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Description, Space radiation affects memory in male and not in female mice, and it is dependent on the innate immune system response., In the coming decade, astronauts will travel back to the moon in preparation for future Mars missions. Exposure to galactic cosmic radiation (GCR) is a major obstacle for deep space travel. Using multivariate principal components analysis, we found sex-dimorphic responses in mice exposed to accelerated charged particles to simulate GCR (GCRsim); males displayed impaired spatial learning, whereas females did not. Mechanistically, these GCRsim-induced learning impairments corresponded with chronic microglia activation and synaptic alterations in the hippocampus. Temporary microglia depletion shortly after GCRsim exposure mitigated GCRsim-induced deficits measured months after the radiation exposure. Furthermore, blood monocyte levels measured early after GCRsim exposure were predictive of the late learning deficits and microglia activation measured in the male mice. Our findings (i) advance our understanding of charged particle–induced cognitive challenges, (ii) provide evidence for early peripheral biomarkers for identifying late cognitive deficits, and (iii) offer potential therapeutic strategies for mitigating GCR-induced cognitive loss.

BACKGROUND: Sixty million rural residents have limited access to orthopedic care due to a small rural orthopedic surgery workforce. Increases in specialized training add to the challenge of attracting orthopedic surgeons to rural communities. Answering the call for research on models to meet the needs of rural orthopedic patients, we examine long-term trends in visiting consultant clinics (VCCs) in Iowa, a state with a large rural population. METHODS: The Office of Statewide Clinical Education Programs (Carver College of Medicine) compiles an annual report of outreach clinic locations, frequencies and participating physicians. Trends in the total number of VCCs, days and locations (1989-2018) were analysed using joinpoint analysis. RESULTS: Total clinic days grew rapidly from 1992-1997 (Average Percent Change: 19.7%) before a decline ending in 2009 (APC: -4.1%). A new growth period (2009-2013, APC: 7.5%) preceded another decline (APC: -3.6%) ending in 2018. The number of cities hosting a VCC grew from 56 (1989) to a peak of 90 (1999) and fell an average of 0.9% a year thereafter. More than 80% of all VCCs in the last ten years were offered 2 or more times per month. The average participation rate for Iowa-based orthopedic surgeons was 44%. The mean number of VCCs staffed by a single physician was 1.32 (std. dev. = 0.53) with a median of 1. The average number of VCC days per month for a participating physician was 3.22 (std. dev. = 2.41) with a median of 2.66. CONCLUSION: The VCC model of rural outreach is sustainable (30+ year history) and self-funded. Most clinics occur with sufficient frequency to allow timely follow-up care. This model of rural outreach is supported by the participation of a large segment (44%) of Iowa’s orthopedic surgeons. Visiting orthopedic surgeons provide access to care in 65 of the 76 Critical Access Hospitals in Iowa offering orthopedic services compared to 8 staffed by a local orthopedic surgeon. Level of Evidence: V

Purpose Studies are required to determine whether exposures to radiation encountered during manned missions in deep space may have adverse effects on the cardiovascular system. Most of the prior studies on effects of simulated space radiation on the heart and vasculature have been performed in mouse models. To provide data from a second animal species, two studies were performed to assess effects of high-energy charged particle radiation on the heart and abdominal aorta in a rat model. Materials and methods In study A, male Long Evans rats were exposed to whole-body protons (250 MeV, 0.5 Gy) or oxygen ions (16O, 600 MeV/n, 0.5 Gy), and ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 3, 5, 9 and 12 months after radiation, followed by tissue collection at 12 months. In study B, male Long Evans rats were exposed to 16O (1 GeV/n, 0.01-0.25 Gy), and hearts collected at 6 to 7 and 12 months for histology and western-blots. Results Both protons (250 MeV) and 16O (600 MeV/n) caused a decrease in left ventricular posterior wall thickness at 3-5 months, but did not change echocardiographic measures of cardiac function. In Pulsed-wave Doppler assessment of the abdominal aorta, an increase was seen in mean velocity, peak velocity, and velocity time integral at 12 months after 16O (600 MeV/n), suggesting a change in vascular function. There were no significant changes in histopathology or histological quantification of total collagens in heart or aorta. On the other hand, an increase was seen in a 75 kDa peptide of collagen type III in the left ventricle of rats exposed to protons (250 MeV) and 16O (600 MeV/n and 1 GeV/n), suggesting that radiation caused remodeling of existing collagens in the heart. 16O (600 MeV/n and 1 GeV/n) caused increases in left ventricular protein levels of immune cell markers CD2, CD4, CD8, and CD68. Conclusion A single low dose of whole body protons or 16O in male Long Evans rats did not change cardiac function or induce gross pathological changes in the heart or aorta, but induced mild changes in vascular function and remodeling of existing collagens in the heart. Altogether, studies in prior mouse models and the current work in rats indicate minor changes in cardiac function and structure after a low dose of single-ion radiation.

Space travel presents a number of environmental challenges to the central nervous system, including changes in gravitational acceleration that alter the terrestrial synergies between perception and action, galactic cosmic radiation that can damage sensitive neurons and structures, and multiple factors (isolation, confinement, altered atmosphere, and mission parameters, including distance from Earth) that can affect cognition and behavior. Travelers to Mars will be exposed to these environmental challenges for up to 3 years, and space-faring nations continue to direct vigorous research investments to help elucidate and mitigate the consequences of these long-duration exposures. This article reviews the findings of more than 50 years of space-related neuroscience research on humans and animals exposed to spaceflight or analogs of spaceflight environments, and projects the implications and the forward work necessary to ensure successful Mars missions. It also reviews fundamental neurophysiology responses that will help us understand and maintain human health and performance on Earth.

There is concern that degradation of vision as a result of space flight may compromise both mission goals and long-term quality of life after space travel. The visual disturbances may be due to a combination of intracerebral pressure changes and exposure to ionizing radiation. The retina and the retinal vasculature play important roles in vision, yet have not been studied extensively in relation to space travel and space radiation. The goal of the present study was to characterize oxidative damage and apoptosis in retinal endothelial cells after whole-body gamma-ray, proton and oxygen ((16)O) ion radiation exposure at 0.1 to 1 Gy. Six month old male C57Bl/6J mice were exposed whole-body to 600 MeV/n (16)O ions (0, 0.1, 0.25, 1 Gy), solar particle events (SPE)-like protons (0, 0.1, 0.25, 0.5 Gy) or (60)Co gamma-rays (0, 0.1, 0.25, 0.5 Gy). Eyes were isolated for examining endothelial nitric oxide synthase (eNOS) expression and characterization of apoptosis in retina and retinal endothelial cells at 2 weeks post irradiation. The expression of eNOS was significantly increased in the retina following proton and (16)O ions exposure. (16)O ions induced over 2-fold increase in eNOS expression compared to protons at the 2-week post irradiation time point (p

Background Space travel is associated with continuous low dose rate exposure to high linear energy transfer (LET) radiation. Pathophysiological manifestations after low dose radiation exposure are strongly influenced by non-cytocidal radiation effects, including changes in the microbiome and host gene expression. Although the importance of the gut microbiome in the maintenance of human health is well established, little is known about the role of radiation in altering the microbiome during deep-space travel. Results Using a mouse model for exposure to high LET radiation, we observed substantial changes in the composition and functional potential of the gut microbiome. These were accompanied by changes in the abundance of multiple metabolites, which were related to the enzymatic activity of the predicted metagenome by means of metabolic network modeling. There was a complex dynamic in microbial and metabolic composition at different radiation doses, suggestive of transient, dose-dependent interactions between microbial ecology and signals from the host’s cellular damage repair processes. The observed radiation-induced changes in microbiota diversity and composition were analyzed at the functional level. A constitutive change in activity was found for several pathways dominated by microbiome-specific enzymatic reactions like carbohydrate digestion and absorption and lipopolysaccharide biosynthesis, while the activity in other radiation-responsive pathways like phosphatidylinositol signaling could be linked to dose-dependent changes in the abundance of specific taxa. Conclusions The implication of microbiome-mediated pathophysiology after low dose ionizing radiation may be an unappreciated biologic hazard of space travel and deserves experimental validation. This study provides a conceptual and analytical basis of further investigations to increase our understanding of the chronic effects of space radiation on human health, and points to potential new targets for intervention in adverse radiation effects. Electronic supplementary material The online version of this article (doi:10.1186/s40168-017-0325-z) contains supplementary material, which is available to authorized users.

Hybrid open access refers to articles freely accessible via the Internet but which originate from an academic journal that provides most of its content via subscription. The effect of hybrid open access on citation counts and author behavior in the field of chemistry is something that has not been widely studied. We compared 814 open access articles and 27,621 subscription access articles published from 2006 through 2011 in American Chemical Society journals. As expected, the 2 comparison groups are not equal in all respects. Cumulative citation data were analyzed from years 2–5 following an article's publication date. A citation advantage for open access articles was correlated with the journal impact factor (IF) in low and medium IF journals, but not in high IF journals. Open access articles have a 24% higher mean citation rate than their subscription counterparts in low IF journals (confidence limits 8–42%, p = .0022) and similarly, a 26% higher mean citation rate in medium IF journals (confidence limits 14–40%, p < .001). Open access articles in high IF journals had no significant difference compared to subscription access articles (13% lower mean citation rate, confidence limits −27–3%, p = .10). These results are correlative, not causative, and may not be completely due to an open access effect. Authors of the open access articles were also surveyed to determine why they chose a hybrid open access option, paid the required article processing charge, and whether they believed it was money well spent. Authors primarily chose open access because of funding mandates; however, most considered the money well spent because open access increases information access to the scientific community and the general public, and potentially increases citations to their scholarship.

Background Raised intracellular Na+ impairs cardiac contractility in severe heart failure (HF). β3 adrenoceptor (β3 AR) agonists activate cardiomyocyte Na+-K+ pump-mediated Na+ export. Treatment with a selective β3 AR agonist in patients with severely reduced left ventricular ejection fraction (LVEF) and stable HF improves LVEF. We examined effects of β3 AR agonists on Na+-K+ pump function in experimental severe HF characterized by organ congestion and, in parallel, the clinical response in human treatment-refractory worsening chronic HF (WCHF). Methods The circumflex coronary artery was ligated in rabbits to induce HF. Treatment with β3 AR agonists was started 2 weeks later and effects on congestive signs were assessed, including ascites and the primary outcome, lung: body weight ratio. Na+-K+ pump current was measured in voltage-clamped myocytes from non-infarcted myocardium. The β3 AR agonist mirabegron was prescribed off-label to patients hospitalized with advanced HF (stage D) that was refractory to maximally tolerated guideline-directed treatment and intravenous furosemide, with or without inotropes, as assessed by ≥2 cardiologists. Results Rabbits developed severe HF with markedly increased lung:body weight ratio and ascites. Na+-K+ pump current was decreased in myocytes from rabbits with HF. β3 AR agonists eliminated pump inhibition, significantly reduced lung:body weight ratio and prevalence of ascites. Mirabegron was given to 9 patients aged 74 ± 7 years (mean ± SD) with advanced HF. LVEF was 26 ± 5%. Signs and symptoms improved within 1-2 days of treatment. Mirabegron was well-tolerated and improvement of ≥1 NYHA Class maintained by all early after discharge. One patient died from HF at 16 months, 4 died from other causes at 2 – 30 months and 4 remain alive at 30 ± 5 months with NYHA Class II symptoms. Conclusion Treatment with β3 AR agonist in a pre-clinical model of severe HF can reverse Na+-K+ pump inhibition and improve organ congestion implicating pump inhibition as a reversible myocardial dysfunction that is a useful treatment target. The changed in-hospital clinical trajectory and a more favourable post-discharge course than expected in advanced HF, suggests efficacy of β3 AR agonist shown in the animal model might translate into efficacy in advanced human HF.

There are serious concerns about possible late radiation damage to ocular tissue from prolonged space radiation exposure, and occupational and medical procedures. This study aimed to investigate the effects of whole-body high-energy proton exposure at a single dose on apoptosis, oxidative stress, and blood-retina barrier (BRB) integrity in the retina and optic nerve head (ONH) region and to compare these radiation-induced effects with those produced by fractionated dose. Six-month-old C57BL/6 male mice were either sham irradiated or received whole-body high energy proton irradiation at an acute single dose of 0.5 Gy or 12 equal dose fractions for a total dose of 0.5 Gy over twenty-five days. At four months following irradiation, mice were euthanized and ocular tissues were collected for histochemical analysis. Significant increases in the number of apoptotic cells were documented in the mouse retinas and ONHs that received proton radiation with a single or fractionated dose (p < 0.05). Immunochemical analysis revealed enhanced immunoreactivity for oxidative biomarker, 4-hydroxynonenal (4-HNE) in the retina and ONH following single or fractionated protons with more pronounced changes observed with a single dose of 0.5 Gy. BRB integrity was also evaluated with biomarkers of aquaporin-4 (AQP-4), a water channel protein, a tight junction (TJ) protein, Zonula occludens-1 (ZO-1), and an adhesion molecule, the platelet endothelial cell adhesion molecule-1 (PECAM-1). A significantly increased expression of AQP-4 was observed in the retina following a single dose exposure compared to controls. There was also a significant increase in the expression of PECAM-1 and a decrease in the expression of ZO-1 in the retina. These changes give a strong indication of disturbance to BRB integrity in the retina. Interestingly, there was very limited immunoreactivity of AQP-4 and ZO-1 seen in the ONH region, pointing to possible lack of BRB properties as previously reported. Our data demonstrated that exposure to proton radiation of 0.5 Gy induced oxidative stress-associated apoptosis in the retina and ONH, and changes in BRB integrity in the retina. Our study also revealed the differences in BRB biomarker distribution between these two regions. In response to radiation insults, the cellular response in the retina and ONH may be differentially regulated in acute or hyperfractionated dose schedules.

Long Interspersed Nucleotide Element 1 (LINE-1) retrotransposons are heavily methylated and are the most abundant transposable elements in mammalian genomes. Here, we investigated the differential DNA methylation within the LINE-1 under normal conditions and in response to environmentally relevant doses of sparsely and densely ionizing radiation. We demonstrate that DNA methylation of LINE-1 elements in the lungs of C57BL6 mice is dependent on their evolutionary age, where the elder age of the element is associated with the lower extent of DNA methylation. Exposure to 5-aza-2′-deoxycytidine and methionine-deficient diet affected DNA methylation of selective LINE-1 elements in an age- and promoter type-dependent manner. Exposure to densely IR, but not sparsely IR, resulted in DNA hypermethylation of older LINE-1 elements, while the DNA methylation of evolutionary younger elements remained mostly unchanged. We also demonstrate that exposure to densely IR increased mRNA and protein levels of LINE-1 via the loss of the histone H3K9 dimethylation and an increase in the H3K4 trimethylation at the LINE-1 5′-untranslated region, independently of DNA methylation. Our findings suggest that DNA methylation is important for regulation of LINE-1 expression under normal conditions, but histone modifications may dictate the transcriptional activity of LINE-1 in response to exposure to densely IR.

DNA methylation is a key epigenetic mechanism, needed for proper control over the expression of genetic information and silencing of repetitive elements. Exposure to ionizing radiation, aside from its strong genotoxic potential, may also affect the methylation of DNA, within the repetitive elements, in particular. In this study, we exposed C57BL/6J male mice to low absorbed mean doses of two types of space radiation-proton (0.1 Gy, 150 MeV, dose rate 0.53 ± 0.08 Gy/min), and heavy iron ions ((56)Fe) (0.5 Gy, 600 MeV/n, dose rate 0.38 ± 0.06 Gy/min). Radiation-induced changes in cardiac DNA methylation associated with repetitive elements were detected. Specifically, modest hypomethylation of retrotransposon LINE-1 was observed at day 7 after irradiation with either protons or (56)Fe. This was followed by LINE-1, and other retrotransposons, ERV2 and SINE B1, as well as major satellite DNA hypermethylation at day 90 after irradiation with (56)Fe. These changes in DNA methylation were accompanied by alterations in the expression of DNA methylation machinery and affected the one-carbon metabolism pathway. Furthermore, loss of transposable elements expression was detected in the cardiac tissue at the 90-day time-point, paralleled by substantial accumulation of mRNA transcripts, associated with major satellites. Given that the one-carbon metabolism pathway can be modulated by dietary modifications, these findings suggest a potential strategy for the mitigation and, possibly, prevention of the negative effects exerted by ionizing radiation on the cardiovascular system. Additionally, we show that the methylation status and expression of repetitive elements may serve as early biomarkers of exposure to space radiation.

Evaluating collections and ultimately removing content poses a variety of difficult issues, including choosing appropriate deselection criteria, communicating with stakeholders, providing accountability, and managing the overall timetable to finish projects on time. The Science and Engineering librarians at Brigham Young University evaluated their entire print collection of over 350,000 items within one year, significantly reducing the number of items kept on the open shelves and the physical collection footprint. Keys to accomplishing this project were extensive preparation, tracking progress and accountability facilitated by Google Sheets and an interactive GIS stacks map, and stakeholder feedback facilitated by a novel web-based tool. This case study discusses guidelines to follow and pitfalls to avoid for any organization that is considering a large- or small-scale collection evaluation project.

Interplanetary exploration will be humankind's most ambitious expedition and the journey required to do so, is as intimidating as it is intrepid. One major obstacle for successful deep space travel is the possible negative effects of galactic cosmic radiation (GCR) exposure. Here, we investigate for the first time how combined GCR impacts long-term behavioral and cellular responses in male and female mice. We find that a single exposure to simulated GCR induces long-term cognitive and behavioral deficits only in the male cohorts. GCR exposed male animals have diminished social interaction, increased anxiety-like phenotype and impaired recognition memory. Remarkably, we find that the female cohorts did not display any cognitive or behavioral deficits after GCR exposure. Mechanistically, the maladaptive behavioral responses observed only in the male cohorts correspond with microglia activation and synaptic loss in the hippocampus, a brain region involved in the cognitive domains reported here. Furthermore, we measured reductions in AMPA expressing synaptic terminals in the hippocampus. No changes in any of the molecular markers measured here are observed in the females. Taken together these findings suggest that GCR exposure can regulate microglia activity and alter synaptic architecture, which in turn leads to a range of cognitive alterations in a sex dependent manner. These results identify sex-dependent differences in behavioral and cognitive domains revealing promising cellular and molecular intervention targets to reduce GCR-induced chronic cognitive deficits thereby boosting chances of success for humans in deep space missions such as the upcoming Mars voyage.

Microglia are the main immune component in the brain that can regulate neuronal health and synapse function. Exposure to cosmic radiation can cause long-term cognitive impairments in rodent models thereby presenting potential obstacles for astronauts engaged in deep space travel. The mechanism/s for how cosmic radiation induces cognitive deficits are currently unknown. We find that temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. Gene array profiling reveals that acute microglia depletion alters the late neuroinflammatory response to cosmic radiation. The repopulated microglia present a modified functional phenotype with reduced expression of scavenger receptors, lysosome membrane protein and complement receptor, all shown to be involved in microglia-synapses interaction. The lower phagocytic activity observed in the repopulated microglia is paralleled by improved synaptic protein expression. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure.

Interest in deep space exploration underlines the needs to investigate the effects of exposure to combined sources of space radiation. The lung is a target organ for radiation, and exposure to protons and heavy ions as radiation sources may lead to the development of degenerative disease and cancer. In this study, we evaluated the pro-fibrotic and epigenetic effects of exposure to protons (150 MeV/nucleon, 0.1 Gy) and heavy iron ions ((56)Fe, 600 MeV/nucleon, 0.5 Gy) alone or in combination (protons on Day 1 and (56)Fe on Day 2) in C57BL/6 male mice 4 weeks after irradiation. Exposure to (56)Fe, proton or in combination, did not result in histopathological changes in the murine lung. At the same time, combined exposure to protons and (56)Fe resulted in pronounced molecular alterations in comparison with either source of radiation alone. Specifically, we observed a substantial increase in the expression of cytokine Il13, loss of expression of DNA methyltransferase Dnmt1, and reactivation of LINE-1, SINE B1 retrotransposons, and major and minor satellites. Given the deleterious potential of the observed effects that may lead to development of chronic lung injury, pulmonary fibrosis, and cancer, future studies devoted to the investigation of the long-term effects of combined exposures to proton and heavy ions are clearly needed.

To determine if high-activity older adults are adversely affected by distal radius malunion.Cross-sectional study.Hand clinics at a tertiary institution.Ninety-six patients 60 years or older at the time of fracture were evaluated at least 1 year after distal radius fracture.Physical Activity Scale of the Elderly scores stratified participants into high- and low-activity groups. Malunions were defined radiographically by change of ≥20 degrees of lateral tilt, ≥15 degrees radial inclination, ≥4 mm of ulnar variance, or ≥4 mm intra-articular gap or step-off, compared with the uninjured wrist.Patient-rated disability of the upper extremity was measured by the QuickDASH and visual analog scales (VAS) for pain/function. Strength and motion measurements objectively quantified wrist function.High-activity participants with a distal radius malunion were compared with high-activity participants with well-aligned fractures. There was no significant difference in QuickDASH scores, VAS function, strength, and wrist motion despite statistically, but not clinically, relevant increases in VAS pain scores (difference 0.5, P = 0.04) between the groups. Neither physical Activity Scale of the Elderly score (β = 0.001, 95% confidence interval: -0.002 to 0.004) nor malunion (β = 0.133, 95% confidence interval: -0.26 to 0.52) predicted QuickDASH scores in regression modeling after accounting for age, sex, and treatment. Operative management failed to improve outcomes and resulted in decreased grip strength (P = 0.05) and more frequent complications (26% vs. 7%, P = 0.01) when compared with nonoperative management.Even among highly active older adults, distal radius malunion does not affect functional outcomes. Judicious use of operative management is warranted provided heightened complication rates.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Physician assistants are expected to have an important role in providing both primary and specialty care. Iowa has a large rural (and aging) population and faces challenges to provide equitable access to care. This study examined changes in the Iowa physician assistant workforce (1995–2015) focusing on practice setting (primary v. subspecialty care) and geographic location (rural/urban, Health Professional Shortage Area). Documenting their current locations and service in HPSAs for primary care will help health planners track future changes. Methods Data from 1995–2015 from the Iowa Health Professions Inventory (Office of Statewide Clinical Education Programs, Carver College of Medicine, University of Iowa) were combined with US census data on rural location and HPSA status. SPSS was used to compare Iowa and national data. Growth trends were analyzed using joinpoint regression. Results The overall Iowa physician assistant workforce increased 161% between 1995 and 2015. In 2015, more than two-thirds (71%) were female and more than 30% practiced in rural counties. The average annual growth rate of primary care PAs (per 100,000 population) was significantly higher in the periods from 1995–1997 and 1997–2001 (22.4% and 7.4% respectively) than in period from 2001–2015 (3.8%). By 2015, 56% of Iowa’s physician assistants practiced in primary care (versus 29.6% nationally). Of these, 44% of primary care physician assistants in Iowa practiced in counties, geographic locations or worksites designated as Health Professional Shortage Areas for primary care. Conclusions A high proportion of Iowa’s physician assistant workforce practiced in primary care and many served patients in Health Professional Shortage Areas. The number of physician assistants in Iowa will continue to grow and serve an important role in providing access to health care, particularly to rural Iowans.

Background Pre-hospital ECG and emergency department (ED) bypass direct to the catheter laboratory may optimize reperfusion times for patients with ST-segment elevation myocardial infarction. Questions remain over feasibility and safety during off hours. Aims To determine if presenting time of day is associated with differences in in-hospital and 30-day mortality and key reperfusion times. Methods/Results Seven hundred and twenty consecutive patients with STEMI triaged directly from the field to the catheter laboratory between June 2004–May 2013. Vital status was reported as of August 2013. The mean age was 65 ± 14 years, and 75.1% were male. Overall mortality (in-hospital/30 days) did not significantly differ for patients (3.4% in hours and 3.1% off hours; P = N/S). Symptom onset-to-arrival to the heart attack was non-significantly lower (100 minutes off hours (IQR 78–174) versus 110 minutes in hours (IQR 75–199), P = N/S). Call-to-balloon time was not significantly affected by the time of presentation: 150 min in hours (IQR 111–239) versus 154 minutes during off hours (IQR 115–225) P = N/S. Overall door-to-balloon time was 36 minutes (IQR 25–51), 34 minutes in hours (IQR 24–49) versus 40 minutes off hours (IQR 29–55) P = N/S. The overall false positive activation rate was only 13.1%, (in hours 12.2% vs. off hours 14.6%, respectively, P = N/S). Conclusions In a unit with an established field triage system facilitating ED bypass, reperfusion times and mortality are not significantly influenced by whether the patient presents during standard working hours or outside of these hours. (J Interven Cardiol 2015;28:24–31)

Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. Innovation: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. Conclusion: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain. Antioxid. Redox Signal. 22, 78–91.

PURPOSE: Exposure to proton irradiation during missions in deep space can lead to bone marrow injury. The acute effects of proton irradiation on hematopoietic stem and progenitor cells remain undefined and thus were investigated. MATERIALS AND METHODS: We exposed male C57BL/6 mice to 0.5 and 1.0 Gy proton total body irradiation (proton-TBI, 150 MeV) and examined changes in peripheral blood cells and bone marrow (BM) progenitors and LSK cells 2 weeks after exposure. RESULTS: 1.0 Gy proton-TBI significantly reduced the numbers of peripheral blood cells compared to0.5 Gy proton-TBI and unirradiated animals, while the numbers of peripheral blood cell counts were comparable between 0.5 Gy proton-TBI and unirradiated mice. The frequencies and numbers of LSK cells and CMPs in BM of 0.5 and 1.0 Gy irradiated mice were decreased in comparison to those of normal controls. LSK cells and CMPs and their progeny exhibited a radiation-induced impairment in clonogenic function. Exposure to 1.0 Gy increased cellular apoptosis but not the production of reactive oxygen species (ROS) in CMPs two weeks after irradiation. LSK cells from irradiated mice exhibited an increase in ROS production and apoptosis. CONCLUSION: Exposure to proton-TBI can induce acute damage to BM progenitors and LSK cells.

Purpose Space travel is associated with an exposure to low-dose rate ionizing radiation and the microgravity environment, both of which may lead to impairments in cardiac function. We used a mouse model to determine short- and long-term cardiac effects to simulated microgravity (hindlimb unloading; HU), continuous low-dose rate γ-irradiation, or a combination of HU and low-dose rate γ-irradiation. Methods Cardiac tissue was obtained from female, C57BL/6J mice 7 days, 1 month, 4 months, and 9 months following the completion of a 21 day exposure to HU or a 21 day exposure to low-dose rate γ-irradiation (average dose rate of 0.01 cGy/h to a total of 0.04 Gy), or a 21 day simultaneous exposure to HU and low-dose rate γ-irradiation. Immunoblot analysis, rt-PCR, high-performance liquid chromatography, and histology were used to assess inflammatory cell infiltration, cardiac remodeling, oxidative stress, and the methylation potential of cardiac tissue in 3 to 6 animals per group. Results The combination of HU and γ-irradiation demonstrated the strongest increase in reduced to oxidized glutathione ratios 7 days and 1 month after treatment, but a difference was no longer apparent after 9 months. On the other hand, no significant changes in 4-hydroxynonenal adducts was seen in any of the groups, at the measured endpoints. While manganese superoxide dismutase protein levels decreased 9 months after low-dose γ-radiation, no changes were observed in expression of catalase or Nrf2, a transcription factor that determines the expression of several antioxidant enzymes, at the measured endpoints. Inflammatory marker, CD-2 protein content was significantly decreased in all groups 4 months after treatment. No significant differences were observed in α-smooth muscle cell actin protein content, collagen type III protein content or % total collagen. Conclusions This study has provided the first and relatively broad analysis of small molecule and protein markers of oxidative stress, T-lymphocyte infiltration, and cardiac remodeling in response to HU with simultaneous exposure to low-dose rate γ-radiation. Results from the late observation time points suggest that the hearts had mostly recovered from these two experimental conditions. However, further research is needed with larger numbers of animals for a more robust statistical power to fully characterize the early and late effects of simulated microgravity combined with exposure to low-dose rate ionizing radiation on the heart.

In the not too distant future, humankind will embark on one of its greatest adventures, the travel to distant planets. However, deep space travel is associated with an inevitable exposure to radiation fields. Space-relevant doses of protons elicit persistent disruptions in cognition and neuronal structure. However, whether space-relevant irradiation alters neurotransmission is unknown. Within the hippocampus, a brain region crucial for cognition, perisomatic inhibitory control of pyramidal cells (PCs) is supplied by two distinct cell types, the cannabinoid type 1 receptor (CB1)-expressing basket cells (CB1BCs) and parvalbumin (PV)-expressing interneurons (PVINs). Mice subjected to low-dose proton irradiation were analyzed using electrophysiological, biochemical and imaging techniques months after exposure. In irradiated mice, GABA release from CB1BCs onto PCs was dramatically increased. This effect was abolished by CB1 blockade, indicating that irradiation decreased CB1-dependent tonic inhibition of GABA release. These alterations in GABA release were accompanied by decreased levels of the major CB1 ligand 2-arachidonoylglycerol. In contrast, GABA release from PVINs was unchanged, and the excitatory connectivity from PCs to the interneurons also underwent cell type-specific alterations. These results demonstrate that energetic charged particles at space-relevant low doses elicit surprisingly selective long-term plasticity of synaptic microcircuits in the hippocampus. The magnitude and persistent nature of these alterations in synaptic function are consistent with the observed perturbations in cognitive performance after irradiation, while the high specificity of these changes indicates that it may be possible to develop targeted therapeutic interventions to decrease the risk of adverse events during interplanetary travel. Electronic supplementary material The online version of this article (doi:10.1007/s00429-016-1345-3) contains supplementary material, which is available to authorized users.

States are seeking ways to retain primary care physicians trained within their borders. We analyzed the 5-year retention and rural Iowa location decisions for 1,645 graduates of the Iowa Family Medicine Training Network (IFMTN)-eight residency programs (in seven different cities) that are affiliated with the Carver College of Medicine (University of Iowa).Data from 1977-2014 includes 98.5% of active graduates. Location in Iowa 5 years after graduation was the dependent variable in a binary logistic regression. A second model used rural location in Iowa as the dependent variable. Independent variables included graduation year cohort, IMG status, sex, undergraduate medical training in Iowa, medical degree, and residency location.Undergraduate medical training in Iowa was strongly related to retention. Compared to graduates of the AMC residency, graduates of six of the seven community-based programs were significantly more likely to be practicing in Iowa. While the overall proportion of graduates practicing in rural Iowa was high (47.3%), women and IMGs were significantly less likely to practice in rural areas. Graduates of the Mason City program were significantly more likely to practice in a rural area after graduation.The experience of the IFMTN suggests that educating family physicians in community-based programs contributes significantly to in-state retention even 5 years after graduation. While all programs contribute to the rural FM workforce in Iowa, the residency program located in a rural community (Mason City) has a disproportionately positive impact.

Space missions necessitate physiological and psychological adaptations to environmental factors not present on Earth, some of which present significant risks for the central nervous system (CNS) of crewmembers. One CNS region of interest is the adult olfactory bulb (OB), as OB structure and function are sensitive to environmental- and experience-induced regulation. It is currently unknown how the OB is altered by spaceflight. In this study, we evaluated OB volume and neurogenesis in mice shortly after a 13-day flight on Space Shuttle Atlantis [Space Transport System (STS)-135] relative to two groups of control mice maintained on Earth. Mice housed on Earth in animal enclosure modules that mimicked the conditions onboard STS-135 (AEM-Ground mice) had greater OB volume relative to mice maintained in standard housing on Earth (Vivarium mice), particularly in the granule (GCL) and glomerular (GL) cell layers. AEM-Ground mice also had more OB neuroblasts and fewer apoptotic cells relative to Vivarium mice. However, the AEM-induced increase in OB volume and neurogenesis was not seen in STS-135 mice (AEM-Flight mice), suggesting that spaceflight may have negated the positive effects of the AEM. In fact, when OB volume of AEM-Flight mice was considered, there was a greater density of apoptotic cells relative to AEM-Ground mice. Our findings suggest that factors present during spaceflight have opposing effects on OB size and neurogenesis, and provide insight into potential strategies to preserve OB structure and function during future space missions.

During deep space missions, astronauts will be exposed to low doses of charged particle irradiation. The long-term health effects of these exposures are largely unknown. We previously showed that low doses of oxygen ion (16O) irradiation induced acute damage to the hematopoietic system, including hematopoietic progenitor and stem cells in a mouse model. However, the chronic effects of low dose 16O irradiation remain undefined. In the current study, we investigated the long-term effects of low dose 16O irradiation on the mouse hematopoietic system. Male C57BL/6J mice were exposed to 0.05 Gy, 0.1 Gy, 0.25 Gy and 1.0 Gy whole body 16O (600 MeV/n) irradiation. The effects of 16O irradiation on bone marrow (BM) hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) were examined three months after the exposure. The results showed that the frequencies and numbers of BM HPCs and HSCs were significantly reduced in 0.1 Gy, 0.25 Gy and 1.0 Gy irradiated mice compared to 0.05 Gy irradiated and non-irradiated mice. Exposure of mice to low dose 16O irradiation also significantly reduced the clongenic function of BM HPCs determined by the colony-forming unit assay. The functional defect of irradiated HSCs was detected by cobblestone area-forming cell assay after exposure of mice to 0.1 Gy, 0.25 Gy and 1.0 Gy of 16O irradiation, while it was not seen at three months after 0.5 Gy and 1.0 Gy of γ-ray irradiation. These adverse effects of 16O irradiation on HSCs coincided with an increased intracellular production of reactive oxygen species (ROS). However, there were comparable levels of cellular apoptosis and DNA damage between irradiated and non-irradiated HPCs and HSCs. These data suggest that exposure to low doses of 16O irradiation induces long-term hematopoietic injury, primarily via increased ROS production in HSCs.

Space radiation represents a significant health risk for astronauts. Ground-based animal studies indicate that space radiation affects neuronal functions such as excitability, synaptic transmission, and plasticity, and it may accelerate the onset of Alzheimer's disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3 month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0.1-1.0 Gy; whole body) and evaluated functional and biochemical hallmarks of AD. We performed behavioral tests in the water maze (WM) before irradiation and in the WM and Barnes maze at 3 and 6 months post-irradiation to evaluate spatial learning and memory. We also performed electrophysiological recordings in vitro in hippocampal slices prepared 6 and 9 months post irradiation to evaluate excitatory synaptic transmission and plasticity. Next, we evaluated amyloid 3 (A(3) deposition in the contralateral hippocampus and adjacent cortex using immunohistochemistry. In cortical homogenates, we analyzed the levels of the presynaptic marker synaptophysin by Western blotting and measured pro-inflammatory cytokine levels (INF alpha, IL-beta, IL-6, CXCL10 and CCL2) by bead-based multiplex assay. TG mice performed significantly worse than WT mice in the WM. Irradiation of TG mice did not affect their behavioral performance, but reduced the amplitudes of population spikes and inhibited paired-pulse facilitation in CA1 neurons. These electrophysiological alterations in the TG mice were qualitatively different from those observed in WT mice, in which irradiation increased excitability and synaptic efficacy. Irradiation increased A beta deposition in the cortex of TG mice without affecting cytokine levels and increased synaptophysin expression in WT mice (but not in the TG mice). Although irradiation with protons increased A beta deposition, the complex functional and biochemical results indicate that irradiation effects are not synergistic to AD pathology.

Background Workforce experts predict a future shortage of cardiologists that is expected to impact rural areas more severely than urban areas. However, there is little research on how rural patients are currently served through clinical outreach. This study examines the impact of cardiology outreach in Iowa, a state with a large rural population, on participating cardiologists and on patient access. Methods and Results Outreach clinics are tracked annually in the Office of Statewide Clinical Education Programs Visiting Medical Consultant Database (University of Iowa Carver College of Medicine). Data from 2014 were analyzed. In 2014, an estimated 5460 visiting consultant clinic days were provided in 96 predominantly rural cities by 167 cardiologists from Iowa and adjoining states. Forty‐five percent of Iowa cardiologists participated in rural outreach. Visiting cardiologists from Iowa and adjoining states drive an estimated 45 000 miles per month. Because of monthly outreach clinics, the average driving time to the nearest cardiologist falls from 42.2±20.0 to 14.7±11.0 minutes for rural Iowans. Cardiology outreach improves geographic access to office‐based cardiology care for more than 1 million Iowans out of a total population of 3 million. Direct travel costs and opportunity costs associated with physician travel are estimated to be more than $2.1 million per year. Conclusions Cardiologists in Iowa and adjoining states have expanded access to office‐based cardiology care from 18 to 89 of the 99 counties in Iowa. In these 71 counties without a full‐time cardiologist, visiting consultant clinics can accommodate more than 50% of office visits in the patients’ home county.

One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic system from space radiation.

A core tradition of HCI lies in the experimental evaluation of the effects of techniques and interfaces to determine if they are useful for achieving their purpose. However, our individual analyses tend to stand alone, and study results rarely accrue in more precise estimates via meta-analysis: in a literature search, we found only 56 meta-analyses in HCI in the ACM Digital Library, 3 of which were published at CHI (often called the top HCI venue). Yet meta-analysis is the gold standard for demonstrating robust quantitative knowledge. We treat this as a user-centered design problem: the failure to accrue quantitative knowledge is not the users' (i.e. researchers') failure, but a failure to consider those users' needs when designing statistical practice. Using simulation, we compare hypothetical publication worlds following existing frequentist against Bayesian practice. We show that Bayesian analysis yields more precise effects with each new study, facilitating knowledge accrual without traditional meta-analyses. Bayesian practices also allow more principled conclusions from small-n studies of novel techniques. These advantages make Bayesian practices a likely better fit for the culture and incentives of the field. Instead of admonishing ourselves to spend resources on larger studies, we propose using tools that more appropriately analyze small studies and encourage knowledge accrual from one study to the next. We also believe Bayesian methods can be adopted from the bottom up without the need for new incentives for replication or meta-analysis. These techniques offer the potential for a more user- (i.e. researcher-) centered approach to statistical analysis in HCI.

The public library in Provo City, Utah, has undergone significant changes since the founding of the original 1906 building that was funded by Andrew Carnegie. The library has changed according to the needs of the community as it has adapted from its pioneer heritage to a modern service-information organization. As it has adapted, however, the Provo Library has maintained its focus on community service with its physical facilities, collection development, community outreach, and quality staffing.

The purpose of the current study was to characterize the effects of simulated microgravity and radiation-induced changes in retina and retinal vasculature, and to assess the accompanying early changes in immune cells and hematological parameters. To better understand the effects of spaceflight, we used a combination of treatments designed to simulate both the radiation and low-gravity aspects of space conditions. To simulate the broad energy spectrum of a large solar particle event (SPE) and galactic cosmic ray (GCR) radiation, male C57BL/6J mice were exposed to whole-body irradiation using fully modulated beams of 150-MeV protons containing particles of energy from 0 to 150 MeV and a uniform dose-vs.-depth profile. The mice were also hindlimb-unloaded (HLU) by tail suspension. Mice were unloaded for 7 days, exposed to 50 cGy, unloaded for an additional 7 days and then sacrificed for tissue isolation at days 4 and 30 after the combined treatments. Increases in the number of apoptotic cells were observed in the endothelial cells of mice that received radiation alone or with HLU compared to controls at both days 4 and 30 (P < 0.05). Endothelial nitric oxide synthase (eNOS) levels were significantly elevated in the retina after irradiation only or combined with HLU compared to controls at the 30-day time point (P < 0.05). The most robust changes were observed in the combination group, suggesting a synergistic response to radiation and unloading. For hematopoietic parameters, our analysis indicated the main effects for time and radiation at day 4 after treatments (day 11 postirradiation) (P < 0.05), but a smaller influence of HLU for both white blood cell and lymphocyte counts. The group treated with both radiation and HLU showed greater than 50% reduction in lymphocyte counts compared to controls. Radiation-dependent differences were also noted in specific lymphocyte subpopulations (T, B, natural killer cells). This study shows indications of an early effect of low-dose radiation and spaceflight conditions on retina and immune populations.

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Clinical outcomes after intra-synovial flexor tendon repair have been substantially improved over the past two decades through advances in tendon suture techniques and postoperative rehabilitation methods. Nevertheless, complications such as repair site elongation (i.e., gap formation) and rupture continue to occur frequently. Experimental studies have shown that repair site strength fails to increase in the first three weeks following tendon suture. After three weeks, the strength and rigidity of the repair site improves significantly, a process that continues for several months. Formation of a repair site gap during the early rehabilitation period has been shown to considerably delay the accrual of repair site strength over time. Thus, it is of prime importance that the method of tendon suture achieves and maintains a stiff and strong repair site during the early healing interval by maintaining close approximation of the tendon stumps and by stimulating, where possible, the intrinsic repair response. In this review we describe recent efforts to enhance the integrity of the immature repair site. We focus on two major areas of advancement: surgical technique modifications and manipulation of the biologic and biochemical environment.

The hippocampus is critical for learning and memory, and injury to this structure is associated with cognitive deficits. The response of the hippocampal microvessels after a relatively low dose of high-LET radiation remains unclear. In this study, endothelial population changes in hippocampal microvessels exposed to (56)Fe ions at doses of 0, 0.5, 2 and 4 Gy were quantified using unbiased stereological techniques. Twelve months after exposure, mice that received 0.5 Gy or 2 Gy of iron ions showed a 34% or 29% loss of endothelial cells, respectively, in the hippocampal cornu ammonis region 1 (CA1) compared to age-matched controls or mice that received 4 Gy (P0.05). We suggest that this "U-shaped" dose response indicates a repopulation from a sensitive subset of endothelial cells that occurred after 4 Gy that was stimulated by an initial rapid loss of endothelial cells. In contrast to the CA1, in the dentate gyrus (DG), there was no significant difference in microvessel cell and length density between irradiated groups and age-matched controls. Vascular topology differences between CA1 and DG may account for the variation in dose response. The correlation between radiation-induced alterations in the hippocampal microvessels and their functional consequences must be investigated in further studies.

On a mission to Mars, astronauts will be exposed to a complex mix of radiation from galactic cosmic rays. We have demonstrated a loss of bone mass from exposure to types of radiation relevant to space flight at doses of 1 and 2 Gy. The effects of space radiation on skeletal muscle, however, have not been investigated. To evaluate the effect of simulated galactic cosmic radiation on muscle fiber area and bone volume, we examined mice from a study in which brains were exposed to collimated iron-ion radiation. The collimator transmitted a complex mix of charged secondary particles to bone and muscle tissue that represented a low-fidelity simulation of the space radiation environment. Measured radiation doses of uncollimated secondary particles were 0.47 Gy at the proximal humerus, 0.24-0.31 Gy at the midbelly of the triceps brachii, and 0.18 Gy at the proximal tibia. Compared to nonirradiated controls, the proximal humerus of irradiated mice had a lower trabecular bone volume fraction, lower trabecular thickness, greater cortical porosity, and lower polar moment of inertia. The tibia showed no differences in any bone parameter. The triceps brachii of irradiated mice had fewer small-diameter fibers and more fibers containing central nuclei. These results demonstrate a negative effect on the skeletal muscle and bone systems of simulated galactic cosmic rays at a dose and LET range relevant to a Mars exploration mission. The presence of evidence of muscle remodeling highlights the need for further study.

The success rate of cataract surgery after trabeculectomy (bleb survival and/or maintenance of IOP control) approaches 80-90%1-3. Successful pseudophakic rehabilitation after glaucoma filtering surgery requires accurate intraocular lens (IOL) power calculation, which depends on several factors including axial length (AL), corneal curvature and anterior chamber depth. Changes in these three parameters following glaucoma surgery have been reported. Decreases in axial length by 0.1 to 0.9 mm have been reported after glaucoma surgery4-7. It is suggested that the AL change after trabeculectomy can occur when the eye loses a significant amount of intraocular pressure (IOP) by the external flow of aqueous humor through a surgical fistula5. Besides, a thickened choroid accompanying a low IOP after glaucoma surgery might have an effect on AL measurement8. Furthermore, a possible increase in IOP in posttrabeculectomy eyes after cataract extraction can result in a longer AL depending on scleral rigidity. Lastly, contact AL measurements, such as A-scan ultrasonography, can induce bias by probe deformation of the eye resulting in falsely low postoperative readings of AL, especially in hypotonous eyes. This may predispose to a greater myopic refractive error than expected. Induction of with-the-rule corneal astigmatism after trabeculectomy with or without using mitomycin C has been reported5, 9-13. However, it tends to resolve over longer follow-up. Several studies14-18 have shown that the anterior chamber tends to shallow in the postoperative period following trabeculectomy, and that maximal shallowing occurs by the fifth day. However, most anterior chambers tend to re-form spontaneously by 2 weeks after surgery. As a result of AL, corneal curvature and anterior chamber depth changes following trabeculectomy, optimum IOL calculation and subsequent predictable refractive error are less easily obtained. In this study we aim at finding whether the final refractive outcome in patients undergoing phacoemulsification of cataract with IOL implantation following trabeculectomy is different from the predicted refraction.

The development of a living, autologous vascular graft with the ability to grow holds great promise for advancing the field of pediatric cardiothoracic surgery.To evaluate the growth potential of a tissue-engineered vascular graft (TEVG) in a juvenile animal model.Polyglycolic acid nonwoven mesh tubes (3-cm length, 1.3-cm id; Concordia Fibers) coated with a 10% copolymer solution of 50:50 L-lactide and epsilon-caprolactone were statically seeded with 1 x 10 cells/cm autologous bone marrow derived mononuclear cells. Eight TEVGs (7 seeded, 1 unseeded control) were implanted as inferior vena cava (IVC) interposition grafts in juvenile lambs. Subjects underwent bimonthly magnetic resonance angiography (Siemens 1.5 T) with vascular image analysis (www.BioimageSuite.org). One of 7-seeded grafts was explanted after 1 month and all others were explanted 6 months after implantation. Neotissue was characterized using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis.All grafts explanted at 6 months were patent and increased in volume as measured by difference in pixel summation in magnetic resonance angiography at 1 month and 6 months. The volume of seeded TEVGs at explant averaged 126.9% +/- 9.9% of their volume at 1 month. Magnetic resonance imaging demonstrated no evidence of aneurysmal dilation. TEVG resembled the native IVC histologically and had comparable collagen (157.9 +/- 26.4 microg/mg), elastin (186.9 +/- 16.7 microg/mg), and glycosaminoglycan (9.7 +/- 0.8 microg/mg) contents. Immunohistochemical staining and Western blot analysis showed that Ephrin-B4, a determinant of normal venous development, was acquired in the seeded grafts 6 months after implantation.TEVGs demonstrate evidence of growth and venous development when implanted in the IVC of a juvenile lamb model.

Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. In the central nervous system (CNS), loss of critical cellular components may lead to performance decrements that could ultimately compromise mission goals and long-term quality of life. Hippocampal-dependent cognitive impairments occur after exposure to ionizing radiation, and while the pathogenesis of this effect is not yet clear, it may involve the production of newly born neurons (neurogenesis) in the hippocampal dentate gyrus. We irradiated mice with 0.5-4 Gy of (56)Fe ions and 2 months later quantified neurogenesis and numbers of activated microglia as a measure of neuroinflammation in the dentate gyrus. Results showed that there were few changes after 0.5 Gy, but that there was a dose-related decrease in hippocampal neurogenesis and a dose-related increase in numbers of newly born activated microglia from 0.5-4.0 Gy. While those findings were similar to what was reported after X irradiation, there were also some differences, particularly in the response of newly born glia. Overall, this study showed that hippocampal neurogenesis was sensitive to relatively low doses of (56)Fe particles, and that those effects were associated with neuroinflammation. Whether these changes will result in functional impairments or if/how they can be managed are topics for further investigation.

Astronauts on exploratory missions will experience a complex environment, including microgravity and radiation. While the deleterious effects of unloading on bone are well established, fewer studies have focused on the effects of radiation. We previously demonstrated that 2 Gy of ionizing radiation has deleterious effects on trabecular bone in mice 4 months after exposure. The present study investigated the skeletal response after total doses of proton radiation that astronauts may be exposed to during a solar particle event. We exposed mice to 0.5, 1 or 2 Gy of whole-body proton radiation and killed them humanely 117 days later. Tibiae and femora were analyzed using microcomputed tomography, mechanical testing, mineral composition and quantitative histomorphometry. Relative to control mice, mice exposed to 2 Gy had significant differences in trabecular bone volume fraction (-20%), trabecular separation (+11%), and trabecular volumetric bone mineral density (-19%). Exposure to 1 Gy radiation induced a nonsignificant trend in trabecular bone volume fraction (-13%), while exposure to 0.5 Gy resulted in no differences. No response was detected in cortical bone. Further analysis of the 1-Gy mice using synchrotron microCT revealed a significantly lower trabecular bone volume fraction (-13%) than in control mice. Trabecular bone loss 4 months after exposure to 1 Gy highlights the importance of further examination of how space radiation affects bone.

The response of the central nervous system to space radiation is largely unknown. The hippocampus, which is known for its critical role in learning and memory, was evaluated for its response to heavy-ion radiation. At 1 month, animals exposed to brain-only 56Fe-particle irradiation (0-4 Gy) were examined using contrast-enhanced T1 imaging (CET1), T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), and (1)H-magnetic resonance spectroscopy (MRS). Correlative histology was performed after imaging. The T2WI, DWI and CET1 images revealed no overt anatomical changes after irradiation. Quantitative analysis demonstrated a significant increase in T2 at 2 Gy compared to 0 Gy. The apparent diffusion coefficient (ADC) revealed an inverse dose-dependent quantitative change in water mobility. Compared to 0 Gy, the ADC increased 122% at 1 Gy and declined to 44% above control levels at 4 Gy. MRS showed a significant increase in the N-acetylaspartate/choline ratio at 4 Gy and a lactate peak. Histology demonstrated no overt pathological changes in neuronal and astrocyte populations. However, a significant inverse dose-dependent morphological change in the microglial population was detected in irradiated animals. Our results suggest that early tissue matrix modifications induced by 56Fe-particle radiation can be detected by MRI in the absence of evident histopathology. These changes may indicate fundamental changes in the structure and function of the hippocampus.