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1.  Phosphorus losses from monitored fields with conservation practices in the Lake Erie Basin, USA 
Ambio  2015;44(Suppl 2):319-331.
Conservation practices are implemented on farm fields in the USA through Farm Bill programs; however, there is a need for greater verification that these practices provide environmental benefits (e.g., water quality). This study was conducted to assess the impact of Farm Bill eligible conservation practices on soluble P (SP) and total P (TP) losses from four fields that were monitored between 2004 and 2013. No-tillage doubled SP loading compared to rotational tillage (e.g., tilled only before planting corn); however, no-tillage decreased TP loading by 69 % compared to rotational tillage. Similarly, grassed waterways were shown to increase SP loads, but not TP loads. A corn–soybean–wheat–oat rotation reduced SP loads by 85 % and TP loads by 83 % compared to the standard corn–soybean rotation in the region. We can potentially attain TP water quality goals using these Farm Bill practices; however, additional strategies must be employed to meet these goals for SP.
PMCID: PMC4329148  PMID: 25681988
Blind inlets; Conservation practices; Crop rotation; Grassed waterway; No-tillage; Water quality
2.  The evolution of treatment strategies for patients with chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation: Can tyrosine kinase inhibitors replace donor lymphocyte infusions? 
Leukemia & lymphoma  2014;56(1):128-134.
The optimal treatment for chronic myeloid leukemia (CML) relapsing following allogeneic bone marrow transplantation (alloBMT) is unknown. We performed a single-center retrospective analysis of 71 consecutive patients undergoing alloBMT for CML from 1995–2008. A multi-state model was used to quantify the cumulative incidences of complete molecular response (CMR) and death following alloBMT. The primary analysis was the comparison of three treatment interventions (tyrosine kinase inhibitor: TKI, donor lymphocyte infusion: DLI, and TKI+DLI) for relapsed disease post-alloBMT. Forty-five (63%) patients relapsed post-alloBMT (molecular relapse: n=16, cytogenetic relapse: n=20, hematologic relapse: n=2, advanced phase relapse: n=7) and 40 patients underwent one of three treatments: TKI-only (n=13), DLI-only (n=11), or TKI+DLI (n=16). Although not statistically significant, the TKI-only group had the highest cumulative incidence of CMR and the lowest cumulative incidence of death compared to DLI and TKI+DLI. These data support the finding that TKI therapy is active in the post-alloBMT setting.
PMCID: PMC4268088  PMID: 24712979
chronic myeloid leukemia; relapse; allogeneic transplantation
3.  Evidence for an electrostatic mechanism of force generation by the bacteriophage T4 DNA packaging motor 
Nature communications  2014;5:4173.
How viral packaging motors generate enormous forces to translocate DNA into viral capsids remains unknown. Recent structural studies of the bacteriophage T4 packaging motor have led to a proposed mechanism wherein the gp17 motor protein translocates DNA by transitioning between extended and compact states, orchestrated by electrostatic interactions between complimentarily charged residues across the interface between the N- and C-terminal subdomains. Here, we show that site-directed alterations in these residues cause force dependent impairments of motor function including lower translocation velocity, lower stall force, and higher frequency of pauses and slips. We further show that the measured impairments correlate with computed changes in free energy differences between the two states. These findings support the proposed structural mechanism and further suggest an energy landscape model of motor activity that couples the free energy profile of motor conformational states with that of the ATP hydrolysis cycle.
PMCID: PMC4157569  PMID: 24937091
4.  Influence of Group Size on the Success of Wolves Hunting Bison 
PLoS ONE  2014;9(11):e112884.
An intriguing aspect of social foraging behaviour is that large groups are often no better at capturing prey than are small groups, a pattern that has been attributed to diminished cooperation (i.e., free riding) in large groups. Although this suggests the formation of large groups is unrelated to prey capture, little is known about cooperation in large groups that hunt hard-to-catch prey. Here, we used direct observations of Yellowstone wolves (Canis lupus) hunting their most formidable prey, bison (Bison bison), to test the hypothesis that large groups are more cooperative when hunting difficult prey. We quantified the relationship between capture success and wolf group size, and compared it to previously reported results for Yellowstone wolves hunting elk (Cervus elaphus), a prey that was, on average, 3 times easier to capture than bison. Whereas improvement in elk capture success levelled off at 2–6 wolves, bison capture success levelled off at 9–13 wolves with evidence that it continued to increase beyond 13 wolves. These results are consistent with the hypothesis that hunters in large groups are more cooperative when hunting more formidable prey. Improved ability to capture formidable prey could therefore promote the formation and maintenance of large predator groups, particularly among predators that specialize on such prey.
PMCID: PMC4229308  PMID: 25389760
5.  Neuroprotective effects of progesterone in traumatic brain injury: blunted in vivo neutrophil activation at the blood-brain barrier 
American journal of surgery  2013;206(6):840-846.
Progesterone (PRO) may confer a survival advantage in traumatic brain injury (TBI) by reducing cerebral edema. We hypothesized that PRO reduces edema by blocking polymorphonuclear (PMN) interactions with endothelium (EC) in the blood-brain barrier (BBB).
CD1 mice received repeated PRO (16 mg/kg intraperitoneally) or vehicle (cyclodextrin) for 36 hours after TBI. Sham animals underwent craniotomy without TBI. The modified Neurological Severity Score graded neurologic recovery. A second craniotomy allowed in vivo observation of pial EC/PMN interactions and vascular macromolecule leakage. Wet/dry ratios assessed cerebral edema.
Compared with the vehicle, PRO reduced subjective cerebral swelling (2.9 ± .1 vs 1.2 ± .1, P <.001), PMN rolling (95 ± 1.8 vs 57 ± 2.0 cells/100 μm/min, P <.001), total EC/PMN adhesion (2.0 ± .4 vs .8 ± .1 PMN/100 μm, P <.01), and vascular permeability (51.8% ± 4.9% vs 27.1% ± 4.6%, P <.01). TBI groups had similar a Neurological Severity Score and cerebral wet/dry ratios (P > .05).
PRO reduces live pericontusional EC/PMN and BBB macromolecular leakage after TBI. Direct PRO effects on the microcirculation warrant further investigation.
PMCID: PMC4149185  PMID: 24112683
Intravital microscopy; Neutrophil; Endothelium; Blood-brain barrier; Traumatic brain injury; Progesterone
6.  Axonal Pathology in Traumatic Brain Injury 
Experimental neurology  2012;246:35-43.
Over the past 70 years, diffuse axonal injury (DAI) has emerged as one of the most common and important pathological features of traumatic brain injury (TBI). Axons in the white matter appear to be especially vulnerable to injury due to the mechanical loading of the brain during TBI. As such, DAI has been found in all severities of TBI and may represent a key pathologic substrate of mild TBI (concussion). Pathologically, DAI encompasses a spectrum of effects from primary mechanical breaking of the axonal cytoskeleton, to transport interruption, swelling and proteolysis, through secondary physiological changes. Depending on the severity and extent of injury, these changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and/or cognitive dysfunction. In addition, recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as insidiously progressive axonal pathology. Indeed, axonal degeneration has been found to continue even years after injury in humans, and appears to play a role in the development of Alzheimer’s disease-like pathological changes. Here we review the current understanding of DAI as a uniquely mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI.
PMCID: PMC3979341  PMID: 22285252
Axon; Diffuse axonal Injury; DAI; axonal pathology; traumatic brain injury; TBI; neurodegeneration; head injury; rotational acceleration; microtubule
7.  Willingness and Appropriateness of Peers Participating in Emerging Adults’ Substance Misuse Treatment 
This study investigates the feasibility of adapting empirically-supported family treatments for emerging adult peer dyads. Data were collected (n=84) from emerging adults and their peers. Peers completed measures of substance use, willingness to participate in their friends’ treatments, and an adapted version of the Significant Other Behavior Questionnaire (SBQ), which measures concerned significant others’ (CSO) responses to another’s use such a punishing, supporting, or withdrawing from the user. Peers were more likely to support sobriety or enable use, versus punishing use or withdrawing from their friends. Overall, peers were quite willing to assist in treatment, but heavily using peers were less enthusiastic. For some emerging adults, their current peers may represent untapped resources to integrate into treatment, and providing peer-enhanced treatments may expand the reach of services to non-treatment seeking populations.
PMCID: PMC3647351  PMID: 23462152
Emerging Adulthood; Close Friendships; Peers; Substance Abuse; Psychotherapy
8.  Why Are the Benefits of Increased Resources Not Impacting the Risk of HIV Infection for High SES Women in Cameroon? 
PLoS ONE  2014;9(6):e100507.
Despite evidence of a positive SES-HIV gradient in some SSA countries, researchers and policy-makers frequently assume that a range of protective interventions – increasing awareness of mechanisms of HIV transmission, techniques for prevention, greater access to health care facilities, and greater availability of condoms – will reduce the likelihood of contracting HIV, even among higher SES populations. We therefore explore the relationships between SES and these intervening behaviors to illuminate the complex factors that link SES and HIV among women in Cameroon.
We use bivariate and multivariate statistical analysis to examine patterns among the 5, 155 women aged 15–49 who participated in the 2004 CDHS.
The results show a strong pattern where higher SES women have greater access to and use of health care facilities, higher levels of condom use, more HIV knowledge, and command higher power within their relationships, yet also have higher rates of HIV. These traditionally protective factors appear to be offset by riskier sexual behaviors on the part of women with increased resources, most notably longer years of premarital sexual experience, multiple partners in last 12 months, and sexual encounters outside of relationship. Multivariate analyses suggests net of the effect of other factors, women who command higher decision-making power, have greater access to health care, more negative attitudes toward wife beating, longer years of premarital sexual exposure, and partners with professional/white collar jobs (characteristics associated with rising SES) had higher odds of testing positive for HIV.
Results show that higher riskier sexual practices on part of high SES women offset benefits that may have accrued from their increased access to resources. The results suggest that traditional approaches to HIV prevention which rely on poverty reduction, improving access to health care, improving HIV knowledge, and boosting women’s social and economic power may be insufficient to address other drivers of HIV infection among women in SSA.
PMCID: PMC4072687  PMID: 24968350
9.  Updating Memory after Mild Traumatic Brain Injury and Orthopedic Injuries 
Journal of Neurotrauma  2013;30(8):618-624.
Few studies have examined the trajectory of recovery of executive function (EF) after mild TBI (mTBI). Therefore, consensus has not been reached on the incidence and extent of EF impairment after mTBI. The present study investigated trajectory of change in executive memory over 3 months after mTBI on 59 right-handed participants with mTBI, as defined by Centers for Disease Control criteria, ages 14–30 years, recruited within 96 hours post-injury and tested <1 week (baseline), 1 month, and 3 months after injury. Also included were 58 participants with orthopedic injury (OI) and 27 typically developing (TD) non-injured participants with similar age, socioeconomic status, sex, and ethnicity. MRI data were acquired at baseline and 3 months. Although criteria included a normal CT scan, lesions were detected by MRI in 19 mTBI patients. Participants completed the KeepTrack task, a verbal recall task placing demands on goal maintenance, semantic memory, and memory updating. Scores reflected items recalled and semantic categories maintained. The mTBI group was divided into two groups: high (score ≥12) or low (score <12) symptoms based on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). Mixed model analyses revealed the trajectory of change in mTBI patients (high and low RPQ), OI patients, and TD subjects were similar over time (although the TD group differed from other groups at baseline), suggesting no recovery from mTBI up to 90 days. For categories maintained, differences in trajectory of recovery were discovered, with the OI comparison group surprisingly performing similar to those in the mTBI group with high RPQ symptoms, and different from low RPQ and the TD groups, bringing up questions about utility of OIs as a comparison group for mTBI. Patients with frontal lesions (on MRI) were also found to perform worse than those without lesions, a pattern that became more pronounced with time.
PMCID: PMC3638547  PMID: 23227898
cognition; executive function, mild traumatic brain injury; memory
10.  Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans 
Acta neuropathologica  2011;122(6):715-726.
The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer’s disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP-43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1–47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI.
PMCID: PMC3979333  PMID: 22101322
TDP-43; 43 kDa transactive response (TAR) DNA binding protein; Traumatic brain injury; Head injury; Diffuse axonal injury; DAI; Neurodegeneration; Dementia; Alzheimer’s disease; Long-term survival; Single versus repetitive TBI
11.  Neural Engineering to Produce in Vitro Nerve Constructs and Neurointerence 
Neurosurgery  2007;60(1):137-142.
Recently, our laboratory recapitulated a natural form of axon growth that occurs between late embryogenesis and early adulthood. In this article, we describe how this novel neural engineering approach may be used to produce a nervous tissue interface to integrate disconnected motor and sensory functions for external control.
For nervous system repair, we recently developed a unique method to engineer nervous tissue constructs in vitro consisting of bundles of axons spanning two populations of neuronal somata. To integrate electronics and nervous tissue to transform electrophysiological signals into electronic signals, we have designed a nervous tissue interface.
Our nervous tissue interface consists of stretch-grown nervous tissue with one end interfaced with a multiple electrode array, enabling us to detect and record real-time efferent signals conducted down the nerve and stimulate afferent sensory signaling.
Our ultimate goal is to develop a neurally controlled prosthesis and a nervous system interface that could be linked to the patient's thoughts, providing two-way signaling for motor control and feedback from multiple external stimuli.
PMCID: PMC3979335  PMID: 17228262
Nervous system repair; Neurally controlled prosthesis; Peripheral nerve injury; Signaling
12.  Partial Interruption of Axonal Transport Due to Microtubule Breakage Accounts for the Formation of Periodic Varicosities after Traumatic Axonal Injury 
Experimental neurology  2011;233(1):364-372.
Due to their viscoelastic nature, white matter axons are susceptible to damage by high strain rates produced during traumatic brain injury (TBI). Indeed, diffuse axonal injury (DAI) is one of the most common features of TBI, characterized by the hallmark pathological profiles of axonal bulbs at disconnected terminal ends of axons and periodic swellings along axons, known as “varicosities.” Although transport interruption underlies axonal bulb formation, it is unclear how varicosities arise, with multiple sites accumulating transported materials along one axon. Recently, axonal microtubules have been found to physically break during dynamic stretch-injury of cortical axons in vitro. Here, the same in vitro model was used in parallel with histopathological analyses of human brains acquired acutely following TBI to examine the potential role of mechanical microtubule damage in varicosity formation post-trauma. Transmission electron microscopy (TEM) following in vitro stretch-injury revealed periodic breaks of individual microtubules along axons that regionally corresponded with undulations in axon morphology. However, typically less than a third of microtubules were broken in any region of an axon. Within hours, these sites of microtubule breaks evolved into periodic swellings. This suggests axonal transport may be halted along one broken microtubule, yet can proceed through the same region via other intact microtubules. Similar axonal undulations and varicosities were observed following TBI in humans, suggesting primary microtubule failure may also be a feature of DAI. These data indicate a novel mechanism of mechanical microtubule damage leading to partial transport interruption and varicosity formation in traumatic axonal injury.
PMCID: PMC3979336  PMID: 22079153
Diffuse axonal injury; DAI; traumatic brain injury; TBI; axons; microtubules; axon varicosities; axonal transport; amyloid precursor prtotein; axonal stretch
13.  Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease? 
Nature reviews. Neuroscience  2010;11(5):361-370.
Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimer's disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques — one of the hallmarks of AD — may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.
PMCID: PMC3979339  PMID: 20216546
14.  Biomechanics of Concussion 
Clinics in sports medicine  2011;30(1):19-vii.
PMCID: PMC3979340  PMID: 21074079
Biomechanics; Tolerance; Mild traumatic Brain injury; Concussion
15.  Widespread Tau and Amyloid-Beta Pathology Many Years After a Single Traumatic Brain Injury in Humans 
Whilst a history of single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment, such as Alzheimer's disease (AD), the long-term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive / mild head injury. Here, post-mortem brains from long-term survivors of just a single TBI (1 to 47 years survival; n=39) versus uninjured, age-matched controls (n=47) were examined for neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques using immunohistochemistry and thioflavin-S staining. Detailed maps of findings permitted classification of pathology using semi-quantitative scoring systems. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one third of TBI cases. In addition, Aβ-plaques were found in a greater density following TBI versus controls. Moreover, thioflavin-S staining revealed that while all plaque-positive control cases displayed predominantly diffuse plaques, 64% of plaque-positive TBI cases, displayed predominantly thioflavin-S positive plaques or a mixed thioflavin-S positive / diffuse pattern. These data demonstrate widespread NFT and Aβ plaque pathologies are present in a proportion of patients following a single TBI, suggesting that some individuals who experience a single TBI may develop long-term neuropathological changes akin to those found in neurodegenerative disease.
PMCID: PMC3979351  PMID: 21714827
16.  Multiple Proteins Implicated in Neurodegenerative Diseases Accumulate in Axons After Brain Trauma in Humans 
Experimental neurology  2007;208(2):185-192.
Studies in animal models have shown that traumatic brain injury (TBI) induces the rapid accumulation of many of the same key proteins that form pathologic aggregates in neurodegenerative diseases. Here, we examined whether this rapid process also occurs in humans after TBI. Brain tissue from 18 cases who died after TBI and from 6 control cases was examined using immunohistochemistry. Following TBI, widespread axonal injury was persistently identified by the accumulation of neurofilament protein and amyloid precursor protein (APP) in axonal bulbs and varicosities. Axonal APP was found to co-accumulate with its cleavage enzymes, beta-site APP cleaving enzyme (BACE), presenilin-1 (PS1) and their product, amyloid-β (Aβ). In addition, extensive accumulation of α-synuclein (α-syn) was found in swollen axons and tau protein was found to accumulate in both axons and neuronal cell bodies. These data show rapid axonal accumulation of proteins implicated in neurodegenerative diseases including Alzheimer’s disease and the synucleinopathies. The cause of axonal pathology can be attributed to disruption of axons due to trauma, or as a secondary effect of raised intracranial pressure or hypoxia. Such axonal pathology in humans may provide a unique environment whereby co-accumulation of APP, BACE, and PS1 leads to intra-axonal production of Aβ as well as accumulation of α-syn and tau. This process may have important implications for survivors of TBI who have been shown to be at greater risk of developing neurodegenerative diseases.
PMCID: PMC3979356  PMID: 17826768
Traumatic brain injury; TBI; axonal injury; amyloid β; APP; BACE; PS-1; α-synuclein; tau
17.  Dendritic alterations after dynamic axonal stretch injury in vitro 
Experimental neurology  2010;224(2):415-423.
Traumatic axonal injury (TAI) is the most common and important pathology of traumatic brain injury (TBI). However, little is known about potential indirect effects of TAI on dendrites. In this study, we used a well-established in vitro model of axonal stretch injury to investigate TAI-induced changes in dendrite morphology. Axons bridging two separated rat cortical neuron populations plated on a deformable substrate were used to create a zone of isolated stretch injury to axons. Following injury, we observed the formation of dendritic alterations or beading along the dendrite shaft. Dendritic beading formed within minutes after stretch then subsided over time. Pharmacological experiments revealed a sodium-dependent mechanism, while removing extracellular calcium exacerbated TAI's effect on dendrites. In addition, blocking ionotropic glutamate receptors with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevented dendritic beading. These results demonstrate that axon mechanical injury directly affects dendrite morphology, highlighting an important bystander effect of TAI. The data also imply that TAI may alter dendrite structure and plasticity in vivo. An understanding of TAI's effect on dendrites is important since proper dendrite function is crucial for normal brain function and recovery after injury.
PMCID: PMC3979358  PMID: 20478308
Dendrite; Traumatic brain injury; Diffuse axonal injury; Cerebral cortex; In vitro
18.  Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs 
Experimental neurology  2008;210(2):645-655.
Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.
PMCID: PMC3979422  PMID: 18291370
Traumatic brain injury; TBI; rFVIIa; Cerebral contusion; Recombinant Activated Factor VII; Hemostasis; Diffuse axonal injury; Neuroprotection
19.  Therapy Development for Diffuse Axonal Injury 
Journal of Neurotrauma  2013;30(5):307-323.
Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.
PMCID: PMC3627407  PMID: 23252624
animal models of injury; axonal injury; non-invasive detection methods, therapeutic targeting; traumatic brain injury
20.  Inhibition of Nogo-66 Receptor 1 Enhances Recovery of Cognitive Function after Traumatic Brain Injury in Mice 
Journal of Neurotrauma  2013;30(4):247-258.
Central nervous system (CNS) axons recover poorly following injury because of the expression of myelin-derived inhibitors of axonal outgrowth such as Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp), all of which bind to the Nogo-66 receptor 1 (NgR1). Herein we examine the role of NgR1 in the recovery of motor and cognitive function after traumatic brain injury (TBI) using a controlled cortical impact (CCI) model in NgR1 knockout (KO) and wild-type (WT) mice. Four weeks post-injury, scores on the Novel Object Recognition test were significantly increased in NgR1 KO mice compared with WT mice (p<0.05), but motor behavior test scores did not differ significantly between the two groups. Nissl staining showed that NgR1 KO mice had less brain injury volume 2 weeks after CCI (p<0.05). Histological analysis revealed more doublecortin (DCX+) cells (p<0.01) and more Ki-67+ cells in the contralateral dentate gyrus (DG) (p<0.05) 2 weeks after CCI in NgR1 KO mice than in WT. Furthermore, DCX+ cells still retained their longer processes in KO mice (p<0.01) 4 weeks following trauma. The number of bromodeoxyuridine (BrdU)+ cells did not differ between the two groups at 4 weeks post-trauma, but KO mice had higher numbers of cells that co-stained with NeuN, a marker of mature neurons. Increased transcription of growth-associated protein (GAP)-43 in both the injured and contralateral sides of the hippocampus (both p<0.05) was detected in NgR1 KO mice relative to WT. These data suggest that NgR1 negatively influences plasticity and cognitive recovery after TBI.
PMCID: PMC3579383  PMID: 22967270
cognitive function; locomotor function; Nogo receptors; recovery
21.  Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant 
Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1– and Th-17–balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell–mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.
PMCID: PMC3948110  PMID: 24532579
22.  Nanoemulsion nasal adjuvant W805EC induces dendritic cell engulfment of antigen-primed epithelial cells 
Vaccine  2012;31(7):1072-1079.
Nanoemulsions are adjuvants that enhance antigen penetration in the nasal mucosa, increase cellular uptake of antigens by both epithelial dendritic cells, and promote migration of antigen-loaded dendritic cells to regional lymph nodes within a day of vaccine administration. The objective of this study was to determine whether the W805EC nanoemulsion adjuvant enhances immune response not only by direct uptake of antigen by dendritic cells, but also indirectly, by phagocytosis of antigen-primed, apoptotic, epithelial cells. Consistent with this, we show that exposure of both epithelial cells (TC-1s) and dendritic cells (JAWS II or bone marrow derived dendritic cells (BMDCs)) to nanoemulsion exhibited augmented antigen uptake in cell culture. TC-1 cells subsequently underwent G2/M cell cycle arrest and apoptosis, and when co-cultured with JAWS II or BMDCs were rapidly engulfed by the dendritic cells, which responded by up-regulating dendritic cell maturation marker CD86. Altogether these results suggest that the effectiveness of nanoemulsions as adjuvants stems, at least in part, from the engulfment of antigen-loaded epithelial cells, leading to enhanced antigen processing and a strong and balanced mucosal and systemic immune response.
PMCID: PMC3556236  PMID: 23273511
Immunization; antigens; cytokines; antibodies
23.  Inflammation and white matter degeneration persist for years after a single traumatic brain injury 
Brain  2013;136(1):28-42.
A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer’s disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer’s disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ≥3 months from injury, cases with traumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.
PMCID: PMC3562078  PMID: 23365092
inflammation; diffuse axonal injury; traumatic brain injury; axonal pathology; microglia
24.  Mental Health and Substance Use Disorders among Foster Youth Transitioning to Adulthood: Past Research and Future Directions 
At a time when there is increasing attention being given to systematically integrating the well-being of children with the goals of safety and permanence in child welfare, little is known about the psychosocial functioning of foster youth transitioning to adulthood from substitute care. This article systematically reviews 17 peer-reviewed articles and/or research reports to identify lifetime and past year prevalence rates of mental health disorders and service utilization. At ages 17 or 18, foster youth are 2 to 4 times more likely to suffer from lifetime and/or past year mental health disorders compared to transition aged youth in the general population. Findings show that mental health service use declines at ages when the prevalence rate of mental health disorders is peaking. The findings of this review suggest the need to focus future efforts in three main areas: 1) Setting a common research agenda for the study of mental health and service use; 2) Routine screening and empirically supported treatments; and 3) Integration and planning between child and adult mental health service systems.
PMCID: PMC3677527  PMID: 23766549
Aging out foster youth; transition aged foster youth; mental health disorders; alcohol and substance use disorders; prevalence rates of lifetime and past year psychiatric disorders; mental health services
25.  Isolation of Cancer Stem Like Cells from Human Adenosquamous Carcinoma of the Lung Supports a Monoclonal Origin from a Multipotential Tissue Stem Cell 
PLoS ONE  2013;8(12):e79456.
There is increasing evidence that many solid tumors are hierarchically organized with the bulk tumor cells having limited replication potential, but are sustained by a stem-like cell that perpetuates the tumor. These cancer stem cells have been hypothesized to originate from transformation of adult tissue stem cells, or through re-acquisition of stem-like properties by progenitor cells. Adenosquamous carcinoma (ASC) is an aggressive type of lung cancer that contains a mixture of cells with squamous (cytokeratin 5+) and adenocarcinoma (cytokeratin 7+) phenotypes. The origin of these mixtures is unclear as squamous carcinomas are thought to arise from basal cells in the upper respiratory tract while adenocarcinomas are believed to form from stem cells in the bronchial alveolar junction. We have isolated and characterized cancer stem-like populations from ASC through application of selective defined culture medium initially used to grow human lung stem cells. Homogeneous cells selected from ASC tumor specimens were stably expanded in vitro. Primary xenografts and metastatic lesions derived from these cells in NSG mice fully recapitulate both the adenocarcinoma and squamous features of the patient tumor. Interestingly, while the CSLC all co-expressed cytokeratins 5 and 7, most xenograft cells expressed either one, or neither, with <10% remaining double positive. We also demonstrated the potential of the CSLC to differentiate to multi-lineage structures with branching lung morphology expressing bronchial, alveolar and neuroendocrine markers in vitro. Taken together the properties of these ASC-derived CSLC suggests that ASC may arise from a primitive lung stem cell distinct from the bronchial-alveolar or basal stem cells.
PMCID: PMC3850920  PMID: 24324581

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