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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.

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%

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

The Department of Defense (DoD) is implementing universal behavioral health screening for all DoD health-care beneficiaries presenting to military primary care clinics. The PTSD Checklist-Civilian Version (PCL-C; Weathers, Litz, Herman, Huska, & Keane, 1993) is used for the identification of posttraumatic stress disorder (PTSD); however, the operating characteristics of the PCL-C remain unstudied in this population. This study examined the operating characteristics of the PCL-C in a sample of 213 patients from 3 Washington, D.C., area military primary care clinics. Blinded raters independently assessed PTSD using the PTSD Symptom Scale Interview (Foa, Riggs, Dancu, & Rothbaum, 1993) as the diagnostic criterion standard. The receiver operating characteristic curve revealed that PCL-C scores accounted for 92% of the area under the curve. A PCL-C score of 31 optimized sensitivity (0.93) and specificity (0.90), and the multilevel likelihood ratio was 5.50 (95% confidence interval [2.26, 13.37]). Internal consistency (0.97) and test-retest reliability (0.87 after a median 13 days) were strong. Results suggest that a PCL-C score of 31 is the optimal cutoff score for use in a military primary care setting serving active duty service members, dependents, and retirees. These findings offer military primary care providers preliminary data to interpret PCL-C scores and to inform treatment decisions as part of routine clinical practice.

Traumatic brain injury (TBI) is closely and bi-directionally linked with alcohol use, as by some estimates intoxication is the direct or indirect cause of one-third to one-half of all TBI cases. Alcohol use following injury can reduce the efficacy of rehabilitation and increase the chances for additional injury. Finally, TBI itself may be a risk factor for the development of alcohol use disorders. Children who suffer TBIs have poorer life outcomes and more risk of substance abuse. We used a standardized closed-head injury to model mild traumatic brain injuries. We found that mice injured as juveniles but not during adulthood exhibited much greater alcohol self-administration in adulthood. Further, this phenomenon was limited to female mice. Using behavioral testing, including conditioned place preference assays, we showed that early injuries increase the rewarding properties of alcohol. Environmental enrichment administered after injury reduced axonal degeneration and prevented the increase in drinking behavior. Additionally, brain-derived neurotrophic factor gene expression, which was reduced by TBI, was normalized by environmental enrichment. Together, these results suggest a novel model of alterations in reward circuitry following trauma during development.

Sleep is regulated by circadian and homeostatic processes, but can be altered by infectious disease. During infection or exposure to inflammatory stimuli, such as bacterial lipopolysaccharide (LPS), the duration and intensity of non–rapid eye movement sleep (NREMS), as measured by electoencephalogram (EEG) delta waves (.5–4 Hz), increase. These sleep alterations are hypothesized to conserve or redirect energy for immune system activation. Many vertebrates exhibit seasonal changes in immune function and sleep-wake cycle, and photoperiod (day length) serves as a reliable environmental cue. For example, winter is energetically demanding for most animals, and Siberian hamsters (Phodopus sungorus) adapted to short winter day lengths display reduced fever after LPS administration to presumably conserve energy. We hypothesized that short days increase the duration and intensity of NREMS after LPS challenge to create additional energy savings, despite evidence to the contrary that high fever is associated with increased NREMS. Male hamsters were housed under long (16 h light (L):8 h dark (D)) or short (8L:16D) day lengths, and chronically implanted with transmitters that recorded EEG and electromyogram (EMG) biopotentials simultaneously or core body temperature. After >10 wks in photoperiod conditions, hamsters received an i.p. injection of LPS or saline (control), and vigilance states (duration and distribution of NREMS, rapid eye movement sleep (REMS), and wakefulness) and EEG delta power spectra (NREMS intensity) were assessed. As expected, LPS treatment increased the duration and intensity of NREMS compared to controls. Hamsters adapted to short photoperiods exhibited cumulatively larger increases in NREMS duration and EEG delta wave amplitude 0–8 h after LPS injection compared to long-day LPS-treated hamsters despite short-day attenuation of fever. These results suggest a seasonal decoupling of LPS-induced fever with sleep to promote energy conservation during predictable energy shortages. Ultimately, the combination of increased sleep and reduced fever could represent a suite of physiological adaptations that increase the probability of surviving winter. (Author correspondence: Noah. Ashley@osumc.edu)

In most parts of the world, environmental conditions vary in a predictable seasonal manner. Thus, seasonal variation in reproductive timing and immune function has emerged in some species to cope with disparate seasonal demands. During the long days of spring and summer when food availability is high and thermoregulatory demands low, Siberian hamsters invest in reproduction, whereas during the harsh short days of winter hamsters divert energy away from reproductive activities and modify immune capabilities. Many seasonal adaptations can be recapitulated in a laboratory setting by adjusting day length (photoperiod). Early-life photoperiods are important sources of seasonal information and can establish an individual’s developmental trajectory. Siberian hamsters housed under short days (SD; 8 h light/day) recover more rapidly than long-day (LD; 16 h light/day) hamsters from immune activation with lipopolysaccharide (LPS). SD hamsters attenuate fever response, reduce cytokine production, and abrogate behavioral responses following LPS injection. The mechanism by which SD Siberian hamsters attenuate febrile response remains unspecified. It is possible that periphery-to-brain communication of inflammatory signals is altered by exposure to photoperiod. Rather than testing photoperiod effects on each of the multiple routes by which immunological cues are communicated to the CNS, we administered LPS intracerebroventricularly (i.c.v.) following adolescent exposure to either 6 weeks of SD or LD. Injection of LPS i.c.v. led to a similar immune reaction in SD hamsters as previously reported with intraperitoneal injection. Short days attenuated the response to LPS with diminished fever spike and duration, as well as decreased locomotor inactivity. Furthermore, only LD hamsters demonstrated anhedonic-like behavior following LPS injection as evaluated by decreased preference for a milk solution. These results suggest that photoperiodic differences in response to infection are due in part to changes in central immune activation.

PURPOSE: Neurogenic detrusor overactivity (NDO) is common in patients who suffer from multiple sclerosis (MS). When the usual pharmacological treatment fails, botulinum toxin type A (BTX-A) injections can be proposed. The safety and efficacy of this treatment are already well known, but only a few studies focus on its use in patients with MS. MATERIALS AND METHODS: Seventy-one patients with MS underwent their first BTX-A injection for refractory NDO. They had clinical and urodynamic cystometry assessment before and three months after injection. The patients were divided in three groups according to treatment efficacy: full success (total urinary continence, no overactive detrusor), improvement, or total failure (urge incontinence and overactive detrusor). RESULTS: 77% of the patients had clinical improvement or full success of the treatment with a reduction of their urgency and incontinence. Significant urodynamic improvement after treatment was shown on different parameters: volume at first involuntary bladder contraction (p = 0.0000001), maximum cystometric capacity (p = 0.0035), maximum detrusor pressure (p = 0.0000001). 46% of the patients were in the "full success" group. 31% of the patients had a partial improvement. 23% of the patients had no efficacy of the treatment. Duration of MS was a predictive factor of treatment failure (p = 0.015). CONCLUSIONS: Despite that a full success was obtained in 46% of the cases, BTX-A injection therapy failed to treat refractory NDO in 23% of patients suffering from MS. Duration of the disease was a predictive factor for an inefficient treatment. The injection therapy should be considered as soon as oral anticholinergic drugs fail to reduce NDO.

Both normal aging and dementia are associated with dysregulation of the biological clock, which contributes to disrupted circadian organization of physiology and behavior. Diminished circadian organization in conjunction with the loss of cholinergic input to the cortex likely contributes to impaired cognition and behavior. One especially notable and relatively common circadian disturbance among the aged is “sundowning syndrome,” which is characterized by exacerbated anxiety, agitation, locomotor activity, and delirium during the hours before bedtime. Sundowning has been reported in both dementia patients and cognitively intact elderly individuals living in institutions; however, little is known about temporal patterns in anxiety and agitation, and the neurobiological basis of these rhythms remains unspecified. In the present study, we explored the diurnal pattern of anxiety-like behavior in aged and amyloid precursor protein (APP) transgenic mice. We then attempted to treat the observed behavioral disturbances in the aged mice using chronic nightly melatonin treatment. Finally, we tested the hypothesis that time-of-day differences in acetylcholinesterase and choline acetyltransferase expression and general neuronal activation (i.e., c-Fos expression) coincide with the behavioral symptoms. Our results show a temporal pattern of anxiety-like behavior that emerges in elderly mice. This behavioral pattern coincides with elevated locomotor activity relative to adult mice near the end of the dark phase, and with time-dependent changes in basal forebrain acetylcholinesterase expression. Transgenic APP mice show a similar behavioral phenomenon that is not observed among age-matched wild-type mice. These results may have useful applications to the study and treatment of age- and dementia-related circadian behavioral disturbances, namely, sundowning syndrome.

The global increase in the prevalence of obesity and metabolic disorders coincides with the increase of exposure to light at night (LAN) and shift work. Circadian regulation of energy homeostasis is controlled by an endogenous biological clock that is synchronized by light information. To promote optimal adaptive functioning, the circadian clock prepares individuals for predictable events such as food availability and sleep, and disruption of clock function causes circadian and metabolic disturbances. To determine whether a causal relationship exists between nighttime light exposure and obesity, we examined the effects of LAN on body mass in male mice. Mice housed in either bright (LL) or dim (DM) LAN have significantly increased body mass and reduced glucose tolerance compared with mice in a standard (LD) light/dark cycle, despite equivalent levels of caloric intake and total daily activity output. Furthermore, the timing of food consumption by DM and LL mice differs from that in LD mice. Nocturnal rodents typically eat substantially more food at night; however, DM mice consume 55.5% of their food during the light phase, as compared with 36.5% in LD mice. Restricting food consumption to the active phase in DM mice prevents body mass gain. These results suggest that low levels of light at night disrupt the timing of food intake and other metabolic signals, leading to excess weight gain. These data are relevant to the coincidence between increasing use of light at night and obesity in humans.

Seasonal changes in day length (i.e., photoperiod) provide animals with a reliable environmental cue to determine time of year, and many physiological changes occur in laboratory animals simply by extending or shortening day length. Male Siberian hamsters (Phodopus sungorus) housed in long summer-like day lengths have significantly elevated body and fat masses compared to short-day hamsters. Because others have demonstrated that the intestinal microbiota of humans and rodents promotes host adiposity, we hypothesized that photoperiod-induced changes in body and fat masses could be associated with changes in the microbial composition in the intestines. We used bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP) to assess microbial diversity in the cecal contents of hamsters; long days significantly increased the relative abundance of bacteria in the phylum Proteobacteria. This effect was primarily due to a significant increase in the abundance of the genus Citrobacter, with both the abundance of Proteobacteria and Citrobacter spp. significantly correlated with body mass and with inguinal fat mass. In general, the abundance of the Firmicutes phylum was inversely associated with body mass. These data indicate that the intestinal microbiota are responsive to changes in photoperiod and suggest that these changes may in part influence photoperiodic changes in body and fat masses.

Individuals are increasingly exposed to light at night. Exposure to constant light (LL) disrupts circadian rhythms of locomotor activity, body temperature, hormones, and the sleep-wake cycle in animals. Other behavioural responses to LL have been reported, but are inconsistent. The present experiment sought to determine whether LL produces changes in affective responses and whether behavioural changes are mediated by alterations in glucocorticoid concentrations. Relative to conspecifics maintained in a light/dark cycle (LD, 16:8 light/dark), male Swiss-Webster mice exposed to LL for three weeks increased depressive-like behavioural responses as evaluated by the forced swim test and sucrose anhedonia. Furthermore, providing a light escape tube reversed the effects of LL in the forced swim test. LL mice displayed reduced anxiety as evaluated by the open field and elevated-plus maze. Glucocorticoid concentrations were reduced in the LL group suggesting that the affective behavioural responses to LL are not the result of elevated corticosterone. Additionally, mice housed in LD with a clear tube displayed increased paired testes mass as compared to LL mice. Taken together, these data provide evidence that exposure to unnatural lighting can induce significant changes in affect, increasing depressive-like and decreasing anxiety-like responses.

Ischemic events in humans are not evenly distributed across the day. To discriminate between temporal differences in the incidence of ischemia and susceptibility to ischemic events, we examined the outcome of global ischemia in a murine model at three time points during the day. Global cerebral ischemia in mice during the light phase impairs survival and exacerbates outcome compared to ischemia at other times of the day. Specifically, mice that underwent cardiac arrest during the light phase had greater numbers of degenerating neurons, greater microglial activation, and increased proinflammatory cytokine production in the ischemia-vulnerable hippocampus, as well as increased locomotor activity. Time-of-day differences were not altered by the melatonin receptor antagonist luzindole. Our results document that brain tissue displays endogenous fluctuations in susceptibility to ischemic damage and demonstrate that small differences in time of onset can significantly influence ischemic outcomes.

Estimates of cancer risks posed to space-flight crews by exposure to high atomic number, high-energy (HZE) ions are subject to considerable uncertainty because epidemiological data do not exist for human populations exposed to similar radiation qualities. We assessed the leukemogenic efficacy of one such HZE species, 1 GeV (56)Fe ions, a component of space radiation, in a mouse model for radiation-induced acute myeloid leukemia. CBA/CaJ mice were irradiated with 1 GeV/nucleon (56)Fe ions or (137)Cs gamma rays and followed until they were moribund or to 800 days of age. We found that 1 GeV/nucleon (56)Fe ions do not appear to be substantially more effective than gamma rays for the induction of acute myeloid leukemia (AML). However, (56)Fe-ion-irradiated mice had a much higher incidence of hepatocellular carcinoma (HCC) than gamma-irradiated mice, with an estimated RBE of approximately 50. These data suggest a difference in the effects of HZE iron ions on the induction of leukemia compared to solid tumors, suggesting potentially different mechanisms of tumorigenesis.

Outside of the tropics, environmental conditions fluctuate in a generally predictable manner across the year. Many small mammals have evolved mechanisms, such as seasonal breeding and annual adjustments in physiology, morphology, and behavior, that promote winter survival when food is scarce and thermoregulation is challenging. Photoperiod (day length) is a cue used by many seasonal breeders to predict seasonal changes in environmental conditions. One system that is uniquely situated to mediate photoperiod-induced alterations in physiology is the autonomic nervous system (ANS). The 2 branches of the ANS are key regulators of immune responses, thermoregulation, and energy balance, functions that undergo marked shifts in baseline and reactivity following acclimation to short day lengths. Although previous studies have investigated the effects of photoperiod on ANS endpoints, this study examined the direct effects of photoperiod on integrated ANS function. To test the hypothesis that short day lengths increase parasympathetic and sympathetic tones, we maintained adult male Siberian hamsters ( Phodopus sungorus ) to either long or short photoperiods and then analyzed electrocardiogram recordings. Short day lengths increased both parasympathetic tone, as measured by respiratory sinus arrhythmia, and sympathetic control of the heart, measured with autonomic blockade. Additionally, short day lengths enhanced the withdrawal of parasympathetic control and the increase of sympathetic tone in response to acute restraint stress. Finally, these effects were discovered to be independent of circulating androgens. These data indicate that the ANS of Siberian hamsters undergoes profound changes following prolonged exposure to short winter-like day lengths.

In most species, sexes differ in levels of parasitism. These differences have traditionally been believed to be static, but a capacity for adjusting anti-parasite investments would allow sexes to allocate resources adaptively contingent on environmental conditions. During stressful periods, such as a food shortage, allocation decisions would be mandated in males and females, but the biasing of resources may differ depending on the value of various physiological alternatives to the fitness of each sex. To determine whether sexes sacrifice immune or reproductive capacity when stressed, male and female Siberian hamsters (Phodopus sungorus) were pharmacologically deprived of glucose. Glucose deprivation was expected to compromise immune activity (delayed-type hypersensitivity) more than reproductive capacity in males because male fitness is limited by reproductive opportunities. The opposite was predicted for females because of the greater value of surviving to breed in favorable conditions. Contrary to expectations, glucoprivation compromised immune activity in female, but not male, hamsters. Conversely, glucoprivation reduced male, but not female, reproductive organ masses. These results may reflect the adjustments made by wild hamsters during food shortages, or they may be influenced by the study design; neither sex was permitted to incur other behavioral and physiological costs, such as lactation and parental care. Regardless, our results indicate that sex differences in parasitism are likely to be plastic in many circumstances, but further work in free-living animals is critical to ascertain whether results of the present study are naturally representative.

To prospectively compare the efficacy of 2-octylcyanoacrylate (Dermabond; Ethicon Inc, Somerville, NJ) with standard suture repair in the management of nail bed lacerations.Forty consecutive patients with acute nail bed lacerations were enrolled in this study. Eighteen patients were randomized to nail bed repair using Dermabond (2-octylcyanoacrylate), and 22 were randomized to standard repair using 6-0 chromic suture. At presentation, demographic information and laceration characteristics were recorded. The time required for nail bed laceration repair with each method was documented, and cosmetic and functional outcomes were assessed at 1, 3, and 6 months after injury. Comparisons between treatment groups were made using unpaired Student's t-tests.The Dermabond repair group was composed of 10 males and 8 females with a mean age of 32.3 years. The suture repair group was composed of 17 males and 5 females with a mean age of 29.5 years. The mean follow-up was 5.1 months (range 4-11 months) and 4.8 months (range 4-11 months) for the Dermabond group and suture group, respectively. There was no difference between the two treatment groups with respect to age, comorbidities, and length of follow-up (p.05). The average time required for nail bed repair using Dermabond was 9.5 minutes, which was significantly less than that required for suture repair (27.8 minutes) (p.0003). At each follow-up time point, there was no statistical difference in physician-judged cosmesis, patient-perceived cosmetic outcome, pain, or functional ability between the Dermabond and suture treatment cohorts (p.05).Nail bed repair performed using Dermabond is significantly faster than suture repair, and it provides similar cosmetic and functional results. In the management of acute nail bed lacerations, Dermabond is an efficient and effective repair technique.Therapeutic I.

Immune activity is variable within and among vertebrates despite the potentially large fitness costs of pathogens to their hosts. From the perspective of life history theory, immunological variability may be the consequence of counterbalancing investments in immune defense against other expensive physiological processes, namely, reproduction. In the present study, we tested the hypothesis that immune defense among captive-bred, disease-free Peromyscus mice would be influenced by their reproductive life history strategies. Specifically, we expected that small species that reproduce prolifically and mature rapidly (i.e., fast pace of life) would favor inexpensive, nonspecific immune defenses to promote reproductive proclivity. Alternatively, we expected that large species that mature slowly and invest modestly in reproduction over multiple events (i.e., slow pace of life) would favor developmentally expensive, specific immune defenses and avoid cheap, nonspecific ones because such defenses are predisposed to self-damage. We found that species exhibited either strong ability to kill (gram-negative) bacteria, a developmentally inexpensive defense, or strong ability to produce antibodies against a novel protein, a developmentally expensive defense, but not both. Cell-mediated inflammation also varied significantly among species, but in a unique fashion relative to bacteria killing or antibody production; wound healing was comparatively similar among species. These results indicate that Peromyscus species use immune strategies that are constrained to a dominant axis, but this axis is not determined solely by reproductive pace of life. Further comparisons, ideally with broader phylogenetic coverage, could identify what ecological and evolutionary forces produce the pattern we detected. Importantly, our study indicates that species may not be differentially immunocompetent; rather, they use unique defense strategies to prevent infection.

During winter, increased thermoregulatory demands coincide with limited food availability necessitating physiological tradeoffs among expensive physiological processes resulting in seasonal breeding among small mammals. In the laboratory, short winter-like day lengths induce regression of the reproductive tract, but also enhance many aspects of immune function. It remains unspecified the extent to which bolstered immune responses in short days represent enhanced immune function per se compared to long days or represents energetic disinhibition mediated by the regression of the reproductive tract. Cohabitation of male Siberian hamsters with intact female conspecifics can block short-day reproductive regression. We sought to determine whether female cohabitation could also block the enhanced immune function associated with short days. Adult male Siberian hamsters were housed in long or short day lengths in one of three housing conditions: (1) single-housed, (2) housed with a same sex littermate, or (3) housed with an ovariectomized female. Delayed-type hypersensitivity (DTH) responses were assessed after 8 weeks of photoperiod treatment. Housing with an ovariectomized female was not sufficient to block short-day reproductive regression, but prevented short-day enhancement of DTH responses. Housing with a male littermate did not alter reproductive or immune responses in either photoperiod. These data suggest that short day enhancement of immune function is independent of photoperiod-mediated changes in the reproductive system.

This study examined photoperiodic regulation of affective behaviours in collared lemmings (Dicrostonyx groenlandicus). Male and female lemmings were housed in either long (LD 22:2), intermediate (LD 16:8), or short days (LD 8:16) for 9 weeks. Exposure to short days induced moult to a winter pelage and gonadal regression in male, but not female, lemmings. Lemmings housed in long days reduced anxiety-like responses in the elevated plus maze. Depressive-like behaviours were decreased in the intermediate photoperiod relative to other photoperiod groups.

The immune system protects organisms against infection, but this protection presumably comes at a cost. Here, we asked whether food restriction would compromise the ability of an organism to generate an immune response on reexposure to an antigen, which would represent a functional cost of immunological memory. Immunological memory is generated when B and T lymphocytes sensitive to components of pathogens (i.e., antigens) proliferate after exposure and persist in circulation to hinder reinfection. To test the possibility that B cell memory, the component of the immune system responsible for antibody production, is expensive to maintain, secondary antibody production against a novel protein [keyhole limpet hemocyanin (KLH)] was compared in food-restricted and ad libitum-fed male deer mice ( Peromyscus maniculatus). To determine whether compromised secondary antibody production was solely due to elevated corticosterone independent of resource availability, some food-restricted and ad libitum-fed mice were subjected to unpredictable, chronic (2 h/day) restraint. Mice fed 70% of their ad libitum diet 2 wk after primary antigen challenge produced ∼95% less IgG against KLH after a second antigen challenge than mice fed ad libitum, even though all mice were fed ad libitum during the secondary antibody response period. Restraint had no effect on secondary IgG production in response to KLH, and corticosterone concentrations 1 day after food restriction did not differ between food-restricted and ad libitum-fed mice. Together, these data imply that secondary antibody responses and the benefits of immunological memory are energetically costly in this species.

Many nontropical rodent species experience predictable annual variation in resource availability and environmental conditions. Individuals of many animal species engage in energetically expensive processes such as breeding during the spring and summer but bias investment toward processes that promote survival such as immune function during the winter. Generally, the suite of responses associated with the changing seasons can be induced by manipulating day length (photoperiod). Collared lemmings ( Dicrostonyx groenlandicus) are arvicoline rodents that inhabit parts of northern Canada and Greenland. Despite the extreme conditions of winter in their native habitat, these lemmings routinely breed during the winter. In the laboratory, collared lemmings have divergent responses to photoperiod relative to other seasonally breeding rodents; short day lengths can stimulate, rather than inhibit, the reproductive system. Male and female collared lemmings were maintained for 11 weeks in 1 of 3 photoperiods (LD 22:2, LD 16:8, or LD 8:16) that induce markedly different phenotypes. Following photoperiod treatment, cell-mediated immune function as assessed by delayed-type hypersensitivity reactions was elevated in lemmings housed in LD 16:8 and LD 8:16 relative to LD 22:2. However, antibody production to a novel antigen was unaffected by photoperiod. Exposure to LD 8:16 induced weight gain, molt to a winter pelage, and in contrast to previous studies, regression of the male, but not the female, reproductive tract. In conclusion, these data indicate that components of immune function among collared lemmings are responsive to changes in day length.

We have investigated the use of the gamma-H2AX assay, reflecting the presence of DNA double-strand breaks, as a possible means for identifying individuals who are mildly hypersensitive to ionizing radiation, such as some ATM heterozygotes. We compared levels of gamma-H2AX foci after irradiation in cells from six apparently normal individuals as well as from individuals from two separate AT families including the proband, mother, father and three unaffected siblings in each family. After a 1-Gy single acute (high-dose-rate) gamma-ray dose delivered to noncycling contact-inhibited monolayers of cells, clear differences were seen between samples from normal individuals (ATM(+/+)) and probands (ATM(-/-)) at nearly all sampling times after irradiation, but no clear distinctions were seen for cells from normal compared to obligate heterozygotes (ATM(+/-)). In contrast, after 24 h of continuous irradiation at a dose rate of 10 cGy/h, appreciable differences in numbers of foci per cell were observed for cells from individuals for all the known ATM genotypes compared with controls. Four unaffected siblings had mean numbers of foci per cell similar to that for the obligate heterozygotes, whereas the other two had mean values similar to that for normal controls. We determined independently that those siblings with mean numbers of foci per cell in the range of ATM heterozygotes carried the mutant allele, while both siblings with a normal number of foci per cell after irradiation had normal alleles. A more limited set of experiments using lymphoblastoid cell strains in the low-dose-rate assay also revealed distinct differences for normal compared to ATM heterozygotes from the same families and opens the possibility of using peripheral blood lymphocytes as a more suitable material for an assay to detect mild hypersensitivities to radiation among individuals.

Background: The prevention and treatment of obesity is a public health challenge. Objective: We investigated the effects of dietary composition, insulin sensitivity (S I ), and energy balance on predicted changes in body composition. Design: In a randomized crossover design study, 39 normal-weight (n = 23), overweight (n = 8), and obese (n = 8) men and women (aged 25-36 y) each followed a 15-d isocaloric high-fat (HF; 50% fat) and high-carbohydrate [HC; 55% carbohydrate (CHO)] diet with a 4-6-wk washout period during the first year. During each treatment, energy balance was measured while the subjects were inactive by using indirect calorimetry on day 15, and S I was measured by using a euglycemic clamp study (40 mU m -2 · min -1 ) on day 16. Weight and body composition were then measured annually for 4 y. The outcomes for fat mass, percentage body fat, and weight were measured by using a linear 2-stage mixed model. Results: CHO balance (day 15) and S I (day 16) on the HC diet were highly and significantly correlated (r = 0.55, P < 0.001). On the HC diet, the subjects who had a higher positive CHO balance (day 15) gained less fat mass (P < 0.001), percentage body fat (P = 0.006), and weight (P = 0.024) over time. When adjusted for S I , CHO balance remained a significant predictor of changes in fat mass (P = 0.021) and percentage body fat (P = 0.025). Conclusions: On a HC diet, the subjects who had a higher positive CHO balance on day 15 while they were inactive gained less fat mass during 4 y, a predictive effect independent of S I . As suggested in rodents, the capacity to expand the glycogen pool might reduce energy intake and protect against fat and weight gain.

Although critical for transducing seasonal information, melatonin has also been implicated in several physiological systems, as well as the regulation of behavioral and cognitive processes. Therefore, we investigated the neurobehavioral effects of mice missing the type 1 melatonin receptor (MT1). Male and female MT1 knockout (MT1-/-) and wild-type (WT) mice were tested in the acoustic startle/prepulse inhibition (PPI), open field and Porsolt forced swim tests. Male and female MT1-/- mice displayed dramatically impaired prepulse inhibition in the acoustic startle response. Female WT mice were more active in the open field than WT males. However, male and female MT1-/- mice did not differ in total locomotor activity. WT animals spent significantly more time in the center of the arena (a behavioral outcome associated with reduced anxiety-like behavior) than MT1-/- mice. Also, the sex difference between male and female WT mice in the amount of time spent in the center versus periphery was not observed among MT1-/- mice. Both male and female MT1-/- mice significantly increased the time spent immobile in the forced swim test, an indication of depressed-like behavior. The lifetime lack of MT1 signaling contributes to behavioral abnormalities including impairments in sensorimotor gating and increases in depressive-like behaviors. Taken together, MT1 receptor signaling may be important for normal brain and behavioral function.

Purpose To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results A total of 210 tumors were induced within the radiation field in 788 mice. An overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor susceptibility among stromal cell populations.

Connections among theta rhythm, long-term potentiation (LTP) and memory in hippocampus are suggested by previous research, but definitive links are yet to be established. We investigated the hypothesis that resetting of local hippocampal theta to relevant stimuli in a working memory task produces optimal conditions for induction of LTP. The timings of the peak and trough of the first wave of reset theta were determined in initial sessions and used to time stimulation (4 pulses, 200 Hz) during subsequent performance. Stimulation on the peak of stimulus-reset theta produced LTP while stimulation on the trough did not. These results suggest that a memory-relevant stimulus produces a phase shift of ongoing theta rhythm that induces optimal conditions for the stimulus to undergo potentiation.

Objective— The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction. Methods and Results— Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG ( P P P P P P P P P =0.054) and post-heparin ( P =0.028) FFA. Conclusions— Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.

Background— The early response of C-reactive protein to initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) is not known. The purpose of this study was to determine the rate at which highly sensitive C-reactive protein (hsCRP) levels change after initiation of simvastatin and whether this occurs independently of the change in LDL cholesterol. Methods and Results— The study was a crossover, double-blind design including 40 subjects with elevated LDL cholesterol. Subjects were randomly assigned to 1 of 2 groups: simvastatin 40 mg for 14 days, then placebo for 14 days, or placebo first, then simvastatin. Simvastatin decreased LDL cholesterol by 56±4 mg/dL ( P P =0.02) at day 14. Baseline log(hsCRP) levels were similar in the 2 groups. By day 14, log(hsCRP) was significantly lower in patients on simvastatin when compared with placebo ( P =0.011). Although there was no significant difference in fibrinogen levels, simvastatin produced a modest increase in log[lipoprotein(a)] ( P =0.03) at days 7 and 14. There were no relationships between the decrease in LDL cholesterol and the decrease in hsCRP. Conclusions— Simvastatin lowers hsCRP by 14 days, independent of its effect on LDL cholesterol. This rapid impact of a statin on hsCRP has potential implications in the management of acute coronary syndromes.

Most murine radiation-induced acute myeloid leukemias involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion and the other allele affected by a recurrent point mutation in codon 235 that is likely to be spontaneous. The short latencies of acute myeloid leukemias occurring in nonirradiated mice engineered with PU.1 conditional knockout or knockdown alleles suggest that once both copies of PU.1 have been lost any other steps involved in leukemogenesis occur rapidly. Yet, spontaneous acute myeloid leukemias have not been reported in mice heterozygous for a PU.1 knockout allele, an observation that conflicts with the understanding that the PU.1 codon 235 mutation is spontaneous. Here we describe experiments that show that the lack of spontaneous leukemia in PU.1 heterozygous knockout mice is not due to insufficient monitoring times or mouse numbers or the genetic background of the knockout mice. The results reveal that spontaneous leukemias that develop in mice of the mixed 129S2/SvPas and C57BL/6 background of knockout mice arise by a pathway that does not involve biallelic PU.1 mutation. In addition, the latency of radiation-induced leukemia in PU.1 heterozygous mice on a genetic background susceptible to radiation-induced leukemia indicates that the codon 235 mutation is not a rate-limiting step in radiation leukemogenesis driven by PU.1 loss.

Repeated head injuries are a major public health concern both for athletes, and members of the police and armed forces. There is ample experimental and clinical evidence that there is a period of enhanced vulnerability to subsequent injury following head trauma. Injuries that occur close together in time produce greater cognitive, histological, and behavioral impairments than do injuries separated by a longer period. Traumatic brain injuries alter cerebral glucose metabolism and the resolution of altered glucose metabolism may signal the end of the period of greater vulnerability. Here, we injured mice either once or twice separated by three or 20 days. Repeated injuries that were separated by three days were associated with greater axonal degeneration, enhanced inflammatory responses, and poorer performance in a spatial learning and memory task. A single injury induced a transient but marked increase in local cerebral glucose utilization in the injured hippocampus and sensorimotor cortex, whereas a second injury, three days after the first, failed to induce an increase in glucose utilization at the same time point. In contrast, when the second injury occurred substantially later (20 days after the first injury), an increase in glucose utilization occurred that paralleled the increase observed following a single injury. The increased glucose utilization observed after a single injury appears to be an adaptive component of recovery, while mice with 2 injuries separated by three days were not able to mount this response, thus this second injury may have produced a significant energetic crisis such that energetic demands outstripped the ability of the damaged cells to utilize energy. These data strongly reinforce the idea that too rapid return to activity after a traumatic brain injury can induce permanent damage and disability, and that monitoring cerebral energy utilization may be a tool to determine when it is safe to return to the activity that caused the initial injury.

Most adult humans have been infected by Epstein-Barr virus (EBV) and carry the latent virus. The EBV genome codes for several proteins that form an early antigen complex important for viral replication; one of these proteins is deoxyuridine triphosphate nucleotidohydrolase (dUTPase). The EBV-encoded dUTPase can induce sickness responses in mice. Because stress can increase latent virus reactivation, we hypothesized that chronic restraint would exacerbate sickness behaviors elicited by EBV-encoded dUTPase. Male Swiss-Webster mice were injected daily for 15 days with either saline or EBV-encoded dUTPase. Additionally, half of the mice from each condition were either restrained for three h daily or left undisturbed. Restraint stress impaired learning and memory in the passive avoidance chamber; impaired learning and memory was due to EBV-encoded dUTPase-injected into restrained mice. EBV-encoded dUTPase induced sickness responses and restraint stress interacts with EBV-encoded dUTPase to exacerbate the sickness response. These data support a role for EBV-encoded dUTPase and restraint stress in altering the pathophysiology of EBV independent of viral replication.

During mammalian spermiogenesis, major restructuring of chromatin takes place. In the mouse, the histones are replaced by the transition proteins, TP1 and TP2, which are in turn replaced by the protamines, P1 and P2. To investigate the role of TP2, we generated mice with a targeted deletion of its gene, Tnp2. Spermatogenesis in Tnp2 null mice was almost normal, with testis weights and epididymal sperm counts being unaffected. The only abnormality in testicular histology was a slight increase of sperm retention in stage IX to XI tubules. Epididymal sperm from Tnp2-null mice showed an increase in abnormal tail, but not head, morphology. The mice were fertile but produced small litters. In step 12 to 16 spermatid nuclei from Tnp2-null mice, there was normal displacement of histones, a compensatory translationally regulated increase in TP1 levels, and elevated levels of precursor and partially processed forms of P2. Electron microscopy revealed abnormal focal condensations of chromatin in step 11 to 13 spermatids and progressive chromatin condensation in later spermatids, but condensation was still incomplete in epididymal sperm. Compared to that of the wild type, the sperm chromatin of these mutants was more accessible to intercalating dyes and more susceptible to acid denaturation, which is believed to indicate DNA strand breaks. We conclude that TP2 is not a critical factor for shaping of the sperm nucleus, histone displacement, initiation of chromatin condensation, binding of protamines to DNA, or fertility but that it is necessary for maintaining the normal processing of P2 and, consequently, the completion of chromatin condensation.

Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well-described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis as males, in addition to having reduced hippocampal volume in short days with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog BrdU at multiple time points across ten weeks of short day exposure. Compared to counterparts held in long day lengths, across the first eight weeks of short day exposure hippocampal neurogenesis was reduced. However, at ten weeks in short day lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in long day lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes, and adaptive responses to changing day lengths affects brain structure, function, and behavior at multiple levels.