to be a high likelihood of a causal relationship between an environmental factor and a health outcome, this framework indicates that an epidemiological relationship be present in humans and that analogous relationship has to exist in a preclinical model system and that the mechanism(s) of action that are identified in the model system must also be plausibly active in humans. In this review we discuss the epidemiological evidence for increased drinking in humans. Further, we discuss, the animal models for increased drinking after TBI and the potential mechanistic insights that have been derived from those animal models. We conclude, based on the framework described, that it is possible that pediatric TBI causes alcohol use disorders in humans.

Fuzzy-Trace Theory (FTT) generalizes research on discourse to predict how health messages can be better understood and remembered, thereby influencing decision making. Applying FTT, BRCA Gist delivers messages interactively through tutorial dialogues and is the first Intelligent Tutoring System designed to help laypeople make sound medical decisions. Previous research indicates that BRCA Gist helps people form useful “gist explanations,” which leads to improved knowledge, comprehension, and risk assessment. The present research examined the effectiveness of different BRCA Gist dialogue moves, including general pumps for information and prompts for specific information. Participants were randomly assigned to a control group or one of four BRCA Gist conditions evoking gist or verbatim representations crossed with general pumps or specific information prompts. Gist-evoking pumps by themselves produced significant gains in knowledge and risk assessment. Specific verbatim prompts increased knowledge without af...

The BRCA Gist Intelligent Tutoring System helps women understand and make decisions about genetic testing for breast cancer risk. BRCA Gist is guided by Fuzzy-Trace Theory, (FTT) and built using AutoTutor LITE. It responds differently to participants depending on what they say. Seven tutorial dialogues requiring explanation and argumentation are guided by three FTT concepts: forming gist explanations in one's own words, emphasizing decision-relevant information, and deliberating the consequences of decision alternatives. Participants were randomly assigned to BRCA Gist, a control, or impoverished BRCA Gist conditions removing gist explanation dialogues, argumentation dialogues, or FTT images. All BRCA Gist conditions performed significantly better than controls on knowledge, comprehension, and risk assessment. Significant differences in knowledge, comprehension, and fine-grained dialogue analyses demonstrate the efficacy of gist explanation dialogues. FTT images significantly increased knowledge. Providing more elements in arguments against testing correlated with increased knowledge and comprehension.

Background: When healthcare providers lack infection prevention and control (IPC) knowledge and skills, patient safety and quality of care can suffer. For this reason, state laws sometimes dictate IPC training; these requirements can be expressed as applying to various categories of healthcare personnel (HCP). We performed a preliminary assessment of the laws requiring IPC training across the United States. Methods: During February–July 2018, we searched WestlawNext, a legal database, for IPC training laws in 51 jurisdictions (50 states and Washington, DC). We used standard legal epidemiology methods, including an iterative search strategy to minimize results that were outside the scope of the coding criteria by reviewing results and refining search terms. A law was defined as a regulation or statute. Laws that include IPC training for healthcare personnel were collected for coding. Laws were coded to reflect applicable HCP categories and specific IPC training content areas. Results: A total of 278 laws requiring IPC training for HCP were identified (range, 1–19 per jurisdiction); 157 (56%) did not specify IPC training content areas. Among the 121 (44%) laws that did specify IPC content, 39 (32%) included training requirements that focused solely on worker protections (eg, sharps injury prevention and bloodborne pathogen protections for the healthcare provider). Among the 51 jurisdictions, dental professionals were the predominant targets: dental hygienists (n = 22; 43%), dentists (n = 20; 39%), and dental assistants (n = 18; 35%). The number of jurisdictions with laws requiring training for other HCP categories included the following: nursing assistants (n = 25; 49%), massage therapists (n = 11; 22%), registered nurses (n = 10; 20%), licensed practical nurses (n = 10; 20%), emergency medical technicians and paramedics (n = 9; 18%), dialysis technicians (n = 8; 18%), home health aides (n = 8;16%), nurse midwives (n = 7; 14%), pharmacy technicians (n = 7; 14%), pharmacists (n = 6; 12%), physician assistants (n = 4; 8%), podiatrists (n = 3; 6%), and physicians (n = 2; 4%). Conclusions: Although all jurisdictions had at least 1 healthcare personnel IPC training requirement, many of the laws lack specificity and some focus only on worker protections, rather than patient safety or quality of care. In addition, the categories of healthcare personnel regulated among jurisdictions varied widely, with dental professionals having the most training requirements. Additional IPC training requirements exist at the facility level, but this information was not analyzed as a part of this project. Further analysis is needed to inform our assessment and identify opportunities for improving IPC training requirements, such as requiring IPC training that more fully addresses patient protections.Funding: NoneDisclosures: None

Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKCς) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Lepr(db) mice. In contrast, AAC2 established glycemic control altering food intake in leptin-deficient Lep(ob) mice. Therefore, AAC2 activated the LepR and acted in a cytokine-like manner distinct from leptin. In a monogenic Ins2(Akita) mouse model for the phenotypes associated with type 1 diabetes, AAC2 rescued systemic glucose uptake in these mice without an increase in insulin levels and adiposity, as seen in insulin-treated Ins2(Akita) mice. In contrast to insulin, AAC2 treatment increased brain mass and reduced anxiety-related behavior in Ins2(Akita) mice. Our data suggests that the unique mechanism of action for AAC2, activating LepR/PKCς/ GLUT1 axis, offers an effective strategy to broaden glycemic control for the prevention of diabetic complications of the nervous system and, possibly, other insulin insensitive or resistant tissues.

To simulate the space radiation environment astronauts are exposed to, most studies involve acute exposures but during a space mission there will be chronic (long-lasting) exposures. To address this knowledge gap, a neutron irradiator using a 252Cf (252Californium) source was used to generate a mixed field of neutrons and photons to simulate chronic, low dose rate exposures to high LET radiation. In the present study, we assessed the effects chronic neutron exposure starting at 60 days of age on behavioral and cognitive performance of BALB/c female and C3H male mice at 600 and 700 days of age as part of an opportunistic study that took advantage of the availability of neutron and sham-irradiated mice from a radiation carcinogenesis experiment. There were profound dose- and time point-dependent effects of chronic neutron exposure. At the 600-day time point, irradiated BALB/c female mice showed improved nest building at all three doses. At the 700-day, but not 600-day, time point slightly but significantly increased body weights were seen in C3H male mice exposed to 0.118 Gy. At the 600-day time point BALB/c female mice irradiated with 0.2 Gy did, like sham-irradiated, not show preferential exploration of the novel object that was seen in mice irradiated with 0.118 or 0.4 Gy. In C3H male mice exposed to 0.4 Gy and at the 600-day time point, increased measures of anxiety were observed on days 1 and 2 in the open field. Thus, different outcome measures show distinct dose-response relationships, with some anticipated to worsen performance during space missions, like increased measures of anxiety, while other anticipated to enhance performance, such as increased nest building and object recognition.

The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in how quickly they repair radiation-induced DNA double-strand breaks (DSBs). We assayed mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA DSBs during protracted irradiation. We measured unrepaired γ-H2AX radiation-induced foci (RIF), which persisted after chronic 24-h gamma irradiation, as a surrogate marker for repair efficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/c founder strain. We observed a very strong correlation (R

Nighttime lighting is one of the great conveniences of modernization; however, there is mounting evidence that inopportune light exposure can disrupt physiological and behavioral functions. Hospital patients may be particularly vulnerable to the consequences of light at night due to their compromised physiological state. Cardiac arrest/cardiopulmonary resuscitation (CA) was used to test the hypothesis in mice that exposure to dim light at night impairs central nervous system (CNS) recovery from a major pathological insult. Mice exposed to dim light at night (5 lx) had higher mortality in the week following cardiac arrest compared to mice housed in dark nights (0 lx). Neuronal damage was significantly greater in surviving mice exposed to dim light at night after CA versus those housed in dark nights. Dim light at night may have elevated neuronal damage by amplifying pro-inflammatory pathways in the CNS; Iba1 immunoreactivity (an indication of microglia activation) and pro-inflammatory cytokine expression were elevated in mice exposed to dim light at night post-CA. Furthermore, selective inhibition of IL-1β or TNFα ameliorated damage in mice exposed to dim light at night. The effects of light at night on CA outcomes were also prevented by using a wavelength of nighttime light that has minimal impact on the endogenous circadian clock, suggesting that replacing broad-spectrum nighttime light with specific circadian-inert wavelengths could be protective. Together, these data indicate that exposure to dim light at night after global cerebral ischemia increases neuroinflammation, in turn exacerbating neurological damage and potential for mortality.

Resume Objectif L’allo-immunisation est une pathologie dont l’incidence a fortement diminue mais dont le pronostic reste sombre en l’absence de traitement. L’objectif de notre etude etait d’evaluer le pronostic fœtal, le taux ainsi que les facteurs de risque de complications des transfusions in utero (TIU). Methodes Il s’agit d’une etude observationnelle retrospective portant sur 86 TIU chez 37 fœtus entre 2001 et 2017. Notre critere de jugement principal etait la survenue d’une complication secondaire a la procedure. Le critere composite de complications etait defini comme suit : rupture prematuree des membranes ou accouchement premature dans les 7 jours suivant le geste, chorioamniotite, anomalies du rythme cardiaque fœtal indiquant la realisation d’une cesarienne en urgence dans les 24 heures suivant une TIU, et deces in utero ou neonatal secondaire a une TIU. Resultats Le taux de survie etait de 88,9 % avec un taux de complications severes de 5,8 % par TIU et de 13,5 % par grossesse. Une TIU avant 20 semaines d’amenorrhee etait un facteur de risque de complications : 50 % de complications en cas de premiere TIU avant 20SA versus 1,3 % en cas de premiere TIU apres 20SA, p = 0,8 × 10−3. Au contraire, l’anasarque ne semblait pas etre un facteur de risque de complication (16,7 % en cas d’anasarque versus 3,9 % en l’absence d’anasarque, p = 0,27) mais ce resultat est a nuancer du fait du faible effectif d’anasarque. La voie d’abord, qu’elle soit intra-abdominale ou au niveau de l’insertion placentaire, n’avait pas d’influence sur le pronostic. Conclusion La TIU est une therapeutique permettant un pronostic obstetrical favorable et peu pourvoyeuse de complications graves. Neanmoins, la necessite de realiser une TIU precoce est souvent associee a des complications.

Most adult humans have been infected with Epstein-Barr virus (EBV), which is thought to contribute to the development of chronic fatigue syndrome. Stress is known to influence the immune system and can exacerbate the sickness response. Although a role for psychological stress in the sickness response, particularly in combination with EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) has been established, and the role of physical stressors in these interactions remains unspecified. In this study, we seek to determine the interaction of chronic physical (swim) stress and EBV-encoded dUTPase injection. We hypothesize that a chronic physical stressor will exacerbate the sickness response following EBV-encoded dUTPase injection. To test this hypothesis mice receive daily injections of EBV-encoded dUTPase or vehicle and are subjected to 15 min of swim stress each day for 14 days or left unmanipulated. On the final evening of injections mice undergo behavioral testing. EBV-encoded dUTPase injection alone produces some sickness behaviors. The physical swimming stress does not alter the sickness response.

Two studies examined the effectiveness of the Fuzzy Processing Preference Index, (FPPI) an individual differences measure of base rate neglect/respect, and an objective numeracy scale in predicting subjective probabilities of the likelihood of breast cancer, BRCA mutations, and the conditional probability of breast cancer given BRCA mutations in medical risk scenarios. FPPI and objective numeracy independently predicted estimate accuracy for breast cancer and genetic mutation risk. Surprisingly, objective numeracy positively correlated with overestimating conditional probabilities across the board, as well as BRCA mutations and breast cancer risk for high-risk scenarios. FPPI was strongest in predictions for high-risk scenarios, but did not predict conditional probability estimates. FPPI uniquely predicts risk estimation accuracy controlling for objective numeracy suggesting the two measures assess distinct cognitive processes. We conclude that FPPI and other numeracy measures may be profitably used together, and FPPI appears better than traditional numeracy measures in some medical decision-making contexts.

The intelligent tutoring system (ITS) BRCA Gist is a Web-based tutor developed using the Shareable Knowledge Objects (SKO) platform that uses latent semantic analysis to engage women in natural-language dialogues to teach about breast cancer risk. BRCA Gist appears to be the first ITS designed to assist patients' health decision making. Two studies provide fine-grained analyses of the verbal interactions between BRCA Gist and women responding to five questions pertaining to breast cancer and genetic risk. We examined how "gist explanations" generated by participants during natural-language dialogues related to outcomes. Using reliable rubrics, scripts of the participants' verbal interactions with BRCA Gist were rated for content and for the appropriateness of the tutor's responses. Human researchers' scores for the content covered by the participants were strongly correlated with the coverage scores generated by BRCA Gist, indicating that BRCA Gist accurately assesses the extent to which people respond appropriately. In Study 1, participants' performance during the dialogues was consistently associated with learning outcomes about breast cancer risk. Study 2 was a field study with a more diverse population. Participants with an undergraduate degree or less education who were randomly assigned to BRCA Gist scored higher on tests of knowledge than those assigned to the National Cancer Institute website or than a control group. We replicated findings that the more expected content that participants included in their gist explanations, the better they performed on outcome measures. As fuzzy-trace theory suggests, encouraging people to develop and elaborate upon gist explanations appears to improve learning, comprehension, and decision making.

Traumatic brain injuries (TBIs) are a common and costly ongoing public health concern. Injuries that occur during childhood development can have particularly profound and long-lasting effects. One common consequence and potential mediator of negative outcomes of TBI is sleep disruption which occurs in a substantial proportion of TBI patients. These individuals report greater incidences of insomnia and sleep fragmentation combined with a greater overall sleep requirement meaning that many patients are chronically sleep-deprived. We sought to develop an animal model of developmental TBI-induced sleep dysfunction. Specifically, we tested the hypothesis that early (postnatal day 21), repeated closed head injuries in Swiss-Webster mice, would impair basal and homeostatic sleep responses in adulthood. Further, we asked whether environmental enrichment (EE), a manipulation that improves functional recovery following TBI and has been shown to alter sleep physiology, would prevent TBI-induced sleep dysfunction and alter sleep-modulatory peptide expression. In contrast to our hypothesis, the mild, repeated head injury that we used did not significantly alter basal or homeostatic sleep responses in mice housed in standard laboratory conditions. Sham-injured mice housed in enriched environments exhibited enhanced rapid eye movement (REM) sleep and expression of the REM-promoting peptide pro-melanin-concentrating hormone, an effect that was not apparent in TBI mice housed in enriched environments. Thus, TBI blocked the REM-enhancing effects of EE. This work has important implications for the management and rehabilitation of the TBI patient population.

Traumatic brain injuries (TBI) sustained during peri-adolescent development produce lasting neuro-behavioral changes that render individuals at an increased risk for developing substance abuse disorders. Experimental and clinical evidence of a prolonged period of hypodopaminergia after TBI have been well documented, but the effect of juvenile TBI on dopaminergic dysfunction and its relationship with substance abuse have not been investigated. In order to determine the effect of juvenile brain injury on dopaminergic signaling, female mice were injured at 21 days of age and then beginning seven weeks later were assessed for behavioral sensitization to amphetamine, a drug that increases synaptic dopamine availability. Together with a histological analysis of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor expression, our data are indicative of a persistent state of hypodopaminergia well into adulthood after a juvenile TBI. Further, mice that sustained a juvenile TBI exhibited a significantly reduced activation of cFos in the urocortin-positive cells of the Edinger-Westphal nucleus in response to ethanol administration. Taken together, these data provide strong evidence for the vulnerability of juveniles to the development of lasting neuro-behavioral problems following TBI, and indicate a role of injury-induced hypodopaminergia as a risk factor for substance abuse later in life.

Traumatic brain injuries are strongly related to alcohol intoxication as by some estimates half or more of all brain injuries involve at least one intoxicated individual. Additionally, there is mounting evidence that traumatic brain injuries can themselves serve as independent risk factors for the development of alcohol use disorders, particularly when injury occurs during juvenile or adolescent development. Here, we will review the epidemiological and experimental evidence for this phenomenon and discuss potential psychosocial mediators including attenuation of negative affect and impaired decision making as well as neurochemical mediators including disruption in the glutamatergic, GABAergic, and dopaminergic signaling pathways and increases in inflammation.

During spaceflight, crewmembers are subjected to biomechanical and biological challenges including microgravity and radiation. In the skeleton, spaceflight leads to bone loss, increasing the risk of fracture. Studies utilizing hindlimb suspension (HLS) as a ground-based model of spaceflight often neglect the concomitant effects of radiation exposure, and even when radiation is accounted for, it is often delivered at a high-dose rate over a very short period of time, which does not faithfully mimic spaceflight conditions. This study was designed to investigate the skeletal effects of low-dose rate gamma irradiation (8.5 cGy gamma radiation per day for 20 days, amounting to a total dose of 1.7 Gy) when administered simultaneously to disuse from HLS. The goal was to determine whether continuous, low-dose rate radiation administered during disuse would exacerbate bone loss in a murine HLS model. Four groups of 16 week old female C57BL/6 mice were studied: weight bearing + no radiation (WB+NR), HLS + NR, WB + radiation exposure (WB+RAD), and HLS+RAD. Surprisingly, although HLS led to cortical and trabecular bone loss, concurrent radiation exposure did not exacerbate these effects. Our results raise the possibility that mechanical unloading has larger effects on the bone loss that occurs during spaceflight than low-dose rate radiation.

Vaccination of the donor might have prevented infection in the recipient and subsequent transmission to healthcare workers., Although transmission of hepatitis A virus (HAV) through blood transfusion has been documented, transmission through organ transplantation has not been reported. In August 2015, state health officials in Texas, USA, were notified of 2 home health nurses with HAV infection whose only common exposure was a child who had undergone multi–visceral organ transplantation 9 months earlier. Specimens from the nurses, organ donor, and all organ recipients were tested and medical records reviewed to determine a possible infection source. Identical HAV RNA sequences were detected from the serum of both nurses and the organ donor, as well as from the multi–visceral organ recipient’s serum and feces; this recipient’s posttransplant liver and intestine biopsy specimens also had detectable virus. The other organ recipients tested negative for HAV RNA. Vaccination of the donor might have prevented infection in the recipient and subsequent transmission to the healthcare workers.

Background: Some highly penetrant familial cancer syndromes exhibit elevated leukaemia risk, and there is evidence for familial clustering of lung cancer and other common cancers. Lung cancer and leukaemia are strongly radiogenic, but there are few indications that high-energy beam irradiation is markedly more effective than lower-energy radiation. Methods: We used a Cox model with familially structured random effects to assess 16 mortality end points in a group of 1850 mice in 47 families maintained in a circular-breeding scheme, exposed to accelerated Si or Fe ions (0.4 Gy) or 137Cs gamma rays (3 Gy). Results: There is periodicity in the effect of familial relatedness, which is most pronounced for pulmonary adenoma, Harderian-gland adenoma, Harderian-gland tumour, ectodermal tumour, pulmonary adenocarcinoma and hepatocellular carcinoma (P=0.0001/0.0003/0.0017/0.0035/0.0257/0.0340, respectively) with families that are 3–4 generations apart most strongly correlated; myeloid leukaemia also exhibited a striking periodic correlation structure. The relative risks of high-energy Si or Fe ions are not significantly different and are less than for 137Cs gamma-rays for most end points at the doses used. Conclusions: There is periodicity in the effect of familial relatedness for various cancer sites. The effects per unit dose of high-energy charged particle beams are no higher than ninefold those of lower-energy gamma radiation.

Kangaroo care is a unique tool to take good care of the mother and the baby in case of opioids and other sub- stances use during pregnancy. Allowing both neonatological medical care and good basis for a tight relation between the mother and the newborn without any separation, the Kangaroo unit is the best place to cure the baby, to evaluate mother's skills and and further- more allows a reduction in withdrawal symptoms requiring the use of opioids in children and durations of less hospitalization.

Rapid remodeling of neurons provides the brain with flexibility to adjust to environmental fluctuations. In Siberian hamsters, hippocampal dendritic morphology fluc- tuates across the day. To reveal the regulatory mechanism of diurnal remodeling of hippocampal neurons, we investi- gated the effects of light signals applied under different photoperiodic conditions on dendritic morphology. A 4-h dark pulse during the morning of long days (LD) increased basilar dendritic length, as well as complexity of basilar den- drites of neurons in the CA1. A light pulse during the late night in short days (SD) reduced basilar dendrite branching and increased primary apical dendrites of CA1 neurons. Spine density of dentate gyrus (DG) dendrites was increased by a dark pulse in LD and spine density of CA1 basilar dendrites was decreased by a light pulse in SD. These results indicate that light signals induce rapid remod- eling of dendritic morphology in a hippocampal subregion- specific manner. A light pulse in SD decreased hippocampal expression of fetal liver kinase 1 (Flk1), a receptor for vascu- lar endothelial growth factor (VEGF), raising the possibility that VEGF-FLK1 signaling might be involved in the rapid decrease of branching or spine density of CA1 basilar dendrites by light. 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Background. Many healthy women consider genetic testing for breast cancer risk, yet BRCA testing issues are complex. Objective. To determine whether an intelligent tutor, BRCA Gist, grounded in fuzzy-trace theory (FTT), increases gist comprehension and knowledge about genetic testing for breast cancer risk, improving decision making. Design. In 2 experiments, 410 healthy undergraduate women were randomly assigned to 1 of 3 groups: an online module using a Web-based tutoring system (BRCA Gist) that uses artificial intelligence technology, a second group read highly similar content from the National Cancer Institute (NCI) Web site, and a third that completed an unrelated tutorial. Intervention. BRCA Gist applied FTT and was designed to help participants develop gist comprehension of topics relevant to decisions about BRCA genetic testing, including how breast cancer spreads, inherited genetic mutations, and base rates. Measures. We measured content knowledge, gist comprehension of decision-relevant information, interest in testing, and genetic risk and testing judgments. Results. Control knowledge scores ranged from 54% to 56%, NCI improved significantly to 65% and 70%, and BRCA Gist improved significantly more to 75% and 77%, P < 0.0001. BRCA Gist scored higher on gist comprehension than NCI and control, P < 0.0001. Control genetic risk-assessment mean was 48% correct; BRCA Gist (61%) and NCI (56%) were significantly higher, P < 0.0001. BRCA Gist participants recommended less testing for women without risk factors (not good candidates; 24% and 19%) than controls (50%, both experiments) and NCI (32%), experiment 2, P < 0.0001. BRCA Gist testing interest was lower than in controls, P < 0.0001. Limitations. BRCA Gist has not been tested with older women from diverse groups. Conclusions. Intelligent tutors, such as BRCA Gist, are scalable, cost-effective ways of helping people understand complex issues, improving decision making.

Stressors during early life induce anxiety- and depressive-like responses in adult rodents. Siberian hamsters (Phodopus sungorus) exposed to short days post-weaning also increase adult anxiety- and depressive-like behaviors. To test the hypothesis that melatonin and exposure to stressors early in life interact to alter adult affective responses, we administered melatonin either during the perinatal (gestational day 7 to postnatal day 14) or postnatal (day 15–56) periods and also exposed a subset of dams to restraint during gestation (1 h–2×/day for 4 days). During the final week of injections, depressive-like behaviors were assessed using the sucrose anhedonia and forced swim tests. Hamsters exposed to prenatal restraint and treated with melatonin only during the postnatal period increased depressive-like responses in the forced swim test relative to all other groups. Offspring from restrained dams increased the number of fecal boli produced during the forced swim test, an anxiety-like response. In the present study, prenatal restraint reduced CA1 dendritic branching overall and perinatal melatonin protected hamsters from this restraint-induced reduction. These results suggest that the photoperiodic conditions coincident with birth and early life stressors are important in the development of adult affective responses.

Photoperiodic regulation of physiology, morphology, and behavior is crucial for many animals to survive seasonally variable conditions unfavorable for reproduction and survival. The photoperiodic response in mammals is mediated by nocturnal secretion of melatonin under the control of a circadian clock. However, artificial light at night caused by recent urbanization may disrupt the circadian clock, as well as the photoperiodic response by blunting melatonin secretion. Here we examined the effect of dim light at night (dLAN) (5 lux of light during the dark phase) on locomotor activity rhythms and short-day regulation of reproduction, body mass, pelage properties, and immune responses of male Siberian hamsters. Short-day animals reduced gonadal and body mass, decreased spermatid nuclei and sperm numbers, molted to a whiter pelage, and increased pelage density compared to long-day animals. However, animals that experienced short days with dLAN did not show these short-day responses. Moreover, short-day specific immune responses were altered in dLAN conditions. The nocturnal activity pattern was blunted in dLAN hamsters, consistent with the observation that dLAN changed expression of the circadian clock gene, Period1. In addition, we demonstrated that expression levels of genes implicated in the photoperiodic response, Mel-1a melatonin receptor, Eyes absent 3, thyroid stimulating hormone receptor, gonadotropin-releasing hormone, and gonadotropin-inhibitory hormone, were higher in dLAN animals than those in short-day animals. These results suggest that dLAN disturbs the circadian clock function and affects the molecular mechanisms of the photoperiodic response.

Environmental light-dark cycles play an important role in behavioural and physiological processes. It is essential that laboratory vivaria be designed to properly control the light conditions in which laboratory mice are housed; however, this is not universally the case. Some laboratory vivarium doors are designed with windows, which allow light from the hallways to leak into the housing space during the rodents’ dark phase. Personnel entering and exiting the housing space during the dark phase can also create excessive light leak from brightly illuminated hallways. In this study, we investigated the hypothesis that exposure to dim light at night, as commonly experienced in many laboratory rodent housing spaces, alters mouse (Mus musculus) behaviour. We specifically analysed patterns of locomotor activity, anxiety- and depressive-like responses. Exposure to dim (5 lux) light at night altered home-cage locomotor activity and increased anxiety and some depressive responses among laboratory mice. These results suggest that light conditions can alter mouse behaviour and potentially influence experimental outcomes. Increased care should be taken to properly control light-dark conditions for laboratory animals.

Elevated nighttime light exposure is associated with symptoms of metabolic syndrome. In industrialized societies, high-fat diet (HFD) and exposure to light at night (LAN) often cooccur and may contribute to the increasing obesity epidemic. Thus, we hypothesized that dim LAN (dLAN) would provoke additional and sustained body mass gain in mice on a HFD. Male mice were housed in either a standard light/dark cycle or dLAN and fed either chow or HFD. Exposure to dLAN and HFD increase weight gain, reduce glucose tolerance, and alter insulin secretion as compared with light/dark cycle and chow, respectively. The effects of dLAN and HFD appear additive, because mice exposed to dLAN that were fed HFD display the greatest increases in body mass. Exposure to both dLAN and HFD also change the timing of food intake and increase TNFα and MAC1 gene expression in white adipose tissue after 4 experimental weeks. Changes in MAC1 gene expression occur more rapidly due to HFD as compared with dLAN; after 5 days of experimental conditions, mice fed HFD already increase MAC1 gene expression in white adipose tissue. HFD also elevates microglia activation in the arcuate nucleus of the hypothalamus and hypothalamic TNFα, IL-6, and Ikbkb gene expression. Microglia activation is increased by dLAN, but only among chow-fed mice and dLAN does not affect inflammatory gene expression. These results suggest that dLAN exaggerates weight gain and peripheral inflammation associated with HFD.

Autonomic dysreflexia (AD), a potentially dangerous complication of high-level spinal cord injury (SCI) characterized by exaggerated activation of spinal autonomic (sympathetic) reflexes, can cause pulmonary embolism, stroke, and, in severe cases, death. People with high-level SCI also are immune compromised, rendering them more susceptible to infectious morbidity and mortality. The mechanisms underlying postinjury immune suppression are not known. Data presented herein indicate that AD causes immune suppression. Using in vivo telemetry, we show that AD develops spontaneously in SCI mice with the frequency of dysreflexic episodes increasing as a function of time postinjury. As the frequency of AD increases, there is a corresponding increase in splenic leucopenia and immune suppression. Experimental activation of spinal sympathetic reflexes in SCI mice (e.g., via colorectal distension) elicits AD and exacerbates immune suppression via a mechanism that involves aberrant accumulation of norepinephrine and glucocorticoids. Reversal of postinjury immune suppression in SCI mice can be achieved by pharmacological inhibition of receptors for norepinephrine and glucocorticoids during the onset and progression of AD. In a human subject with C5 SCI, stimulating the micturition reflex caused AD with exaggerated catecholamine release and impaired immune function, thus confirming the relevance of the mouse data. These data implicate AD as a cause of secondary immune deficiency after SCI and reveal novel therapeutic targets for overcoming infectious complications that arise due to deficits in immune function.

With the exception of high latitudes, life has evolved under bright days and dark nights. Most organisms have developed endogenously driven circadian rhythms that are synchronized to this daily light/dark cycle. In recent years, humans have shifted away from the naturally occurring solar light cycle in favor of artificial and sometimes irregular light schedules produced by electric lighting. Exposure to unnatural light cycles is increasingly associated with obesity and metabolic syndrome; however, the means by which environmental lighting alters metabolism are poorly understood. Thus, we exposed mice to dim light at night and investigated changes in the circadian system and metabolism. Here we report that exposure to ecologically relevant levels of dim (5 lux) light at night altered core circadian clock rhythms in the hypothalamus at both the gene and protein level. Circadian rhythms in clock expression persisted during light at night; however, the amplitude of Per1 and Per2 rhythms was attenuated in the hypothalamus. Circadian oscillations were also altered in peripheral tissues critical for metabolic regulation. Exposure to dimly illuminated, as compared to dark, nights decreased the rhythmic expression in all but one of the core circadian clock genes assessed in the liver. Additionally, mice exposed to dim light at night attenuated Rev-Erb expression in the liver and adipose tissue. Changes in the circadian clock were associated with temporal alterations in feeding behavior and increased weight gain. These results are significant because they provide evidence that mild changes in environmental lighting can alter circadian and metabolic function. Detailed analysis of temporal changes induced by nighttime light exposure may provide insight into the onset and progression of obesity and metabolic syndrome, as well as other disorders involving sleep and circadian rhythm disruption.

Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-α gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA.