Surgery Commons^™

Sepsis: Current Dogma And New Perspectives, C. S. Deutschman, K. J. Tracey

Journal Articles

Sepsis, a clinical syndrome occurring in patients following infection or injury, is a leading cause of morbidity andmortality worldwide. Current immunological mechanisms do not explain the basis of cellular dysfunction and organ failure, the ultimate cause of death. Here we review current dogma and argue that it is time to delineate novel immunometabolic and neurophysiological mechanisms underlying the altered cellular bioenergetics and failure of epithelial and endothelial barriers that produce organ dysfunction and death. These mechanisms might hold the key to future therapeutic strategies.

A Systematic Nomenclature For The Redox States Of High Mobility Group Box (Hmgb) Proteins, D. J. Antoine, H. E. Harris, U. Andersson, K. J. Tracey, M. E. Bianchi

Journal Articles

High mobility group box 1 (HMGB1) is a central mediator in inflammation and immunity. Recently, it was shown that different redox states of the three cysteines of HMGB1 endow it with mutually exclusive activities, such as inducing chemotaxis or the transcription of cytokines and chemokines, via the interaction with different receptors. The different HMGB1 redox forms can be identified by mass spectrometry in body fluids of patients and may hold promise as biomarkers. We propose here a systematic nomenclature of the different redox forms of HMGB1 and related proteins, to replace the conflicting names used so far by different laboratories.

Ruptured Splenic Artery Aneurysms And The Use Of An Adapted Fast Protocol In Reproductive Age Women With Hemodynamic Collapse: Case Series, Hope T. Jackson, Silviu C. Diaconu, Patrick J. Maluso, Bruce Abell, Juliet Lee

Surgery Faculty Publications

Nontraumatic symptomatic hypotension in all patients requires prompt diagnosis and appropriate treatment for optimum outcome. The female population specifically has an expanded differential diagnosis that should be considered when these patients present with hemodynamic collapse. While the most common causes of hypotension in pregnant patients are dehydration, ruptured ectopic pregnancy, and placental and uterine abnormalities, less common nonobstetrical etiologies such as hepatic rupture and ruptured abdominal and visceral artery aneurysms should also be considered. Splenic artery aneurysms are associated with high rates of mortality and in cases of pregnancy, maternal and fetal mortality. These high rates can be attributed to …

Loss Of Nuclear Pten In Hcv-Infected Human Hepatocytes, Wenjie Bao, Liliana Florea, Ningbin Wu, Zhao Wang, Krishna K. Banaudha, Jason Qian, Laurent Houzet, Rakesh Kumar, Ajit Kumar

Surgery Faculty Publications

Background

Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC); however, the mechanism of HCV-mediated hepatocarcinogenesis is not well understood. Insufficiency of PTEN tumor suppressor is associated with more aggressive cancers, including HCC. We asked whether viral non-coding RNA could initiate oncogenesis in HCV infected human hepatocytes. The results presented herein suggest that loss of nuclear PTEN in HCV-infected human hepatocytes results from depletion of Transportin-2, which is a direct target of viral non-coding RNA, vmr11.

Methods

The intracellular distribution of PTEN in HCV-infected cells was monitored by immunostaining and Western blots …

Hereditary Angioedema: What The Gastroenterologist Needs To Know, M. Aamir Ali, Marie L. Borum

Surgery Faculty Publications

Up to 93% of patients with hereditary angioedema (HAE) experience recurrent abdominal pain. Many of these patients, who often present to emergency departments, primary care physicians, general surgeons, or gastroenterologists, are misdiagnosed for years and undergo unnecessary testing and surgical procedures. Making the diagnosis of HAE can be challenging because symptoms and attack locations are often inconsistent from one episode to the next. Abdominal attacks are common and can occur without other attack locations. An early, accurate diagnosis is central to managing HAE. Unexplained abdominal pain, particularly when accompanied by swelling of the face and extremities, suggests the diagnosis of …

Experience With Miniaturized Cardiopulmonary Bypass In Cardiac Surgery: A Prospective Comparison Of The Novosci Ready System To Off-Pump And Conventional Coronary Artery Bypass Grafting, Dominic Emerson, Debbie Baldwin, Miguel Pinales, Michael Greenberg, Melissa Mattes, Gregory D. Trachiotis

Surgery Faculty Publications

The major source of morbidity following cardiopulmonary bypass (CPB) is the systemic inflammatory response (SIRS response) which leads to multiple derangements in different organ systems. To combat this, miniaturized cardiopulmonary bypass circuits (MCPBC) have been created to lessen the inflammatory response to CPB. Here we examine early outcomes following coronary artery bypass grafting (CABG) using a MCPBC system compared to conventional bypass techniques at a single institution. Methods: 60 consecutive patients undergoing elective CABG were prospectively enrolled. Nine patients underwent coronary artery bypass grafting (CABG) with conventional CPB (cCABG), 33 underwent off-pump CABG (OPCAB), and the remaining 18 patients underwent …

Corticocortical Evoked Potentials Reveal Projectors And Integrators In Human Brain Networks, C. J. Keller, C. J. Honey, L. Entz, S. Bickel, D. M. Groppe, E. Toth, I. Ulbert, F. A. Lado, A. D. Mehta

Journal Articles

The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter-regional influence within the cerebral cortex of awake humans. These networks …

Evoked Effective Connectivity Of The Human Neocortex, L. Entz, E. Toth, C. J. Keller, S. Bickel, D. M. Groppe, D. Fabo, L. R. Kozak, L. Eross, I. Ulbert, A. D. Mehta

Journal Articles

The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an …

Exemplar Selectivity Reflects Perceptual Similarities In The Human Fusiform Cortex, I. Davidesco, E. Zion-Golumbic, S. Bickel, M. Harel, D. M. Groppe, C. J. Keller, C. A. Schevon, G. M. Mckhann, R. R. Goodman, G. Goelman, C. E. Schroeder, A. D. Mehta, R. Malach

Journal Articles

While brain imaging studies emphasized the category selectivity of face-related areas, the underlying mechanisms of our remarkable ability to discriminate between different faces are less understood. Here, we recorded intracranial local field potentials from face-related areas in patients presented with images of faces and objects. A highly significant exemplar tuning within the category of faces was observed in high-Gamma (80-150 Hz) responses. The robustness of this effect was supported by single-trial decoding of face exemplars using a minimal (n = 5) training set. Importantly, exemplar tuning reflected the psychophysical distance between faces but not their low-level features. Our results reveal …

Guanine Nucleotide Exchange Factor Dock7 Mediates Hgf- Induced Glioblastoma Cell Invasion Via Rac Activation, D. W. Murray, S. Didier, A. Chan, V. Paulino, L. Van Aelst, R. Ruggieri, N. L. Tran, A. T. Byrne, M. Symons

Journal Articles

Background: Glioblastoma multiforme (GBM), a highly invasive primary brain tumour, remains an incurable disease. Rho GTPases and their activators, guanine nucleotide exchange factors (GEFs), have central roles in GBM invasion. Anti-angiogenic therapies may stimulate GBM invasion via HGF/c-Met signalling. We aim to identify mediators of HGF-induced GBM invasion that may represent targets in a combination anti-angiogenic/anti-invasion therapeutic paradigm. Methods: Guanine nucleotide exchange factor expression was measured by microarray analysis and western blotting. Specific depletion of proteins was accomplished using siRNA. Cell invasion was determined using matrigel and brain slice assays. Cell proliferation and survival were monitored using sulforhodamine B and …

Head Model And Electrical Source Imaging: A Study Of 38 Epileptic Patients, G. Birot, L. Spinelli, S. Vulliemoz, P. Megevand, D. Brunet, M. Seeck, C. M. Michel

Journal Articles

Electrical source imaging (ESI) aims at reconstructing the electrical brain activity from scalp EEG. When applied to interictal epileptiform discharges (IEDs), this technique is of great use for identifying the irritative zone in focal epilepsies. Inaccuracies in the modeling of electro-magnetic field propagation in the head (forward model) may strongly influence ESI and lead to mislocalization of IED generators. However, a systematic study on the influence of the selected head model on the localization precision of IED in a large number of patients with known focus localization has not yet been performed. We here present such a performance evaluation of …

Hmgb1 Enhances Immune Suppression By Facilitating The Differentiation And Suppressive Activity Of Myeloid-Derived Suppressor Cells, K. H. Parker, P. Sinha, L. A. Horn, V. K. Clements, H. Yang, J. H. Li, K. J. Tracey, S. Ostrand-Rosenberg

Journal Articles

Chronic inflammation often precedes malignant transformation and later drives tumor progression. Likewise, subversion of the immune system plays a role in tumor progression, with tumoral immune escape now well recognized as a crucial hallmark of cancer. Myeloid-derived suppressor cells (MDSC) are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. Thus, MDSCs may define an element of the pathogenic inflammatory processes that drives immune escape. The secreted alarmin HMGB1 is a proinflammatory partner, inducer, and chaperone for many proinflammatory molecules that MDSCs develop. Therefore, in this study, we examined HMGB1 as a potential …

Inflammation Induces Irreversible Biophysical Changes In Isolated Nucleus Pulposus Cells, R. Maidhof, T. Jacobsen, A. Papatheodorou, N. O. Chahine

Journal Articles

Intervertebral disc degeneration is accompanied by elevated levels of inflammatory cytokines that have been implicated in disease etiology and matrix degradation. While the effects of inflammatory stimulation on disc cell metabolism have been well-studied, their effects on cell biophysical properties have not been investigated. The hypothesis of this study is that inflammatory stimulation alters the biomechanical properties of isolated disc cells and volume responses to step osmotic loading. Cells from the nucleus pulposus (NP) of bovine discs were isolated and treated with either lipopolysaccharide (LPS), an inflammatory ligand, or with the recombinant cytokine TNF-alpha for 24 hours. We measured cellular …

Jak/Stat1 Signaling Promotes Hmgb1 Hyperacetylation And Nuclear Translocation, B. Lu, K. Kwan, M. Robinson, M. A. D. Van Zoelen, H. Yang, J. Li, S. S. Chavan, H. Wang, U. Andersson, K. J. Tracey, +5 Additional Authors

Journal Articles

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation …

Mapping Epileptic Activity: Sources Or Networks For The Clinicians?, F. Pittau, P. Megevand, L. Sheybani, E. Abela, F. Grouiller, L. Spinelli, C. M. Michel, M. Seeck, S. Vulliemoz

Journal Articles

Epileptic seizures of focal origin are classically considered to arise from a focal epileptogenic zone and then spread to other brain regions. This is a key concept for semiological electro-clinical correlations, localization of relevant structural lesions, and selection of patients for epilepsy surgery. Recent development in neuro-imaging and electro-physiology and combinations, thereof, have been validated as contributory tools for focus localization. In parallel, these techniques have revealed that widespread networks of brain regions, rather than a single epileptogenic region, are implicated in focal epileptic activity. Sophisticated multimodal imaging and analysis strategies of brain connectivity patterns have been developed to characterize …

O-020 Modifying Flow In The Ica Bifurcation: Pipeline Deployment From The Supraclinoid Ica Extending Into The M1 Segment: Clinical And Anatomical Results, E. Nossek, D. J. Chalif, S. Chakraborty, A. Setton

Journal Articles

BACKGROUND: Utility of the pipeline embolization device (PED) extending to the M1 segment as well as its clinical and flow consequences at the ICA bifurcation, has not clearly described. We describe clinical and anatomical flow modifications results at the ICA bifurcation. METHODS: In this retrospective analysis of patients treated for distal supraclinoid carotid aneurysms, a single PED was deployed from the proximal M1 segment to the distal supraclinoid carotid. Flow assessment prior to the procedure, to predict the competence of the ACA/AcomA complex, was achieved by formal DSA angiography and occasional manual cross compression. In all cases a single PED …

The Regulation Of Rhoa At Focal Adhesions By Stard13 Is Important For Astrocytoma Cell Motility, B. D. Khalil, S. Hanna, B. A. Saykali, S. El-Sitt, A. Nasrallah, D. Marston, M. El-Sabban, K. M. Hahn, M. Symons, M. El-Sibai

Journal Articles

Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Rho GTPases are small monomeric G proteins that play important roles in cytoskeleton rearrangement, cell motility and tumor invasion. In the present study, we show that the knock down of StarD13, a GTPase activating protein (GAP) for RhoA and Cdc42, inhibits astrocytoma cell migration through modulating focal adhesion dynamics and cell adhesion. This effect is mediated by the resulting constitutive activation of RhoA and the subsequent indirect inhibition of Rac. Using Total Internal Reflection Fluorescence (TIRF)-based Forster Resonance Energy Transfer (FRET), we show that RhoA activity …

Semapimod Sensitizes Glioblastoma Tumors To Ionizing Radiation By Targeting Microglia, I. S. Miller, S. Didier, D. W. Murray, T. H. Turner, M. Issaivanan, R. Ruggieri, Y. Al-Abed, M. Symons

Journal Articles

Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia-stimulated GL261 …

Terror Medicine As Part Of The Medical School Curriculum, L. A. Cole, K. Wagner, S. Scott, N. D. Connell, A. Cooper, C. A. Kennedy, B. Natal, S. Lamba

Journal Articles

Terror medicine, a field related to emergency and disaster medicine, focuses on medical issues ranging from preparedness to psychological manifestations specifically associated with terrorist attacks. Calls to teach aspects of the subject in American medical schools surged after the 2001 jetliner and anthrax attacks. Although the threat of terrorism persists, terror medicine is still addressed erratically if at all in most medical schools. This paper suggests a template for incorporating the subject throughout a 4-year medical curriculum. The instructional framework culminates in a short course for fourth year students, such as one recently introduced at Rutgers New Jersey Medical School, …

Athletic Pubalgia And Associated Rehabilitation, A. A. Ellsworth, M. P. Zoland, T. F. Tyler

Journal Articles

BACKGROUND: Evaluation and treatment of groin pain in athletes is challenging. The anatomy is complex, and multiple pathologies often coexist. Different pathologies may cause similar symptoms, and many systems can refer pain to the groin. Many athletes with groin pain have tried prolonged rest and various treatment regimens, and received differing opinions as to the cause of their pain. The rehabilitation specialist is often given a non-specific referral of "groin pain" or "sports hernia." The cause of pain could be as simple as the effects of an adductor strain, or as complex as athletic pubalgia or inguinal disruption. The term …

Aicar Attenuates Organ Injury And Inflammatory Response After Intestinal Ischemia And Reperfusion, J. P. Idrovo, W.L. Yang, A. Jacob, M. Aziz, Jeffrey Nicastro, Gene Coppa, P. Wang

Journal Articles

Intestinal ischemia and reperfusion (I/R) is encountered in various clinical conditions and contributes to multiorgan failure and mortality as high as 60% to 80%. Intestinal I/R not only injures the intestine, but affects remote organs such as the lung leading to acute lung injury. The development of novel and effective therapies for intestinal I/R are critical for the improvement of patient outcome. AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) is a cell-permeable compound that has been shown to possess antiinflammatory effects. The objective is to determine that treatment with AICAR attenuates intestinal I/R injury and subsequent acute lung injury (ALI). Male Sprague Dawley rats …

Arterio-Enteric Fistula In Failed Enteric-Drained Pancreas Transplants: An Impending Danger, M. Villa, E. Siskind, N. Jaimes, D. Eckstein, M. Bhaskaran, M. Sachdeva, K. Jhaveri, K. Calderon, C. Greben, L. Sharan, G. Coppa, K. Krishnasastry, E. Molmenti, J. Nicastro

Journal Articles

Enteric drainage is the preferred method of exocrine diversion in simultaneous kidney-pancreas transplantation. Because of improvements in immunosuppression, enteric drainage has become the preferred method of pancreas transplantation in general. Although associated with less potential complications than bladder-drained pancreas, potentially lethal arterio-enteric fistulas in the setting of nonfunctioning allografts represent a constant threat. We herein present a case report, a review of the literature, and a call for caution.

Brain Region-Specific Alterations In The Gene Expression Of Cytokines, Immune Cell Markers And Cholinergic System Components During Peripheral Endotoxin-Induced Inflammation, H. A. Silverman, M. Dancho, A. Regnier-Golanov, M. Nasim, M. Ochani, P. S. Olofsson, M. Ahmed, E. J. Miller, S. S. Chavan, E. Golanov, C. Metz, K. J. Tracey, V. A. Pavlov

Journal Articles

Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune - brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels) remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum, and thalamus in mice following an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels …

Approaching The Next Revolution? Evolutionary Integration Of Neural And Immune Pathogen Sensing And Response, K. J. Tracey

Journal Articles

Mammalian immunity evolved by the process of natural selection that produced differential survival and reproduction advantages through combinations of hereditary traits underlying the response to pathogens. Primitive animals sense the presence of microbial pathogens through recognition of pathogen-derived molecules in their rudimentary immune and nervous systems. No molecular biological mechanism assigns primacy of pathogen sensing mechanisms to immune cells over neurons. Rather, in animals as diverse as Caenorhabditis elegans to mammals, neural reflexes are activated by the presence of pathogens and transduce neural mechanisms that control the development of immunity. A coming revolution in immunological thinking will require immunologists to …

Central Cholinergic Activation Of A Vagus Nerve-To-Spleen Circuit Alleviates Experimental Colitis, H. Ji, M. F. Rabbi, B. Labis, V. A. Pavlov, K. J. Tracey, J. E. Ghia

Journal Articles

The cholinergic anti-inflammatory pathway is an efferent vagus nerve-based mechanism that regulates immune responses and cytokine production through alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) signaling. Decreased efferent vagus nerve activity is observed in inflammatory bowel disease. We determined whether central activation of this pathway alters inflammation in mice with colitis and the mediating role of a vagus nerve-to-spleen circuit and alpha 7nAChR signaling. Two experimental models of colitis were used in C57BL/6 mice. Central cholinergic activation induced by the acetylcholinesterase inhibitor galantamine or a muscarinic acetylcholine receptor agonist treatments resulted in reduced mucosal inflammation associated with decreased major histocompatibility …

High-Mobility Group Box 1 Protein Initiates Postoperative Cognitive Decline By Engaging Bone Marrow-Derived Macrophages, S. Vacas, V. Degos, K. J. Tracey, M. Maze

Journal Articles

Background: Aseptic trauma engages the innate immune response to trigger a neuroinflammatory reaction that results in postoperative cognitive decline. The authors sought to determine whether high-mobility group box 1 protein (HMGB1), an ubiquitous nucleosomal protein, initiates this process through activation and trafficking of circulating bone marrow-derived macrophages to the brain. Methods: The effects of HMGB1 on memory (using trace fear conditioning) were tested in adult C57BL/6J male mice; separate cohorts were tested after bone marrow-derived macrophages were depleted by clodrolip. The effect of anti-HMGB1 neutralizing antibody on the inflammatory and behavioral responses to tibial surgery were investigated. Results: A single …

Lymphocyte Called Home: Beta2-Adreneric Neurotransmission Confines T Cells To Lymph Nodes To Suppress Inflammation, K J. Tracey

Journal Articles

No abstract provided.

Mapping Human Brain Networks With Cortico-Cortical Evoked Potentials, C. J. Keller, C. J. Honey, P. Megevand, L. Entz, I. Ulbert, A. D. Mehta

Journal Articles

The cerebral cortex forms a sheet of neurons organized into a network of interconnected modules that is highly expanded in humans and presumably enables our most refined sensory and cognitive abilities. The links of this network form a fundamental aspect of its organization, and a great deal of research is focusing on understanding how information flows within and between different regions. However, an often-overlooked element of this connectivity regards a causal, hierarchical structure of regions, whereby certain nodes of the cortical network may exert greater influence over the others. While this is difficult to ascertain non-invasively, patients undergoing invasive electrode …

Nanocomposite Scaffold For Chondrocyte Growth And Cartilage Tissue Engineering: Effects Of Carbon Nanotube Surface Functionalization, N. O. Chahine, N. M. Collette, C. B. Thomas, D. C. Genetos, G. G. Loots

Journal Articles

The goal of this study was to assess the long-term biocompatibility of single-wall carbon nanotubes (SWNTs) for tissue engineering of articular cartilage. We hypothesized that SWNT nanocomposite scaffolds in cartilage tissue engineering can provide an improved molecular-sized substrate for stimulation of chondrocyte growth, as well as structural reinforcement of the scaffold's mechanical properties. The effect of SWNT surface functionalization (-COOH or -PEG) on chondrocyte viability and biochemical matrix deposition was examined in two-dimensional cultures, in three-dimensional (3D) pellet cultures, and in a 3D nanocomposite scaffold consisting of hydrogels + SWNTs. Outcome measures included cell viability, histological and SEM evaluation, GAG …

Targeting A Heterogeneous Tumor: The Promise Of The Interleukin-13 Receptor Alpha2, I. Bodhinayake, M. Ottenhausen, J. A. Boockvar

Journal Articles

No abstract provided.