Traumatic brain injury (TBI) causes disconnection and degeneration of white matter pathways, including long tracts that convey information between brain regions. TBI damage and subsequent ...degeneration of white matter tracts is important for interpreting TBI effects on neural circuits that are the basis of patient symptoms.Axonal injury is central to white matter damage in TBI. TBI disrupts axon–myelin interactions that are required for signal conduction, bioenergetics, and plasticity. Indicators of axon damage after TBI include impaired axonal transport, cytoskeleton collapse, demyelination, and node of Ranvier disruption.Secondary injury causes the majority of axon damage over time and involves dynamic, multifactorial pathophysiological processes. An emerging time course of early reparative cellular responses opens an opportunity for interventions to promote durable recovery and interrupt the transition to chronic processes that lead to post-traumatic neurodegeneration.
Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.
Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.
To estimate the prevalence and consequences of receiving prescription opioids from both the Department of Veterans Affairs (VA) and Medicare Part D.
Among US veterans enrolled in both VA and Part D ...filling 1 or more opioid prescriptions in 2012 (n = 539 473), we calculated 3 opioid safety measures using morphine milligram equivalents (MME): (1) proportion receiving greater than 100 MME for 1 or more days, (2) mean days receiving greater than 100 MME, and (3) proportion receiving greater than 120 MME for 90 consecutive days. We compared these measures by opioid source.
Overall, 135 643 (25.1%) veterans received opioids from VA only, 332 630 (61.7%) from Part D only, and 71 200 (13.2%) from both. The dual-use group was more likely than the VA-only group to receive greater than 100 MME for 1 or more days (34.3% vs 10.9%; adjusted risk ratio ARR = 3.0; 95% confidence interval CI = 2.9, 3.1), have more days with greater than 100 MME (42.5 vs 16.9 days; adjusted difference = 16.4 days; 95% CI = 15.7, 17.2), and to receive greater than 120 MME for 90 consecutive days (7.8% vs 3.1%; ARR = 2.2; 95% CI = 2.1, 2.3).
Among veterans dually enrolled in VA and Medicare Part D, dual use of opioids was associated with more than 2 to 3 times the risk of high-dose opioid exposure.
We present high-resolution mid-infrared (MIR) imaging, nuclear spectral energy distributions (SEDs), and archival Spitzer spectra for 22 low-luminosity active galactic nuclei (LLAGNs; L sub(bol) 10 ...super(42) erg s super(-1)). Infrared (IR) observations may advance our understanding of the accretion flows in LLAGNs, the fate of the obscuring toms at low accretion rates, and, perhaps, the star formation histories of these objects. We separate the present TI AGN sample into three categories depending on their Eddington ratio and radio emission, finding different IR characteristics for each class. The nuclear SEDs of these galaxies are diverse; some resemble typical Seyfert nuclei, while others lack a well-defined MIR "dust bump." Strong silicate emission is present in many of these objects. We speculate that this, together with high ratios of silicate strength to hydrogen column density, could suggest optically thin dust and low dust-to-gas ratios, in accordance with model predictions that LLAGNs do not host a Seyfert-like obscuring torus.
Noninvasive detection of mild traumatic brain injury (mTBI) is important for evaluating acute through chronic effects of head injuries, particularly after repetitive impacts. To better detect ...abnormalities from mTBI, we performed longitudinal studies (baseline, 3, 6, and 42 days) using magnetic resonance diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) in adult mice after repetitive mTBI (r-mTBI; daily × 5) or sham procedure. This r-mTBI produced righting reflex delay and was first characterized in the corpus callosum to demonstrate low levels of axon damage, astrogliosis, and microglial activation, without microhemorrhages. High-resolution DTI-DKI was then combined with post-imaging pathological validation along with behavioral assessments targeted for the impact regions. In the corpus callosum, only DTI fractional anisotropy at 42 days showed significant change post-injury. Conversely, cortical regions under the impact site (M1-M2, anterior cingulate) had reduced axial diffusivity (AD) at all time points with a corresponding increase in axial kurtosis (K
) at 6 days. Post-imaging neuropathology showed microglial activation in both the corpus callosum and cortex at 42 days after r-mTBI. Increased cortical microglial activation correlated with decreased cortical AD after r-mTBI (r = -0.853; n = 5). Using Thy1-YFP-16 mice to fluorescently label neuronal cell bodies and processes revealed low levels of axon damage in the cortex after r-mTBI. Finally, r-mTBI produced social deficits consistent with the function of this anterior cingulate region of cortex. Overall, vulnerability of cortical regions is demonstrated after mild repetitive injury, with underlying differences of DTI and DKI, microglial activation, and behavioral deficits.
Silver nanoparticles (AgNPs) and fluoride (F) are pharmacological agents widely used in oral medicine and dental practice due to their anti-microbial/anti-cavity properties. However, risks associated ...with the co-exposure of local cells and tissues to these xenobiotics are not clear. Therefore, we have evaluated the effects of AgNPs and F co-exposure on human gingival fibroblast cells.
Human gingival fibroblast cells (CRL-2014) were exposed to AgNPs and/or F at different concentrations for up to 24 hours. Cellular uptake of AgNPs was examined by transmission electron microscopy. Downstream inflammatory effects and oxidative stress were measured by real-time quantitative polymerase chain reaction (PCR) and reactive oxygen species (ROS) generation. Cytotoxicity and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and real-time quantitative PCR and flow cytometry, respectively. Finally, the involvement of mitogen-activated protein kinases (MAPK) was studied using Western blot.
We found that AgNPs penetrated the cell membrane and localized inside the mitochondria. Co-incubation experiments resulted in increased oxidative stress, inflammation, and apoptosis. In addition, we found that co-exposure to both xenobiotics phosphorylated MAPK, particularly p42/44 MAPK.
A combined exposure of human fibroblasts to AgNPs and F results in increased cellular damage. Further studies are needed in order to evaluate pharmacological and potentially toxicological effects of AgNPs and F on oral health.
More than half of enrollees in the U.S. Department of Veterans Affairs (VA) are also covered by Medicare and can choose to receive their prescriptions from VA or from Medicare-participating ...providers. Such dual-system care may lead to unsafe opioid use if providers in these 2 systems do not coordinate care or if prescription use is not tracked between systems.
To evaluate the association between dual-system opioid prescribing and death from prescription opioid overdose.
Nested case-control study.
VA and Medicare Part D.
Case and control patients were identified from all veterans enrolled in both VA and Part D who filled at least 1 opioid prescription from either system. The 215 case patients who died of a prescription opioid overdose in 2012 or 2013 were matched (up to 1:4) with 833 living control patients on the basis of date of death (that is, index date), using age, sex, race/ethnicity, disability, enrollment in Medicaid or low-income subsidies, managed care enrollment, region and rurality of residence, and a medication-based measure of comorbid conditions.
The exposure was the source of opioid prescriptions within 6 months of the index date, categorized as VA only, Part D only, or VA and Part D (that is, dual use). The outcome was unintentional or undetermined-intent death from prescription opioid overdose, identified from the National Death Index. The association between this outcome and source of opioid prescriptions was estimated using conditional logistic regression with adjustment for age, marital status, prescription drug monitoring programs, and use of other medications.
Among case patients, the mean age was 57.3 years (SD, 9.1), 194 (90%) were male, and 181 (84%) were non-Hispanic white. Overall, 60 case patients (28%) and 117 control patients (14%) received dual opioid prescriptions. Dual users had significantly higher odds of death from prescription opioid overdose than those who received opioids from VA only (odds ratio OR, 3.53 95% CI, 2.17 to 5.75; P < 0.001) or Part D only (OR, 1.83 CI, 1.20 to 2.77; P = 0.005).
Data are from 2012 to 2013 and cannot capture prescriptions obtained outside the VA or Medicare Part D systems.
Among veterans enrolled in VA and Part D, dual use of opioid prescriptions was independently associated with death from prescription opioid overdose. This risk factor for fatal overdose among veterans underscores the importance of care coordination across health care systems to improve opioid prescribing safety.
U.S. Department of Veterans Affairs.
Background and Objectives
Tumor deposit (TD) is a poor prognostic factor in colorectal cancer (CRC) patients. This study aimed to determine whether TD carry the same risk of peritoneal recurrence as ...known high‐risk (HR) features in CRC patients.
Methods
A retrospective cohort‐study of stage I−III CRC patients from 2010 to 2015 was conducted. TD group was defined by the presence of TD on histopathology whereas HR group was defined by the presence of obstruction, perforation, or T4‐stage.
Results
A total of 151 patients with CRC were identified, of which 50 had TD and 101 had a HR feature. The overall risk of peritoneal recurrence was higher in the TD group versus HR group (36.0% vs. 19.8%, p = 0.03). The risk of peritoneum as the site of first recurrence was also higher in the TD group (22.0% vs. 12.9%, p = 0.03). Overall cancer recurrence at any site was also higher in the TD group (56.0% vs. 34.7%, p = 0.01). Median time to first recurrence was 1.2 (0.7−1.9) years in the TD group compared to 1.4 (0.8−2.1) years in the HR group (p = 0.31).
Conclusions
In non‐metastatic CRC patients, TD might have a higher risk of tumor recurrence versus their HR counterparts. Alternative strategies for surveillance and treatment should be considered.
Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural ...circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. SARM1 protein is a central driver of axon degeneration through a conserved molecular pathway. Sarm1-/- mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of the SARM1 pathway as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classification of pathology of individual axons, using electron microscopy, demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. Longitudinal MRI studies in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited beneficial effects in motor learning and sleep behavior. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.
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