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1.  The Parkland Protocol's Modified Berne-Norwood Criteria Predict Two Tiers of Risk for Traumatic Brain Injury Progression 
Journal of Neurotrauma  2014;31(20):1737-1743.
Abstract
As a basis for venous thromboembolism (VTE) prophylaxis after traumatic brain injury (TBI), we have previously published an algorithm known as the Parkland Protocol. Patients are classified by risk for spontaneous progression of hemorrhage with chemoprophylaxis regimens tailored to each tier. We sought to validate this schema. In our algorithm, patients with any of the following are classified “low risk” for spontaneous progression: subdural hemorrhage ≤8 mm thick; epidural hemorrhage ≤8 mm thick; contusions ≤20 mm in diameter; a single contusion per lobe; any amount of subarachnoid hemorrhage; or any amount of intraventricular hemorrhage. Patients with any injury exceeding these are “moderate risk” for progression, and any patient receiving a monitor or craniotomy is “high risk.” From February 2010 to November 2012, TBI patients were entered into a dedicated database tracking injury types and sizes, risk category at presentation, and progression on subsequent computed tomgraphies (CTs). The cohort (n=414) was classified as low risk (n=200), moderate risk (n=75), or high risk (n=139) after first CT. After repeat CT scan, radiographic progression was noted in 27% of low-risk, 53% of moderate-risk, and 58% of high-risk subjects. Omnibus analysis of variance test for differences in progression rates was highly significant (p<0.0001). Tukey's post-hoc test showed the low-risk progression rate to be significantly different than both the moderate- and high-risk arms; no difference was noted between the moderate- and high-risk arms themselves. These criteria are a valid tool for classifying TBI patients into two categories of risk for spontaneous progression. This supports tailored chemoprophylaxis regimens for each arm.
doi:10.1089/neu.2014.3366
PMCID: PMC4180120  PMID: 24945196
progression; TBI; validation; venous thromboembolism
2.  Does Isolated Traumatic Subarachnoid Hemorrhage Merit a Lower Intensity Level of Observation Than Other Traumatic Brain Injury? 
Journal of Neurotrauma  2014;31(20):1733-1736.
Abstract
Evidence is emerging that isolated traumatic subarachnoid hemorrhage (ITSAH) may be a milder form of traumatic brain injury (TBI). If true, ITSAH may not benefit from intensive care unit (ICU) admission, which would, in turn, decrease resource utilization. We conducted a retrospective review of all TBI admissions to our institution between February 2010 and November 2012 to compare the presentation and clinical course of subjects with ITSAH to all other TBI. We then performed descriptive statistics on the subset of ITSAH subjects presenting with a Glasgow Coma Score (GCS) of 13–15. Of 698 subjects, 102 had ITSAH and 596 had any other intracranial hemorrhage pattern. Compared to all other TBI, ITSAH had significantly lower injury severity scores (p<0.0001), lower head abbreviated injury scores (p<0.0001), higher emergency department GCS (p<0.0001), shorter ICU stays (p=0.007), higher discharge GCS (p=0.005), lower mortality (p=0.003), and significantly fewer head computed tomography scans (p<0.0001). Of those ITSAH subjects presenting with a GCS of 13–15 (n=77), none underwent placement of an intracranial monitor or craniotomy. One subject (1.3%) demonstrated a change in exam (worsened headache and dizziness) concomitant with a progression of his intracranial injury. His symptoms resolved with readmission to the ICU and continued observation. Our results suggest that ITSAH are less-severe brain injuries than other TBI. ITSAH patients with GCS scores of 13–15 demonstrate low rates of clinical progression, and when progression occurs, it resolves without further intervention. This subset of TBI patients does not appear to benefit from ICU admission.
doi:10.1089/neu.2014.3377
PMCID: PMC4180123  PMID: 24926612
isolated; progression; sequelae; subarachnoid; traumatic
3.  Orexin modulates brown adipose tissue thermogenesis 
Biomolecular concepts  2012;3(4):381-386.
Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulation. In addition, activations of BAT have important implications for energy homeostasis due to the metabolic consumption of energy reserves entailed in the production of heat in this tissue. In this conceptual overview we describe the role of orexins/hypocretins within the central nervous system in the modulation of thermogenesis in BAT under several physiological conditions. Within this framework, we consider potential neural mechanisms underlying the pathological conditions associated with the absence of the central orexinergic modulation of BAT thermogenesis and energy expenditure. Overall, the experimental basis for our understanding of the role of central orexin in regulating body temperature and energy homeostasis provides an illustrative example that highlights several general principles and caveats that should help to guide future investigations of the neurochemical regulation of thermogenesis and metabolism.
doi:10.1515/bmc-2011-0066
PMCID: PMC3535439  PMID: 23293681
cannabinoid; narcolepsy; obesity; stress; ultradian rhythm
4.  Alpha-2 adrenergic receptor-mediated inhibition of thermogenesis 
Alpha2-adrenergic receptor (α2-AR) agonists have been use as anti-hypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since α2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by α2-AR agonists. Nanoinjection of the α2-AR agonist, clonidine (1.2 nmol), into the rostral raphe pallidus (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the α2-AR antagonist, idazoxan (6nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the α2-AR agonists, dexmedetomidine (25ug/kg, iv) or clonidine (100ug/kg, iv) inhibited shivering EMGs, BAT SNA and BAT thermogenesis effects that were reversed by nanoinjection of idazoxan (6nmol) into the rRPa. Dexmedetomidine (100µg/kg, ip) prevented and reversed lipopolysaccharide (10µg/kg ip)-evoked thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of VLM neurons expressing of the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of α2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by α2-AR activation in the rRPa, and suggest a therapeutic potential of α2-AR agonists for reducing potentially-lethal elevations in body temperature during excessive fever.
doi:10.1523/JNEUROSCI.4701-12.2013
PMCID: PMC3711400  PMID: 23365239
5.  Efferent projections of NPY expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models 
The Journal of comparative neurology  2013;521(8):1891-1914.
The dorsomedial hypothalamus (DMH) has long been implicated in feeding behavior and thermogenesis. The DMH contains orexigenic neuropeptide Y (NPY) neurons, but the role of these neurons in the control of energy homeostasis is not well understood. NPY expression in the DMH is low under normal conditions in adult rodents, but is significantly increased during chronic hyperphagic conditions such as lactation and diet-induced obesity (DIO). To better understand the role of DMH-NPY neurons, we characterized the efferent projections of DMH-NPY neurons using the anterograde tracer biotinylated dextran amine (BDA) in lactating rats and DIO mice. In both models, BDA and NPY co-labeled fibers were mainly limited to the hypothalamus including the paraventricular nucleus of the hypothalamus (PVH), lateral hypothalamus/perifornical area (LH/PFA), and anteroventral periventricular nucleus (AVPV). Specifically in lactating rats, BDA and NPY co-labeled axonal swellings were in close apposition to CART expressing neurons in the PVH and AVPV. Although the DMH neurons project to the rostral raphe pallidus (rRPa) these projections did not contain NPY immunoreactivity in either the lactating rat or DIO mouse. Instead, the majority of BDA-labeled fibers in the rRPa were orexin positive. Furthermore, DMH-NPY projections were not observed within the nucleus of the solitary tract (NTS), another brainstem site critical for the regulation of sympathetic outflow. The present data suggest that NPY expression in the DMH during chronic hyperphagic conditions plays important roles in feeding behavior and thermogenesis by modulating neuronal functions within the hypothalamus, but not in the brainstem.
doi:10.1002/cne.23265
PMCID: PMC3618613  PMID: 23172177
hypothalamus; lactation; obesity; food intake; thermogenesis
6.  Central Activation of the A1 Adenosine Receptor (A1AR) Induces a Hypothermic, Torpor-Like State in the Rat 
The Journal of Neuroscience  2013;33(36):14512-14525.
Since central activation of A1 adenosine receptors (A1ARs) plays an important role in the induction of the hypothermic and hypometabolic torpid state in hibernating mammals, we investigated the potential for the A1AR agonist N6-cyclohexyladenosine to induce a hypothermic, torpor-like state in the (nonhibernating) rat. Core and brown adipose tissue temperatures, EEG, heart rate, and arterial pressure were recorded in free-behaving rats, and c-fos expression in the brain was analyzed, following central administration of N6-cyclohexyladenosine. Additionally, we recorded the sympathetic nerve activity to brown adipose tissue; expiratory CO2 and skin, core, and brown adipose tissue temperatures; and shivering EMGs in anesthetized rats following central and localized, nucleus of the solitary tract, administration of N6-cyclohexyladenosine. In rats exposed to a cool (15°C) ambient temperature, central A1AR stimulation produced a torpor-like state similar to that in hibernating species and characterized by a marked fall in body temperature due to an inhibition of brown adipose tissue and shivering thermogenesis that is mediated by neurons in the nucleus of the solitary tract. During the induced hypothermia, EEG amplitude and heart rate were markedly reduced. Skipped heartbeats and transient bradycardias occurring during the hypothermia were vagally mediated since they were eliminated by systemic muscarinic receptor blockade. These findings demonstrate that a deeply hypothermic, torpor-like state can be pharmacologically induced in a nonhibernating mammal and that recovery of normothermic homeostasis ensues upon rewarming. These results support the potential for central activation of A1ARs to be used in the induction of a hypothermic, therapeutically beneficial state in humans.
doi:10.1523/JNEUROSCI.1980-13.2013
PMCID: PMC3761054  PMID: 24005302
7.  Autonomic regulation of brown adipose tissue thermogenesis in health and disease: potential clinical applications for altering BAT thermogenesis 
From mouse to man, brown adipose tissue (BAT) is a significant source of thermogenesis contributing to the maintenance of the body temperature homeostasis during the challenge of low environmental temperature. In rodents, BAT thermogenesis also contributes to the febrile increase in core temperature during the immune response. BAT sympathetic nerve activity controlling BAT thermogenesis is regulated by CNS neural networks which respond reflexively to thermal afferent signals from cutaneous and body core thermoreceptors, as well as to alterations in the discharge of central neurons with intrinsic thermosensitivity. Superimposed on the core thermoregulatory circuit for the activation of BAT thermogenesis, is the permissive, modulatory influence of central neural networks controlling metabolic aspects of energy homeostasis. The recent confirmation of the presence of BAT in human and its function as an energy consuming organ have stimulated interest in the potential for the pharmacological activation of BAT to reduce adiposity in the obese. In contrast, the inhibition of BAT thermogenesis could facilitate the induction of therapeutic hypothermia for fever reduction or to improve outcomes in stroke or cardiac ischemia by reducing infarct size through a lowering of metabolic oxygen demand. This review summarizes the central circuits for the autonomic control of BAT thermogenesis and highlights the potential clinical relevance of the pharmacological inhibition or activation of BAT thermogenesis.
doi:10.3389/fnins.2014.00014
PMCID: PMC3916784  PMID: 24570653
brown adipose tissue; hypothermia; adenosine; hibernation; torpor; therapeutic hypothermia; fever; obesity
8.  2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated glioma patients 
Nature medicine  2012;18(4):624-629.
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1, 2) have been demonstrated in the majority of World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) within the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). The pulse sequence was developed and optimized with numerical and phantom analyses for 2HG detection. The concentrations of 2HG were estimated using spectral fitting in the tumors of 30 patients. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of resected tumor. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.
doi:10.1038/nm.2682
PMCID: PMC3615719  PMID: 22281806
9.  An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis 
Adipocyte  2012;1(2):116-120.
Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulatory cold-defense and, through its metabolic consumption of energy reserves to produce heat, can affect the long-term regulation of adiposity. An orexinergic pathway from the perifornical lateral hypothalamus (PeF/LH) to the rostral raphe pallidus (rRPa) has been demonstrated to increase the gain of the excitatory drives to medullary sympathetic premotor neurons controlling BAT sympathetic outflow and BAT thermogenesis. With this background, we consider neural mechanisms that could underlie orexin’s modulation of the excitability of BAT sympathetic premotor neurons in rRPa and the potential role of altered BAT thermogenesis in pathological conditions associated with the absence of the central orexin system. Overall, these new data enhance our understanding of the role of central orexin in regulating body temperature and energy homeostasis and provide further insight into the neurochemical regulation of BAT thermogenesis and metabolism.
doi:10.4161/adip.19736
PMCID: PMC3607627  PMID: 23538704
endocannabinoid; narcolepsy; obesity; stress; ultradian rhythm
10.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
Objectives
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Design
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Setting
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Results
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Conclusion
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
doi:10.1001/archneurol.2010.149
PMCID: PMC3465162  PMID: 20625067
11.  An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis 
Adipocyte  2012;1(2):116-120.
Non-shivering thermogenesis in brown adipose tissue (BAT) plays an important role in thermoregulatory cold-defense and, through its metabolic consumption of energy reserves to produce heat, can affect the long-term regulation of adiposity. An orexinergic pathway from the perifornical lateral hypothalamus (PeF/LH) to the rostral raphe pallidus (rRPa) has been demonstrated to increase the gain of the excitatory drives to medullary sympathetic premotor neurons controlling BAT sympathetic outflow and BAT thermogenesis. With this background, we consider neural mechanisms that could underlie orexin’s modulation of the excitability of BAT sympathetic premotor neurons in rRPa and the potential role of altered BAT thermogenesis in pathological conditions associated with the absence of the central orexin system. Overall, these new data enhance our understanding of the role of central orexin in regulating body temperature and energy homeostasis and provide further insight into the neurochemical regulation of BAT thermogenesis and metabolism.
doi:10.4161/adip.19736
PMCID: PMC3607627  PMID: 23538704
endocannabinoid; narcolepsy; obesity; stress; ultradian rhythm
12.  Central control of brown adipose tissue thermogenesis 
Frontiers in endocrinology  2012;3(5):00005.
Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. Mitochondrial oxidation in brown adipose tissue (BAT) is a significant source of neurally regulated metabolic heat production in many species from mouse to man. BAT thermogenesis is regulated by neural networks in the central nervous system which responds to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate BAT sympathetic nerve activity. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates BAT thermogenesis and includes the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E2, to increase body temperature during fever. The cold thermal afferent circuit from cutaneous thermal receptors, through second-order thermosensory neurons in the dorsal horn of the spinal cord ascends to activate neurons in the lateral parabrachial nucleus which drive GABAergic interneurons in the preoptic area (POA) to inhibit warm-sensitive, inhibitory output neurons of the POA. The resulting disinhibition of BAT thermogenesis-promoting neurons in the dorsomedial hypothalamus activates BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus, which provide excitatory, and possibly disinhibitory, inputs to spinal sympathetic circuits to drive BAT thermogenesis. Other recently recognized central sites influencing BAT thermogenesis and energy expenditure are also described.
doi:10.3389/fendo.2012.00005
PMCID: PMC3292175  PMID: 22389645
brown adipose tissue; thermogenesis; thermoregulation; sympathetic nerve activity; preoptic hypothalamus; fever; rostral raphe pallidus; rostral ventromedial medulla
13.  Central Control of Brown Adipose Tissue Thermogenesis 
Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. Mitochondrial oxidation in brown adipose tissue (BAT) is a significant source of neurally regulated metabolic heat production in many species from mouse to man. BAT thermogenesis is regulated by neural networks in the central nervous system which responds to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate BAT sympathetic nerve activity. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates BAT thermogenesis and includes the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E2, to increase body temperature during fever. The cold thermal afferent circuit from cutaneous thermal receptors, through second-order thermosensory neurons in the dorsal horn of the spinal cord ascends to activate neurons in the lateral parabrachial nucleus which drive GABAergic interneurons in the preoptic area (POA) to inhibit warm-sensitive, inhibitory output neurons of the POA. The resulting disinhibition of BAT thermogenesis-promoting neurons in the dorsomedial hypothalamus activates BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus, which provide excitatory, and possibly disinhibitory, inputs to spinal sympathetic circuits to drive BAT thermogenesis. Other recently recognized central sites influencing BAT thermogenesis and energy expenditure are also described.
doi:10.3389/fendo.2012.00005
PMCID: PMC3292175  PMID: 22389645
brown adipose tissue; thermogenesis; thermoregulation; sympathetic nerve activity; preoptic hypothalamus; fever; rostral raphe pallidus; rostral ventromedial medulla
14.  Excess Dietary Salt Intake Alters the Excitability of Central Sympathetic Networks 
Physiology & behavior  2010;100(5):519-524.
The ingestion of excess dietary salt (defined as NaCl) is strongly correlated with cardiovascular disease, morbidity, mortality, and is regarded as a major contributing factor to the pathogenesis of hypertension. Although several mechanisms contribute to the adverse consequences of dietary salt intake, accumulating evidence suggest that dietary salt loading produces neurogenically-mediated increases in total peripheral resistance to raise arterial blood pressure (ABP). Evidence from clinical studies and experimental models clearly establish a hypertensive effect of dietary salt loading in a subset of individuals who are deemed “salt-sensitive”. However, we will discuss and present evidence to develop a novel hypothesis to suggest that while chronic increases in dietary salt intake do not elevate mean ABP in “non-salt-sensitive” animals, dietary salt intake does enhance several sympathetic reflexes thereby predisposing these animals and/or individuals to the development of salt-sensitive hypertension. Additional evidence raises an intriguing hypothesis that these enhanced sympathetic reflexes are largely attributed to the ability of excess dietary salt intake to selectively enhance the excitability of sympathetic-regulatory neurons in the rostral ventrolateral medulla. Insight into the cellular mechanisms by which dietary salt intake alters the responsiveness of RVLM circuits will likely provide a foundation for developing new therapeutic approaches to treat salt-sensitive hypertension.
doi:10.1016/j.physbeh.2010.04.024
PMCID: PMC3024145  PMID: 20434471
dietary salt; blood pressure; sympathetic; rostral ventrolateral medulla; salt-sensitivity; hypertension
15.  The Telomerase Antagonist Imetelstat Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth 
Purpose
Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo.
Experimental design
Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat.
Results
Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45μM). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg q3d) showed ∼70% inhibition of telomerase activity. Chronic systemic treatment on the same dose schedule produced a marked decrease in the rate of xenograft subcutaneous tumor growth.
Conclusion
This pre-clinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies.
doi:10.1158/1078-0432.CCR-09-2850
PMCID: PMC2883447  PMID: 20048334
neurospheres; telomeres; temozolomide; radiation; orthotopic
16.  The receptor interacting protein (RIP1) inhibits p53 induction through NF-κB activation and confers a worse prognosis in glioblastoma 
Cancer research  2009;69(7):2809-2816.
NF-κB activation may play an important role in the pathogenesis of cancer and also in resistance to treatment. Inactivation of the p53 tumor suppressor is a key component of the multi-step evolution of most cancers. Links between the NF-κB and p53 pathways are under intense investigation. In this study, we show that the receptor interacting protein (RIP, RIP1), a central component of the NF-κB signaling network, negatively regulates p53 tumor suppressor signaling. Loss of RIP1 from cells results in augmented induction of p53 in response to DNA damage, while increased RIP1 level leads to a complete shutdown of DNA-damage induced p53 induction by enhancing levels of cellular mdm2. The key signal generated by RIP1 to upregulate mdm2 and inhibit p53 is activation of NF-κB. The clinical implication of this finding is demonstrated in glioblastoma (GBM), the most common primary malignant brain tumor in adults. We show that RIP1 is commonly overexpressed in GBM but not in grade II-III glioma and increased expression of RIP1 confers a worse prognosis in GBM. Importantly, RIP1 levels correlate strongly with mdm2 levels in GBM. Our results demonstrate a key interaction between the NF-κB and p53 pathways that may have implications for the targeted treatment of GBM.
doi:10.1158/0008-5472.CAN-08-4079
PMCID: PMC2859885  PMID: 19339267
inflammation; cancer; p53; RIP1; NF-kappa B; prognosis; glioblastoma
17.  Cerebral Atrophy after Traumatic White Matter Injury: Correlation with Acute Neuroimaging and Outcome 
Journal of Neurotrauma  2008;25(12):1433-1440.
Abstract
Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = −0.69, −0.59, −0.58, respectively; p < 0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = −0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = −0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.
doi:10.1089/neu.2008.0683
PMCID: PMC2858299  PMID: 19072588
MR imaging; post-traumatic atrophy; TBI
18.  Central control of thermogenesis in mammals 
Experimental physiology  2008;93(7):773-797.
Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature in mammals and birds during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. The primary sources of neurally regulated metabolic heat production are mitochondrial oxidation in brown adipose tissue, increases in heart rate and shivering in skeletal muscle. Thermogenesis is regulated in each of these tissues by parallel networks in the central nervous system, which respond to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate the appropriate sympathetic and somatic efferents. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates thermogenesis and discusses the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E2, to increase body temperature. The cold thermal afferent circuit from cutaneous thermal receptors ascends via second-order thermosensory neurons in the dorsal horn of the spinal cord to activate neurons in the lateral parabrachial nucleus, which drive GABAergic interneurons in the preoptic area to inhibit warm-sensitive, inhibitory output neurons of the preoptic area. The resulting disinhibition of thermogenesis-promoting neurons in the dorsomedial hypothalamus and possibly of sympathetic and somatic premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, activates excitatory inputs to spinal sympathetic and somatic motor circuits to drive thermogenesis.
doi:10.1113/expphysiol.2007.041848
PMCID: PMC2496891  PMID: 18469069
19.  Central Pathway for Spontaneous and Prostaglandin E2-evoked Cutaneous Vasoconstriction 
A reduction of heat loss to the environment through increased cutaneous vasoconstrictor (CVC) sympathetic outflow contributes to elevated body temperature during fever. We determined the role of neurons in the dorsomedial hypothalamus (DMH) in the increases in CVC sympathetic tone evoked by prostaglandin E2 (PGE2) into the preoptic area (POA) in chloralose/urethane-anesthetized rats. The frequency of axonal action potentials of CVC sympathetic ganglion cells recorded from the surface of the tail artery was increased by 1.8Hz following nanoinjections of bicuculline (50 pmol) into the DMH. PGE2 nanoinjection into the POA elicited a similar excitation of tail CVC neurons (+2.1Hz). Subsequent to PGE2 into the POA, muscimol (400 pmol/side) into the DMH did not alter the activity of tail CVC neurons. Inhibition of neurons in the rostral raphe pallidus (rRPa) eliminated the spontaneous discharge of tail CVC neurons, but only reduced the PGE2-evoked activity. Residual activity was abolished by subsequent muscimol into the rostral ventrolateral medulla. Transections through the neuraxis caudal to the POA increased the activity of tail CVC neurons which was sustained through transections caudal to DMH. We conclude that while activation of neurons in the DMH is sufficient to activate tail CVC neurons, it is not necessary for their PGE2-evoked activity. These results support a CVC component of the increased core temperature elicited by PGE2 in POA that arises from relief of a tonic inhibition, from neurons in POA, of CVC sympathetic premotor neurons in rRPa and is dependent on the excitation of CVC premotor neurons from a site caudal to DMH.
doi:10.1152/ajpregu.00115.2008
PMCID: PMC2494816  PMID: 18463193

Results 1-19 (19)