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OBJECTIVE The aim of this study was to determine if the distinction between planum sphenoidale (PS) and tuberculum sellae (TS) meningiomas is clinically meaningful and impacts the results of the endoscopic endonasal approach (EEA). METHODS A consecutive series of patients who were 18 years of age or older and underwent EEA for newly diagnosed grade I PS meningiomas (PSMs) and TS meningiomas (TSMs) between October 2007 and May 2021 were included. The PS and TS were distinguished by drawing a line passing through the center of the TS and perpendicular to the PS on postcontrast T1-weighted MRI. Probabilistic heatmaps were created to display the actual distribution of tumor volumes. Tumor volume, extent of resection (EOR), visual outcome, and complications were assessed. RESULTS The 47 tumors were distributed in a smooth continuum. Using an arbitrary definition, 24 (51%) were PSMs and 23 (49%) were TSMs. The mean volume of PSMs was 5.6 cm3 compared with 4.5 cm3 for TSMs. Canal invasion was present in 87.5% of PSMs and 52% of TSMs. GTR was achieved in 38 (84%) of 45 cases in which it was the goal, slightly less frequently for PSMs (78%) compared with TSMs (91%), although the difference was not significant. Th mean EOR was 99% ± 2% for PSMs and 98% ± 11% for TSMs. Neither the suprasellar notch angle nor the percentage of tumor above the PS impacted the rate of GTR. After a median follow-up of 28.5 months (range 0.1–131 months), there were 2 (5%) recurrences after GTR (n = 38) both of which occurred in patients with PSMs. Forty-two (89%) patients presented with preoperative impaired vision. Postoperative vision was stable or improved in 96% of patients with PSMs and 91% of patients with TSMs. CSF leakage occurred in 4 (16.6%) patients with a PSM, which resolved with only lumbar drainage, and in 1 (4.3%) patient with a TSM, which required reoperation. CONCLUSIONS PSM and TSMs arise in a smooth distribution, making the distinction arbitrary. Those classified as PSMs were larger and more likely to invade the optic canals. Surgical outcome for both locations was similar, slightly favoring TSMs. The arbitrary distinction between PSMs and TSMs is less useful at predicting outcome than the lateral extent of the tumor, regardless of the site of origin.

Proper establishment of connectivity in the nervous system is essential for higher cognitive functions. Progressive and regressive developmental events build and sculpt these circuits to reach functional maturity. A key progressive step during the assembly of neural circuits is the guidance of growing axons. The direction that an axon grows is largely influenced by the degree of adhesion to the extracellular matrix (ECM) substrate, which is locally regulated in response to guidance cues. Adhesion must also be regulated during fasciculation into axon bundles and dissociation for innervation of individual targets. The modulation of adhesion by guidance cues is mediated by intracellular cascades of signaling proteins, of which very little is known. In Aim 1, we provide genetic evidence for the requirement of Cas signaling adaptor proteins in guidance and fasciculation of DRG projections in mice. Our results demonstrate that Cas proteins play important roles in allowing sensory axons to distinguish between adhesion to the substrate and to other axons.A critical regressive event during the refinement of neural circuits is the pruning of exuberant synapses and projections. Activity-dependent pruning ensures that only the most functional connections are maintained. Although clearly important for proper connectivity, this developmental process is understudied. An apparent roadblock in the investigation of these refinement events is the need for tools that are able to reversibly modulate neuronal activity for a protracted period of time. In Aim 2, we offer a solution with the design and characterization of the Expression by Boolean Exclusion (ExBoX) system, a simple AAV-based approach to control expression by exclusion logic (AND NOT). This ExBoX system encodes for a gene of interest which is turned ON by a particular recombinase (Cre or FlpO) and turned OFF by another. We show the ability of the ExBoX system to tightly regulate expression of fluorescent reporters both in vitro and in vivo, and demonstrate the adaptability of the system by achieving expression of a variety of virally-delivered functional manipulations in the mouse brain. This simple strategy will expand the molecular toolkit available for cell- and time-specific gene expression.

Demyelination is a critical neurological disease, and there is still a lack of effective treatment methods. In the past two decades, stem cells have emerged as a novel therapeutic effector for neural regeneration. However, owing to the existence of the blood-brain barrier (BBB) and the complex microenvironment, targeted therapy still faces multiple challenges. Targeted exosome carriers for drug delivery may be considered a promising therapeutic method. Exosomes were isolated from mice neural stem cells. To develop targeting exosomes, we generated a lentivirus armed PDGFR

Objective To determine the in-hospital cost implications of an endoscopic expanded endonasal approach (EEEA) for meningioma resection relative to the open transcranial approach. Methods All anterior skull base meningioma surgeries performed over a period from January 1st, 2015 to October 31th, 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate analysis was performed using R software. All cost data were converted into August 2021-equivalent dollar amounts using the United States Bureau of Labor Statistics consumer price index. Results Thirty-five patients met study criteria, including 27 patients undergoing an open transcranial approach and 8 undergoing an EEEA. Average length of stay for patients undergoing an open approach was 9.3 days compared to 5.6 within the EEEA group ( P = .126). The average total in-hospital cost of patient undergoing an EEEA was $35417.1 compared to $46406.9 among patients undergoing an open transcranial approach ( P = .168). On univariate analysis, the cost of an open transcranial approach relative to the EEEA was $10989.8 ( P = .411). Conclusions The open transcranial approach remained the dominant surgical approach to anterior skull base meningiomas over our study time period. However, despite limited patient numbers the EEEA was associated with decreased total in-hospital costs.

Survival rates of childhood acute lymphoblastic leukemia (ALL) have improved greatly due to advanced therapies and supportive care. Intrathecal chemotherapy replaced cranial radiation due to radiation-induced neurotoxicity and late-effects. Survivors treated with chemotherapy-only experience neurologic and cognitive problems following cessation of treatment. Very long-term cognitive outcomes remain unclear. Animal models are being generated to assess late-effects of chemotherapy on cognitive function. Although, few address juvenile models of chemotherapy-induced cognitive impairment (CICI) and developing brain, results of this review outline neurocognitive effects of chemotherapy consistent with childhood ALL therapy. Studies demonstrate deficits across cognitive domains including spatial memory, executive function, short-term memory, anxiety and depression. Inflammation, oxidative stress, excitotoxity, and other metabolic disruptions may lead to neurodegeneration associated with cognitive impairment observed in ALL survivors. Interventions directly targeting these mechanisms may prevent and/or promote recovery of cognitive function and improve long-term outcomes. Evidence suggests success of anti-inflammatory and antioxidant treatments in reducing cognitive decline. Animal models provide basis for assessing effects of chemotherapy on neurologic processes to guide future clinical investigations.

To determine the in-hospital cost implications of an expanded endoscopic endonasal approach (EEEA) for craniopharyngioma resection relative to the traditional open transcranial approach.All craniopharyngioma surgeries performed at a single institution over a period from January 1st 2001 to October 31th 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate regression analysis was performed using R software.Thirty-six patients met study criteria, including 22 undergoing an open approach and 14 undergoing an EEEA. There was a significantly longer average length of stay among patients undergoing open resection (21.5 vs. 10.6 days, p = 0.024). The average total in-hospital cost of a patient undergoing an EEEA was $58979.3 compared to $89142.3 for an open approach (p = 0.127). On univariate regression analysis, the total in-hospital cost for a patient undergoing an open approach relative to an EEEA was $30163.0 (p = 0.127). The open approach was exclusively performed from study onset until April 2010 (16 patients). From April 2010 to August 2013, 6 open approaches and 5 EEEA were performed. The EEEA has been exclusively performed from August 2013 until the conclusion of our study period (9 patients).There has been a shift toward surgical resection of craniopharyngioma via an EEEA approach for amenable tumors. Our study demonstrates that the EEEA has become the preferred surgical approach at our institution, and shows that the EEEA is associated with shorter postoperative length of stay and lower total in-hospital cost. Laryngoscope, 133:83-87, 2023.

The overall investigation of devices when it comes to the transformation of heat flux into electrical power, and electrical energy to heat power, significantly involves thermoelectric devices (TEDs). These devices provide the potential to build clean energy using a combination of appropriate materials. It has been recognized that more than 60% of the energy generated worldwide disappears, frequently due to the heat involved (exothermic reactions, friction, combustion, and radiation). Economically feasible TED materials and devices have not been successfully developed for larger-scale industrial use due to their low efficiency, unreliability, and high cost of materials and manufacturing. In this study, simple and inexpensive materials and methods were used to tailor the properties of thermoelectric materials to improve their figure of merit, which may be of great potential for meeting future energy demand. Stoichiometric bismuth telluride (Bi2Te3) powder was compounded with numerous concentrations of sodium chloride (NaCl) salt particles ranging from 0 to 50% by volume. The NaCl was ground to microscale particles, and cylindrical pellets were crafted using cold pressing and sintering operations. Consequently, the NaCl was leached separately within the samples using hot water, which caused porous structures. Testing equipment was designed to measure the three essential parameters of TEDs—electrical conductivity, Seebeck coefficient, and thermal conductivity—before and after the NaCl leaching process. Following that, the figure of merit was also calculated for each concentration. Primarily porous structures containing 20% NaCl had a 37.55% higher figure-of-merit value compared to the base samples (0% NaCl), and an increase of 89.07% in the figure of merit from the solids content of the samples was observed with NaCl inclusions at a concentration of 30% by volume. The existence of both NaCl and pores was sufficient to increase the figure of merit. Inclusions and porosity detrimentally influenced the electrical conductivity, but there was a substantial rise in the Seebeck coefficient and thermal conductivity changes leading to an increase in the figure of merit. The figure of merit obtained from this study is relatively moderate for the latest generation of thermoelectric materials. However, the materials and methods used here were simple, economical, and scalable and have great potential for use with optimized thermoelectric materials in hopes of further improvement in the figure of merit.

Knot tying boards are low fidelity surgical simulators used to practice tying suture, but devices on the market currently provide no feedback and no way of changing out bands. A simple-to-use knot tying board with interchangeable bands capable of measuring force was designed. This board is comparable in cost to products currently available on the market. The knot tying board was then prototyped and tested. Four MD students completed trials of one-handed and two-handed knot tying with three throws per trail. In testing, the knot tying board was capable of measuring force data, such as peak force during knot tying and the final force the knot exerts on the bands. The device used in conjunction with experienced surgical skills coaches could prove a powerful tool for providing feedback to trainees, and a similar approach could be used with other low fidelity surgical simulators to improve feedback.

Mosquito-borne viruses, such as dengue virus (DENV), Zika virus (ZIKV), chikungunya virus (CHIKV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and West Nile virus (WNV) are major threats to global public health resulting in millions of infections and hundreds of thousands of deaths annually. The presence of these viruses and their increasing emergence/spread continues to escalate. Notably, Usutu virus (USUV; Genus: Flavivirus; Family: Flaviviridae) is one such pathogen currently causing mass die-offs of avian hosts throughout Europe. USUV is categorized in the Japanese Encephalitis virus (JEV) antigenic complex and thus shares many antigenic and pathologic characteristics with fellow members, such as JEV and WNV. Respective to human infections, USUV cases are generally asymptomatic; nonetheless, acute cases have been reported. These acute cases typically cause mild symptoms, such as fevers and rashes; however, more severe cases can result in neurologic diseases, such as encephalitis and/or meningoencephalitis. In addition to these pathologic similarities, USUV shares several ecological and geographical traits with WNV, a pathogen responsible for several outbreaks during its spread from Africa, to Europe, and eventually the United States. Currently, WNV is considered endemic in areas across the United States due to its transmission via Culex spp.; mosquitoes that are ubiquitous in the United States. These parallels suggest the possible emergence of USUV into the United States and therefore, it is imperative to broaden our knowledge of USUV and assess its potential to become a major global health concern. The overall goal of this thesis was to characterize USUV and evaluate its emergence potential in the United States by: (1) developing infectious clones of recent European and African USUV isolates as tools for characterization and analysis of USUV and (2) assessing the transmission potential of several species of North American mosquitoes. In Aim 1, we show that the aforementioned infectious clones infect and replicate similarly to their parental strains in vitro in both vertebrate and invertebrate models, as well as in transiently immunocompromised CD-1 and IFNAR-/- murine models, and thus serve as useful tools for future molecular studies focusing on USUV. Furthermore, in Aim 2, we describe the ability of field-caught (Southwest Virginia, USA) Culex spp. and Aedes spp. mosquitoes to become infected with a recent European isolate of USUV; although, we report an overall limited potential for these species to transmit this virus. Altogether, these studies form a foundation for understanding the potential emergence of USUV in the United States as well as provide necessary tools needed to aid future research on USUV emergence, transmission, and pathogenesis. Master of Science Usutu virus (USUV) is an emerging mosquito-borne virus that was first isolated from a mosquito in 1959 in South Africa, and since then, has become a major problem throughout Africa and Europe causing acute to severe infection in dozens of patients. Additionally, this virus is causing massive die-offs in Eurasian blackbird populations. This is particularly problematic because birds play a critical role in ecosystems as they act as forms of pest control, pollinators, and seed dispersers. Depletion of these species could lead to an imbalance and, eventually, collapse of our natural ecosystem. Additionally, there is a growing concern of USUV making its way into the United States, following a similar track of emergence to WNV's introduction in New York in 1999 and its subsequent spread throughout the states. WNV's introduction to the United States was detrimental to native bird populations and humans, and has caused tens of thousands of infections and thousands of deaths since this introduction. Research has shown USUV causes similar disease symptoms to WNV. The self-limiting illness from these viruses typically includes fever and rashes but some infections can result in more severe cases causing inflammation of the brain and surrounding areas. Like many other prominent mosquito-borne viruses, there is no specific treatment or vaccine for WNV or USUV. Because USUV is so closely related to WNV, and their similar characteristics may point towards similar emergence in the United States, it is essential to garner more information on USUV. The overall goal of this thesis was to establish a reliable tool(s) for further characterization of USUV and demonstrate the potential for USUV emergence in the United States. We first developed molecular tools, known as viral clones, that are valuable to the scientific community which allows the manipulation of USUV genetic material to perform further downstream studies. Our objective for this initial study was to create a molecular tool that would behave similarly to their natural, or "parental", virus. The results from this study suggest we have successfully produced these tools. Furthermore, we sought to determine the potential for field-caught mosquitoes from Southwest Virginia, USA to transmit a recently isolated strain of USUV. These data suggest that while these mosquitoes do have the ability to become infected with USUV, they have a limited potential to transmit this virus to animal hosts. Altogether, these studies have allowed us to expand our knowledge on USUV's potential emergence in the United States and develop powerful tools to continue this essential research.

Cranial and craniospinal irradiation are the oldest central nervous system prophylaxis treatments considered for pediatric patients with acute lymphoblastic leukemia (ALL). However, survivors of childhood ALL that received cranial radiotherapy are at increased risk for deficits in neurocognitive skills. The continuous and dynamic response of normal tissue after irradiation has been identified as one of the causative factors for cognitive changes after cranial radiation therapy. The aim of our study was to investigate the radiation effects on social behavior and neuronal morphology in the hippocampus of adult mice. Twenty-oneday-old male C57BL/6 mice were irradiated with the small-animal radiation research platform (SARRP). Animals were given a single 10-Gy dose of radiation of X-ray cranial radiation. One month following irradiation, animals underwent behavioral testing in the Three-Chamber Sociability paradigm. Radiation affected social discrimination during the third stage eliciting an inability to discriminate between the familiar and stranger mouse, while sham successfully spent more time exploring the novel stranger. Proteomic analysis revealed dysregulation of metabolic and signaling pathways associated with neurocognitive dysfunction such as mitochondrial dysfunction, Rac 1 signaling, and synaptogenesis signaling. We observed significant decreases in mushroom spine density in the Cornu Ammonis 2 of the hippocampus, which is associated with sociability processing.

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide—approximately 3,000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals’ hippocampus-dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL.

Astronauts exposed to high linear energy transfer radiation may experience cognitive injury. The pathogenesis of this injury is unknown but may involve glutamate receptors or modifications to dendritic structure and/or dendritic spine density and morphology. Glutamate is the major excitatory neurotransmitter in the central nervous system, where it acts on ionotropic and metabotropic glutamate receptors located at the presynaptic terminal and in the postsynaptic membrane at synapses in the hippocampus. Dendritic spines are sites of excitatory synaptic transmission, and changes in spine structure and dendrite morphology are thought to be morphological correlates of altered brain function associated with hippocampal-dependent learning and memory. The aim of the current study is to assess whether behavior, glutamate receptor gene expression, and dendritic structure in the hippocampus are altered in mice after early exposure to 16O radiation in mice. Two weeks post-irradiation, animals were tested for hippocampus-dependent cognitive performance in the Y-maze. During Y-maze testing, mice exposed to 0.1 Gy and 0.25 Gy radiation failed to distinguish the novel arm, spending approximately the same amount of time in all 3 arms during the retention trial. Exposure to 16O significantly reduced the expression of Nr1 and GluR1 in the hippocampus and modulated spine morphology in the dentate gyrus and cornu Ammon 1 within the hippocampus. The present data provide evidence that 16O radiation has early deleterious effects on mature neurons that are associated with hippocampal learning and memory.

NASA’s Missions to Mars and beyond will expose flight crews to potentially dangerous levels of charged-particle radiation. Of all charged nuclei, 1H is the most abundant charged particle in both the galactic cosmic ray (GCR) and solar particle event (SPE) spectra. There are currently no functional spacecraft shielding materials that are able to mitigate the charged-particle radiation encountered in space. Recent studies have demonstrated cognitive injuries due to high-dose 1H exposures in rodents. Our study investigated the effects of 1H irradiation on neuronal morphology in the hippocampus of adult male mice. 6-month-old mice received whole-body exposure to 1H at 0.5 and 1 Gy (150 MeV/n; 0.35–0.55 Gy/min) at NASA's Space Radiation Laboratory in Upton, NY. At 9-months post-irradiation, we tested each animal's open-field exploratory performance. After sacrifice, we dissected the brains along the midsagittal plane, and then either fixed or dissected further and snap-froze them. Our data showed that exposure to 0.5 Gy or 1 Gy 1H significantly increased animals’ anxiety behavior in open-field testing. Our micromorphometric analyses revealed significant decreases in mushroom spine density and dendrite morphology in the Dentate Gyrus, Cornu Ammonis 3 and 1 of the hippocampus, and lowered expression of synaptic markers. Our data suggest 1H radiation significantly increased exploration anxiety and modulated the dendritic spine and dendrite morphology of hippocampal neurons at a dose of 0.5 or 1 Gy.

As bacteriophage therapy is being investigated more as an alternative to antibiotics, laboratories are isolating and characterizing the functions of bacteriophages. Additionally, with large variations between gut microbiome studies and inconsistencies in results, there is a need for discrete characterization of specific gut microbes in situ. This hypothesis paper describes a method to utilize bacteriophages in order to outline the functions of specific gut bacteria in existing biological systems with minimal disturbance. Further, the effects of specific microbe depletion on gut bacterial composition and host health can theoretically also be measured.

Radiation from galactic cosmic rays (GCR) poses a significant health risk for deep-space flight crews. GCR are unique in their extremely high-energy particles. With current spacecraft shielding technology, some of the predominant particles astronauts would be exposed to are 1H + 16O. Radiation has been shown to cause cognitive deficits in mice. The hippocampus plays a key role in memory and cognitive tasks; it receives information from the cortex, undergoes dendritic-dependent processing and then relays information back to the cortex. In this study, we investigated the effects of combined 1H + 16O irradiation on cognition and dendritic structures in the hippocampus of adult male mice three months postirradiation. Six-month-old male C57BL/6 mice were irradiated first with 1H (0.5 Gy, 150 MeV/n) and 1 h later with 16O (0.1 Gy, 600 MeV/n) at the NASA Space Radiation Laboratory (Upton, NY). Three months after irradiation, animals were tested for hippocampus-dependent cognitive performance using the Y-maze. Upon sacrifice, molecular and morphological assessments were performed on hippocampal tissues. During Y-maze testing, the irradiated mice failed to distinguish the novel arm, spending approximately the same amount of time in all three arms during the retention trial relative to sham-treated controls. Irradiated animals also showed changes in expression of glutamate receptor subunits and synaptic density-associated proteins. 1H + 16O radiation compromised dendritic morphology in the cornu ammonis 1 and dentate gyrus within the hippocampus. These data indicate cognitive injuries due to 1H + 16O at three months postirradiation.

Breast cancer (BC) is the most common cancer among women. Fortunately, BC survival rates have increased because the implementation of adjuvant chemotherapy leading to a growing population of survivors. However, chemotherapy-induced cognitive impairments (CICIs) affect up to 75% of BC survivors and may be driven by inflammation and oxidative stress. Chemotherapy-induced cognitive impairments can persist 20 years and hinder survivors’ quality of life. To identify early effects of CMF administration in mice, we chose to evaluate adult female mice at 2-week postchemotherapy. Mice received weekly IP administration of CMF (or saline) for 4 weeks, completed behavioral testing, and were sacrificed 2 weeks following their final CMF injection. Behavioral results indicated long-term memory (LTM) impairments postchemotherapy, but did not reveal short-term memory deficits. Dendritic morphology and spine data found increases in overall spine density within CA1 basal and CA3 basal dendrites, but no changes in DG, CA1 apical, or CA3 apical dendrites. Further analysis revealed decreases in arborization across the hippocampus (DG, CA1 apical and basal, CA3 apical and basal). These physiological changes within the hippocampus correlate with our behavioral data indicating LTM impairments following CMF administration in female mice 2-week postchemotherapy. Hippocampal cytokine analysis identified decreases in IL-1α, IL-1β, IL-3, IL-10, and TNF-α levels.

Aging is characterized by increased inflammation and deterioration of the cellular stress responses such as the oxidant/antioxidant equilibrium, DNA damage repair fidelity, and telomeric attrition. All these factors contribute to the increased radiation sensitivity in the elderly as shown by epidemiological studies of the Japanese atomic bomb survivors. There is a global increase in the aging population, who may be at increased risk of exposure to ionizing radiation (IR) as part of cancer therapy or accidental exposure. Therefore, it is critical to delineate the factors that exacerbate age-related radiation sensitivity and neurocognitive decline. The transcription factor CCAAT enhancer binding protein delta (C/EBP&delta, ) is implicated with regulatory roles in neuroinflammation, learning, and memory, however its role in IR-induced neurocognitive decline and aging is not known. The purpose of this study was to delineate the role of C/EBP&delta, in IR-induced neurocognitive decline in aged mice. We report that aged Cebpd&minus, /&minus, mice exposed to acute IR exposure display impairment in short-term memory and spatial memory that correlated with significant alterations in the morphology of neurons in the dentate gyrus (DG) and CA1 apical and basal regions. There were no significant changes in the expression of inflammatory markers. However, the expression of superoxide dismutase 2 (SOD2) and catalase (CAT) were altered post-IR in the hippocampus of aged Cebpd&minus, mice. These results suggest that Cebpd may protect from IR-induced neurocognitive dysfunction by suppressing oxidative stress in aged mice.

12013 Background: Childhood cancer therapy increases risk for cognitive impairment and other chronic conditions, which also may impact cognition. We assessed the unique impact of metabolic syndrome (MetS) on cognition in survivors participating in the St. Jude Lifetime Cohort Study. Methods: Participants included 4058 survivors of childhood cancer (53.9% female; mean [SD] age 30.1 [10.5] years at evaluation; 22.6 [10.1] years from diagnosis) who completed clinical evaluation and cognitive testing. MetS criteria followed Adult Treatment Panel III guidelines (at least 3 of: hypertension, high triglycerides, abdominal obesity, low high-density lipoprotein [HDL], high fasting glucose). Multivariable log-binomial regression models assessed risk of cognitive impairment associated with MetS stratified by survivors who did (n = 2301) or did not (n = 1757) receive central nervous system (CNS)-directed therapy. Mediation analysis assessed effects of MetS and physical activity in cranial radiotherapy (CRT)-associated cognitive impairment. Models were adjusted for age, sex, follow-up time and treatment exposures. Results: MetS was associated with increased risk of impaired attention (relative risk [RR] 1.34 95% confidence interval [CI] 1.07-1.66), processing speed (RR 1.25 CI 1.11-1.41) and executive function (RR 1.18 CI 1.01-1.37) in survivors with CNS-directed therapy and academic achievement (RR 1.84 CI 1.18-2.89), attention (RR 1.43 CI 1.10-1.87), and processing speed (RR 1.46 CI 1.21-1.75) in those without CNS-directed therapy. MetS components associated with cognitive impairment included abdominal obesity (memory RR 1.34 CI 1.13-1.59; processing speed RR 1.41 CI 1.24-1.59; executive function RR 1.21 CI 1.05-1.39) and low HDL (intelligence RR 1.26 CI 1.06-1.49; attention RR 1.27 CI 1.03-1.57; processing speed RR 1.17 CI 1.01-1.35; executive function RR 1.20 CI 1.05-1.37) in survivors with CNS-directed therapy. In survivors treated without CNS-directed therapy hypertension (academic achievement RR 1.49 CI 1.18-1.88; intelligence RR 1.34 CI 1.02-1.76; attention RR 1.42 CI 1.12-1.79; memory RR 1.45 CI 1.14-1.84; processing speed RR 1.30 CI 1.08-1.55; executive function RR 1.32 CI 1.08-1.62) and abdominal obesity (academic achievement RR 1.71 CI 1.07-2.72; processing speed RR 1.23 CI 1.02-1.49; executive function RR 1.38 CI 1.09-1.75) were associated with impairment. In mediation analyses, direct effects of CRT were identified, as were indirect effects through physical activity (processing speed β = 0.035 p < 0.01; attention β = 0.03 p < 0.01; executive function β = 0.172 p < 0.01). Conclusions: MetS increases risk of cognitive impairment in survivors, particularly abdominal obesity, hypertension and low HDL. Physical activity appears to partially mediate impact of CRT on cognitive outcomes and is an important target for interventions to lower impairment risk.

The radiation environment in space remains a major concern for manned space exploration, as there is currently no shielding material capable of fully protecting flight crews. Additionally, there is growing concern for astronauts’ social and cognitive welfare, due to the prolonged radiation exposure and confinement they will experience on a mission to Mars. This study investigated the late effects of (16)O irradiation on social and cognitive behavior and neuronal morphology in the hippocampus of adult female mice. We gave 6-month-old mice whole-body exposure to (16)O at 0.25 or 0.1Gy (600 MeV/n; 18–33 cGy/min) at NASA’s Space Radiation Laboratory in Upton, NY. Nine months following irradiation, animals underwent behavioral testing in the Three-Chamber Sociability and Novel Object Recognition and Y-maze paradigms. Exposure to 0.1 or 0.25 Gy (16)O significantly impaired object memory, a dosage of 0.25 Gy impaired social novelty learning, but neither dosage impaired short-term spatial memory. We observed significant decreases in mushroom spine density and dendrite morphology in the Dentate Gyrus, Cornu Ammonis 3, 2 and 1 of the hippocampus, which are consistent with key areas associated with object novelty and sociability processing. Our data suggest exposure to (16)O modulates hippocampal pyramidal and granular neurons and induces behavioral deficits at a time point of nine months after exposure in females.

Wider implementation of ultralight magnesium (Mg) alloys in engineering applications can be achieved if the mechanical properties of mass produced as-cast alloys can be further enhanced. Grain refinement of aluminum alloys has supported such initiatives over the past few decades; however, a potent and cost-effective grain refiner for common aluminum containing Mg alloys remains elusive. Further, the effect of grain refinement on common casting defects, such as hot tearing, in Mg alloys remains unclear. In this work, several novel grain refiners were produced via the powder metallurgical process known as spark plasma sintering (SPS). The novel grain refiners were used to treat AZ91D Mg alloy and a grain size reduction of ~75 - 85% was achieved, along with improved dispersion of secondary phases and modified eutectics. Such microstructure modifications during solidification resulted in the elimination of hot tearing in castings where hot tearing was typically observed. The SPS’ed refiners were also observed to outperform a common commercially available grain refiner. Many advanced analysis techniques that were implemented in this research provided further understanding of the mechanism behind the effectiveness of the SPS’ed grain refiners. Additionally, the casting experiments were completed using a unique force contraction mold, providing quantitative data during solidification. Furthermore, the results of microstructure evolution, solidification kinetics and forces, as well as in-situ solidification analysis via neutron diffraction, was related to the grain refinement and hot tearing of AZ91D Mg alloy.

Chemotherapy has been successfully used to reduce radiation dose and volume for most pediatric patients. However, because of the failure of chemotherapeutic agents to cross the blood-brain barrier and the lack of response of some brain tumors to these agents, radiation therapy is still used to treat many childhood cancers with CNS involvement. In this study, we investigated the radiation effects on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty-one-day-old male C57BL/6 mice were irradiated using the small animal radiation research platform (SARRP). Animals were exposed to either a 10 Gy single dose or 10 Gy × 2 fractionated doses of X-ray cranial radiation. Five weeks after irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. Significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received either 10 Gy single-dose or 10 Gy × 2 fractionated doses. However, by day 5, mice that received a 10 Gy single dose showed spatial memory retention in the probe trials, whereas mice that received the 20 Gy fractionated doses remained impaired. During Y-maze testing, animals exposed to radiation were impaired; the irradiated mice were not able to distinguish among the three Y-maze arms and spent approximately the same amount of time in all three arms during the retention trial. Radiation significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal trisynaptic network.

Radiation from galactic cosmic rays (GCR) poses a significant health risk for deep-space flight crews. GCR are unique in their extremely high-energy particles. Because of current spacecraft shielding technology, some of the predominant particles astronauts would be exposed to are (1)H + (16)O. Radiation has been shown to cause cognition deficits in mice. The hippocampus plays a key role in memory and cognitive tasks in that it receives information from the cortex, undergoes dendritic-dependent processing, and then relays information back to the cortex. The aim of our study is to investigate the effects of combined (1)H + (16)O irradiation on cognition and dendritic structures in the hippocampus of adult male mice three months postirradiation. Six-month old male C57BL/6 mice were irradiated first with (1)H (.5Gy, 150MeV/n) and one hour after with (16)O (.1Gy, 600MeV/n) at the NASA Space Radiation Laboratory in Upton, NY. Three months after irradiation, animals were tested for hippocampus-dependent cognitive performance in the Y-maze test. Upon sacrifice, molecular and morphological assessments were conducted on hippocampal tissues. During Y-maze testing, mice exposed to radiation failed to distinguish the novel arm, spending approximately the same amount of time in all three arms during the retention trial relative to sham. Irradiated animals also showed changes in expression of glutamate receptor subunits and synaptic density-associated proteins. (1)H + (16)O irradiation compromised dendritic morphology in the cornu ammonis 1 and dentate gyrus within the hippocampus. These data indicate cognitive injuries due to (1)H + (16)O 3 months post-irradiation.

NASA’s Missions to Mars and beyond will expose flight crews to potentially dangerous levels of charged-particle radiation. Of all charged nuclei, (1)H is the most abundant charged particle in both the galactic cosmic ray (GCR) and solar particle event (SPE) spectra. There are currently no functional spacecraft shielding materials that are able to mitigate the charged-particle radiation encountered in space. Recent studies have demonstrated cognitive injuries due to high-dose (1)H exposures in rodents. Our study investigated the effects of (1)H irradiation on neuronal morphology in the hippocampus of adult male mice. 6-month-old mice received whole-body exposure to (1)H at 0.5 and 1Gy (150 MeV/n; 0.35-0.55Gy/min) at NASA’s Space Radiation Laboratory in Upton, NY. At 9-months post-irradiation, we tested each animal’s open-field exploratory performance. After sacrifice, we dissected the brains along the midsagittal plane, and then either fixed or dissected further and snap-froze them. Our data showed that exposure to 0.5 Gy or 1 Gy (1)H significantly increased animals’ anxiety behavior in open-field testing. Our micromorphometric analyses revealed significant decreases in mushroom spine density and dendrite morphology in the Dentate Gyrus, Cornu Ammonis 3 and 1 of the hippocampus, and lowered expression of synaptic markers. Our data suggest (1)H radiation significantly increased exploration anxiety and modulated the dendritic spine and dendrite morphology of hippocampal neurons at a dose of 0.5 or 1 Gy.

Cylindrical pellets of near stoichiometric bismuth telluride (Bi2Te3) powder with NaCl particles were made using a cold pressing and pressureless sintering technique. The sodium chloride was leached out from the samples in hot water, resulting in porous samples with varying levels of porosity. The electrical conductivity, Seebeck coefficient, and thermal conductivity were measured at room temperature using a testing apparatus designed and built by the researcher, both before and after the leaching of sodium chloride. From this data, the figure of merit was calculated. Samples of pure bismuth telluride (0% NaCl) served as the baseline samples for comparison. Both the presence of NaCl and pores were efficient at increasing the dimensionless figure of merit. Porous samples initially containing 20% NaCl had a 37.55% higher figure of merit compared to baseline samples, and an 89.07% increase in the figure of merit was seen from the solid samples with NaCl inclusions at a concentration of 30% by volume. The electrical conductivity was negatively affected by both inclusions and porosity, but significant increases in Seebeck coefficient, and reduced thermal conductivity were significantly enough for an overall increase in dimensionless figure of merit. The figure of merit for the baseline sample was approximately 0.18, and the highest values observed for the NaCl inclusion and porous samples were 0.34 and 0.25 respectively. These values are far less than that of what is considered a state of the art thermoelectric material, but the materials and methods used were simple, inexpensive, and scalable, showing great potential for applicability for use with optimized thermoelectric materials in hopes of further increasing their figure of merit.

Cancer survivorship has increased greatly as therapies have become more advanced and effective. Thus, we must now focus on improving the quality of life of patients after treatment. After chemotherapy, many patients experience chemotherapy-induced cognitive decline, indicating a need to investigate pathologies associated with this condition. In this study, we addressed cognitive impairment after thioTEPA treatment by assessing behavior and assaying cytokine production and the structure of dendrites in the hippocampus. Male mice were given three intraperitoneal injections of thioTEPA. Five weeks later, the mice underwent behavior testing, and brains were collected for Golgi staining and cytokine analysis. Behavior tests included y-maze and Morris water maze and licking behavioral task. Cytokines measured include: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-10, IL-12p70, MCP-1, TNF-α, GMCSF, and RANTES. We observed decreased memory retention in behavioral tasks. Also, dendritic arborization and length were decreased after chemotherapy treatment. Finally, thioTEPA decreased cytokine production in animals treated with chemotherapy, compared to saline-treated controls. Here, we used a mouse model to correlate the decreases in dendritic complexity and inflammatory cytokine production with cognitive impairment after chemotherapy.

5-Fluorouracil (5-Fu) is commonly used chemotherapy drug, but it can lead to the impairment of cognitive function. The pathogenesis of this injury is unknown but may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology. Dendritic spines are sites of excitatory synaptic transmission and changes in spine structure and dendrite morphology are thought to represent a morphological correlate of altered brain functions associated with hippocampal dependent learning and memory. A total of 28 one-year-old C57BL6/J male mice were used in this study; 14 mice received 5-Fu treatment and 14 were given saline injections. One month post treatment, 14 cytokines were measured at the same time Golgi samples were taken. 8 analytes were significantly elevated in mice treated with 5-Fu. 5-Fu significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal tri-synaptic network. The present data provide the evidence that 5-Fu has deleterious effects on mature neurons associated with hippocampal learning and memory.

The radiation environment in space remains a major concern for manned space exploration, as there is currently no shielding material capable of fully protecting flight crews. Additionally, there is...

Astronauts traveling to Mars will be exposed to high levels of ionizing radiation upon leaving low-Earth orbit. During prolonged space travel, astronauts are exposed to galactic cosmic rays (GCRs) composed of protons, oxygen molecules, and high energy, high mass charged particles. Notably, oxygen molecules can travel through the shielding of spacecraft, potentially impacting 25% of the hippocampus. The aim of the current study was to assess whether 16O-particle radiation induced a behavioral deficit and histological changes in mice. Mice were sent to the National Aeronautics and Space Administration (NASA) Space Radiation Laboratory at Brookhaven National Laboratory and exposed to particulate 16O radiation at doses of 0 and 0.05 Gy. Nine months after irradiation, the mice were tested for novel object recognition and in the Y-maze, after which the animals were sacrificed. The brains were then dissected along the midsagittal plane for Golgi staining. Exposure to 0.05 Gy significantly impaired novel object recognition. However, short term memory and exploratory activity in the Y-maze were not affected. Micromorphometric analysis revealed significant decreases in mushroom spine density in the dentate gyrus and cornu Ammonis-1 and -3 of the hippocampus. Sholl analysis revealed a significant decrease in dendritic complexity in the dentate gyrus. The present data provide evidence that space radiation has deleterious effects on mature neurons associated with hippocampal learning and memory.