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Report on Research, 2008 (PDF) Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women's Hospital Harvard Medical School Overview The Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women's Hospital is involved in laboratory and clinical research at the forefront of academic medicine. The mission of this research is to understand the mechanisms of disease that underlay the causes and conditions during and after surgical anesthesia and other operative procedures, and to apply this understanding to develop new and better treatments and thus to advance the clinical practice of anesthesia. Research in the department is funded primarily through grants from the National Institutes of Health, and is conducted by both basic scientists and by clinical anesthesiologists. The organization of the basic research laboratories reflects the focussed interest of the department in the problematic areas of surgical anesthesia and its immediate sequelae, in chronic and acute pain and in other medical problems not directly related to anesthesia, such as myocardial muscle degeneration, periodontal disease and nerve regeneration, muscular dystrophy and spinal cord injury. In this regard, the departmental investigators often collaborate with researchers in other departments at BWH, at the medical school and other Harvard University teaching hospitals, and with many nationally and internationally known researchers at other institutions. In several research projects, successful efforts have supported collaborations between industry and departmental investigators, both at the lab bench and in the operating room. These activities have not only brought additional resources to the department and the hospital but have also facilitated a strong translational pathway for the development of new drugs and procedures. Education Education is a major responsibility in the department's research activities, enabling residents, post-graduate fellows, medical students, graduate students and undergraduates to participate in modern medical research. For more than 30 years the department has participated in the NIH- sponsored Harvard Anesthesia Training Grant that funds two year post-residency Anesthesia Fellows. There is also an active summer student program for undergraduates, and graduate students from Harvard and MIT have conducted their dissertation research in the Anesthesia Research Laboratories. In the past fifteen years the department's research activities have increased more than four-fold, and continued to grow during the five year period covered by this report. The following passages describe in more detail the resources and organization of departmental research, and the activities and accomplishments of individual Principal Investigators. Resources and Productivity In 2008 research in the Anesthesiology Department was supported by 32 NIH grants and sub-contracts, of which 21 were individual investigator (R-01) grants, 4 were Program Project Grants and 1 was a P50 Center Grant and 6 sub contracts. In addition, there were 27 Sponsored Research Projects (private industry), many of the latter being clinical trials. Three Fellowships had been awarded to researchers in training. The five laboratory Research Centers, comprised of the Center for Experimental Therapeutics and Reperfusion Injury, Cardiovascular Research Laboratories, Center for Molecular Anesthesia, the Tissue Engineering Center and the Center for Pain Research, are housed in locations within the hospital totaling 27,132 square feet. In addition, there are many interdisciplinary projects that are conducted with investigators in other departments in Brigham and Women's Hospital, other institutions affiliated with Harvard Medical School, the larger University, and throughout the world. These collaborations, in turn, bring a rich stream of visiting scientists to our department, providing opportunities for students and residents to learn a broad and diverse range of subjects. In 2008 there were 22 faculty conducting independent laboratory research and 22 faculty conducting clinical research. Publications for the 2006 calendar year (those for 2007 are still being collected) included 38 original basic research reports, 18 clinical research reports and 6 educational reviews, book chapters or editorials. Faculty serve on a broad range of scientific committees, including the editorial boards of the leading journals in anesthesia, inflammation and pain, research committees of the American Society of Anesthesiologists and the International Association for the Study of Pain, and four different Scientific Review Groups of NIH's Center for Scientific Review. The department sponsors four annual named lectures on scientific and clinical topics that have been delivered by internationally prominent figures, and also annually sponsors the Gelman Scientific Symposium on Inflammation. Gary Strichartz, PhD Vice-Chairman for Research RESEARCH REPORTS This section first contains overviews of each of the four Research Centers, followed by reports from individual investigators in that center, and a list of recent publications. Listed next are the reports of clinical research in the department, alphabetically by investigator. Ending the report is a chronological compilation of publications by departmental researchers for the past 3 years (2006-2008). LABORATORY RESEARCH CENTER FOR EXPERIMENTAL THERAPEUTICS AND REPERFUSION INJURY Charles N. Serhan, Director Opportunities in Interdisciplinary and Translational Research Our Center for Experimental Therapeutics and Reperfusion Injury offers many opportunities for research and training in topics that are of interest in internal medicine, surgery, pathology and their respective subspecialties (hematology, nephrology, etc.). This Center is a multidisciplinary research effort with a cluster of talented faculty members that have both unique scientific expertise and perspective focusing on defining key molecular events of importance in the biopathogenesis of reperfusion injury, a sequence of events that affects many diseases including asthma, cardiovascular diseases, pulmonary and renal disorders, as well as diseases with inflammatory components such as arthritis and oral medicine with clinical sequelae such as periodontal disease. In addition to these clinical endpoints, the underlying interactions between blood cells and vascular tissues evoke acute inflammatory responses that can be initiated within the host by way of surgical stress and persist in the perioperative arena. The perioperative arena represents a wide, unmet clinical challenge and need for development of novel therapeutics that, if achieved, can shorten the duration of perioperative holding time and eventual hospital stay. In many respects, the cell biology and molecular mechanisms that are involved in acute reperfusion injury as observed in the surgical arena resemble the cellular and molecular events that take place in acute inflammation and host defense. Hence, detailed understanding of these molecular mechanisms and events can provide a wealth of new information that could have wide-ranging implications for the medical subspecialties and our appreciation of host defense as well as preventative medicine. Scope of Research The research programs within the Center take a multidisciplinary approach. The current tools of molecular medicine, namely biochemistry, cell and molecular biology, pharmacology, physiology and structural elucidation of small molecule natural products, all converge, with representatives from each discipline focused on elucidating key components in ischemia and reperfusion injury. This provides a unique opportunity for program development and a balanced training environment, as evidenced by the large number of trainees and the strong extramural support to this Center. Mission Statements & Goals of the CET&RI An interdisciplinary research team of experienced as well as new investigators is assembled within the Center with the following general mission statements: "To identify novel targets and pathways critical in regulating neutrophil mediated inflammation and establish the templates for physiologic small molecule-based interventions." "To define the molecular mechanisms underlying reperfusion injury and identify novel therapeutic interventions that can prevent cell injury." From these two broad mission statements we have created a platform for the interweaving of molecular definition and put a focus on structural elucidation, physiology and pharmacology as they intertwine in a modern appreciation and powerful use of molecular biology in evaluating the cell biology of inflammation and reperfusion injury in animal models such as transgenic and knockout mice and genetically engineered larger animal models including transgenic rabbits. To accomplish our objectives, the Center environment and structure provides a platform that brings together a group of investigators and faculty members who have recognized expertise in the areas of biochemistry, pharmacology, physiology, physiological chemistry, cell biology, and molecular biology, all with a special interest in the function of white blood cells and their interactions with cells of the vessel wall as well as mucosal lining. Hence, one focal strength of the Center is its multidisciplinary approach to the well-appreciated problems associated with aberrant neutrophil activation that can occur during inflammation in a wide range of clinical scenarios as well as in ischemia-reperfusion injury. The individual research report narratives of the Center's faculty (see following pages of individual labs) indicate that research in each principal investigator's laboratory tests hypothesis-driven research based on recent discoveries in their laboratories that are funded by several extramural research sources. Current support includes grants from the National Institutes of Health, American Heart Association, Arthritis Foundation, Fulbright Scholars Program and the Crohn's and Colitis Foundation. A strategic research cluster This coming together of very talented investigators in a strategic alliance to solve problems of fundamental importance in the biomedical sciences places the Center in a highly unique and strategic position to rapidly translate basic research discoveries at the molecular and cellular level into shaping thoughts regarding the pathobiology of human disease and potential novel approaches and clinical treatments. On the other side of this equation, the opportunity for a cross dialogue with clinicians and clinician-scientists provides scientists working in this Center the ability to articulate well informed hypotheses in their experiments, aimed to elucidate clinical observations and phenomena to provide insight and a basis for informed intervention. This alliance between clinicians, clinician-scientists and basic scientists within each laboratory within the Center places this group of investigators in a strong position to achieve success in their individual research programs. CET&RI Location and Environment The laboratories of our faculty members are located in the Thorn building, floors 7 and 13, of the Brigham and Women's Hospital. Our location provides an opportunity for daily interactions between individual laboratories and a framework for synergy with faculty members of the Center, their trainees, postdoctoral fellows and research associates as well as other investigators located within the Thorn Building for Medical Research and the Harvard Medical and Longwood Area research community. Charles N. Serhan, Ph.D. Director and Principal Investigator
Personnel: Research in the Serhan laboratory focuses on structural elucidation of bioactive molecules. Dr. Serhan's overall mission is "To identify novel compounds, pathways, and cellular targets critical in regulating resolution of inflammation and their relation to human disease." Recently Dr. Serhan's studies have focused on structural elucidation of novel molecules and pathways that serve as pro-resolving and/or endogenous anti-inflammatory chemical signals. To meet this overall mission, Dr. Serhan is currently the program director of a federally supported NIH Center grant for a Specialized Center for Oral Inflammation and Resolution. He is also Principal Investigator on NIH research grants entitled Blood Cell Lipoxygenase Products: Formation and Action, funded since 1987 and receiving a MERIT Award, and an R01 from NIDDK, Phagocyte Resolving Metabolism. Recent fellowships have included an Arthritis Foundation Fellowship awarded to Kie Kasuga (2006-2008). Jan Schwab was the recipient of a Deutsche Forschungsgemeinschaft Fellowship (2005-2006). Matthew Spite received an NIH NRSA Fellowship (2008-2011). Until recently, the resolution of inflammation was widely believed to be a passive rather than active process. Uncontrolled inflammation is now appreciated as a unifying pathophysiologic basis for many widely occurring chronic diseases, including Alzheimer's disease, cardiovascular disease and asthma, as well as the more traditional diseases associated with aberrant inflammation such as arthritis and periodontal disease. Dr. Serhan's current research focuses on the cellular and molecular mechanisms involved in endogenous anti-inflammation and resolution mechanisms in inflammation. From his research, a body of evidence has emerged indicating that the resolution of inflammation is an active process. Dr. Serhan's approach in elucidating the molecular map or resolution circuitry involves a multidisciplinary systems approach employing lipid mediator informatics, cellular and molecular analyses integrated in a systems approach to elucidate critical biochemical pathways in the resolution response in vivo. The evidence that resolution is an active process comes from Dr. Serhan's discovery of the endogenous anti-inflammatory and pro-resolving lipid mediators that possess potent anti-inflammatory and tissue protective properties as well as activate previously unappreciated anti-microbial defenses mechanisms in host mucosal epithelia. Dr. Serhan's results demonstrated the assembly and activation of anti-inflammatory, pro-resolving lipid mediator circuits activated during the resolution phase of acute inflammation. These include the discovery, structural elucidation, and temporal-spatial distinct actions of the lipoxins, resolvins, and most recently the protectins. Each of these families of mediators is biosynthesized within the resolution phase to promote the return of the host tissues to homeostasis. Widely used drugs, such as aspirin, have a unique and direct impact on these biosynthetic circuits of resolution, in that they jump-start resolution by triggering the biosynthesis of endogenous epimers of these lipid mediators, termed aspirin-triggered lipid mediators, specifically, aspirin-triggered lipoxins (15-epi-lipoxins), aspirin-triggered 17(R)-series resolvins, and protectins. The structural elucidation of these pathways and mediators, identification of their anti-inflammatory and pro-resolving receptors and establishing their pro-resolving actions are discoveries that formulate the basis of this current paradigm shift in our appreciation of resolution as an active process. These discoveries provide a new appreciation of endogenous anti-inflammatory mechanisms and the return of tissues to homeostasis following inflammatory challenge. Moreover, they give opportunities to treat many common human diseases, where unresolved inflammation is a component of disease pathophysiology, with small molecule agonists of resolution based on the natural biotemplates of the lipoxins, resolvins and protectins. Knowledge of these pro-resolving biochemical circuits and previously unappreciated families of lipid derived mediators also links the importance of dietary essential omega-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, in healthy diets and their deficiencies to dysregulated resolution as well as the potential to correct defective resolution mechanisms. The control of inflammation in the perioperative stage and the pain associated with chronic inflammation and post-surgical events are of increasing importance in the practice of anesthesia. Dr. Serhan's research provides new avenues to control inflammation and its natural resolution pathways with precision. Selected Publications: Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin-23, interferon-gamma and lipoxin A4 to promote resolution of allergic airway inflammation. Nat Immunol. 2008; 9:873-79 (published on-line 6/22/08; doi: 10.1038/ni.1627). Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 2007; 447:869-74. Sun Y-P, Oh SF, Uddin J, Yang R, Gotlinger K, Campbell E, Colgan SP, Petasis NA, Serhan CN. Resolvin D1 and its aspirin-triggered 17R epimer: stereochemical assignments, anti-inflammatory properties and enzymatic inactivation. J Biol Chem. 2007; 282:9323-34. Yacoubian S, Serhan CN. New endogenous anti-inflammatory and pro-resolving lipid mediators: implications for rheumatic diseases. Nat Clin Pract Rheumatol. 2007; 3:570-79. Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006; 176:1848-59. Gregory L. Stahl, Ph.D. Gregory L. Stahl's lab continues his investigations on the contribution of the innate immune system to tissue injury and inflammation following ischemia and reperfusion injury. During the past several years, Dr. Stahl's lab has focused on the contributions of the complement pathways responsible for the initiation of complement activation following ischemia/reperfusion, as well as the role of the early versus late complement components. The Stahl laboratory has also contributed to the success of obtaining a SCOR grant from the NIH and is a co-Project Leader on this grant. The main findings from the Stahl lab have demonstrated the significant importance of the terminal/late complement components (e.g., C5a and C5b-9) in mediating tissue inflammation and injury compared to the early complement components (e.g., C3a, C3b, etc.) in ischemia/reperfusion and sepsis. Additionally, the seminal work from the Stahl lab has established the importance of mannose-binding lectin (MBL) initiating the complement activation, tissue injury and inflammation following ischemia/reperfusion.Recent publications by the Stahl lab have demonstrated the importance of MBL in diabetes and its role in the cardiomyopathies associated with this disease. The results from these studies will directly affect the clinical practice of Anesthesia in the near future. The Stahl lab has developed a new high throughput assay that directly assesses the complete functional status of the lectin complement pathway in humans. Using this assay, in collaboration with our Cardiac group, they have begun to screen patients to determine whether the functional status of this pathway determines clinical outcomes. Findings from the Stahl lab during this time frame have led to the following patent and patent applications: i) Gregory L. Stahl and Charles D. Collard. Methods and products for regulating lectin complement pathway associated complement activation. US Patent Application Serial No. 7,273,925, filed 1999 December 15, issued 2007 September 25. ii) Gregory L. Stahl and Mary C. Walsh. Lectin complement pathway assays and related compositions and methods. US Patent Application Serial No.: 12/223,763, filed 2007 February 9. iii) Gregory L. Stahl.Methods and compositions for the regulation of lectin complement pathway (LCP)-associated complement activation in hyperglycemic myocardial damage. B0801.70360WO00, BWH 1316, filed 2008 February 29 Selected Publications: Costa C, Zhao L, Shen Y, Su X, Hao L, Colgan SP, Stahl GL, Zhou T, Wang Y. Role of complement component C5 in cerebral ischemia/reperfusion injury. Brain Research 2006; 1100:142-51 McMullen ME, Hart ML, Walsh MC, Buras J, Takahashi K, Stahl GL. Mannose binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology 2006; 211:759-66 (Epub July 28, 2006) (cover issue) Ganter MT, Brohi K, Cohen MJ, Shaffer LA, Walsh MC, Stahl GL, Pittet JF.Role of the alternative pathway in the early complement activation following major trauma. Shock; 2007, 28:29-34 Walsh MC, Shaffer LA, Guikema BJ, Body SC, Shernan SK, Fox AA, Collard CD, Fung M, Taylor RP, Stahl GL.Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. J Immunological Methods 2007; 323:147-59 Griffin RS, Costigan M, Brenner GJ, Ma CHE, Scholz J, Moss A, Allchorne AJ, Stahl GL, Woolf CJ. Complement induction in spinal cord microglia results in anaphylatoxin C5a mediated pain hypersensitivity. J Neuroscience 2007; 27:8699-708 (cover issue) Murata K, Fox-Talbot K, Qian Z, Takahashi K, Stahl GL, Baldwin WM, Wasowska BA. Synergistic deposition of C4d by complement-activating and nonactivating antibodies in cardiac transplants.Am J Transplantation 2007; 7:2605-14 CENTER FOR MOLECULAR ANESTHESIA Paul D. Allen, MD, PhD, Director This research Center, which focuses on the pathophysiology of skeletal muscle, has 18 members including a Laboratory Manager, six faculty (1 Professor, 1 Lecturer, 2 Assistant Professors, and 2 instructors), five Post-Doctoral Fellows, two Research Associates, two Senior Research Technicians, a Grants Manager and an Administrative Assistant. The primary focuses of the laboratory are on Excitation Contraction Coupling (skeletal and cardiac), calcium metabolism in skeletal muscle and novel therapies for treatment of muscle diseases. Because of its diverse interests the Laboratory is associated with the Musculoskeletal, Cardiovascular, Neuroscience and Stem Cell Research Centers of the Brigham Research Institute, the Department of Cell Biology at Harvard Medical School, as well as having members in the Harvard Stem Cell Institute and Dana Farber Cancer Institute. The Laboratory of Molecular Anesthesia is broken up into five collaborative groups each headed by a Faculty PI. The Allen group is the largest of the five groups (P. D. Allen M.D., Ph.D., J. Rafael Lopez M.D., Ph.D., S. Mukherjee M.S., J. M. Eltit, Ph.D. Ayuk Agbor Anderson, Ph.D., Hongli Li, M.D, Ronit Hirsch M.S. and honorary member Tianzhong Yang, M.D.) and focuses its attention on the interaction among proteins involved in skeletal muscle EC coupling (Hirsh), Structure Function Studies of the skeletal muscle sarcoplasmic reticulum Ca2+ release channel (also know as RyR1) (Lopez, Anderson, Mukherjee, Eltit), and mechanisms responsible for the anesthetic-caused disease malignant hyperthermia (MH)(Lopez, Eltit Yang). In a multi-center program project in collaboration with Drs. Isaac Pessah, Kurt Beam and Clara Franzini-Armstrong, the Allen group has created knockout mice with null mutations in RyR1, Triadin (all isoforms), Skeletal and cardiac Calsequestrin, and in collaboration with others has used other null mice to make double and triple null mutants. After creating myoblast cell lines from these null mice the Allen group uses HSV virions developed by the Wang group and lentivirons developed by the Westerman group to transduce myotubes with mutated RyR1 constructs and studies the effects of these mutations on their intracellular Ca2+ handling using high-speed Ca2+ imaging. In a second multicenter program project in collaboration with Drs. Isaac Pessah, Robert Dirksen, Susan Hamilton, Clara Franzini-Armstrong and Sheila Muldoon they have made MH mice which they have shown have a phenotype similar to that in humans. In addition to their molecular studies, with the expertise of Dr. Lopez using Ca2+ selective microelectrodes, the Allen group is unique in the world in its ability to study the effects of EC coupling protein mutations on resting free Ca2+ using Ca2+ selective microelectrodes. In collaboration with the Samso Group (Allen, Samso), the Allen lab is devising new ways to express integral membrane proteins for structural analysis. The Allen lab group is funded by NIH (P01, 2 R01s) Selected Publications: Gach MP, Cherednichenko G, Haarmann C, Lopez JR, Beam KG, Pessah IN, Franzini-Armstrong C, Allen PD. Alpha2delta1 dihydropyridine receptor subunit is a critical element for excitation-coupled calcium entry but not for formation of tetrads in skeletal myotubes. Biophys J. 2008 94:3023-34. Cherednichenko G, Ward CW, Feng W, Cabrales E, Michaelson L, Samso M, Lopez JR, Allen PD, Pessah IN. Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene. Mol Pharmacol. 2008 73:1203-12. Epub 2008 Jan 2. Voss AA, Allen PD, Pessah IN, Perez CF. Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras. Biochem Biophys Res Commun. 2008 366:988-93. Epub 2007 Dec 26. Shen X, Franzini-Armstrong C, Lopez JR, Jones LR, Kobayashi YM, Wang Y, Kerrick WG, Caswell AH, Potter JD, Miller T, b, Perez CF. Triadins modulate intracellular Ca(2+) homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.J Biol Chem. 2007 282:37864-74. Yang T, Allen PD, Pessah IN, Lopez JR. Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. J Biol Chem. 2007 282:37471-8. Epub 2007 Oct 16. Nakai J, Dirksen RT, Nguygen HT, Pessah IN, Beam KG, Allen PD: Enhanced Dihydropyridine Receptor channel activity in the presence of ryanodine receptor.Nature 380, 72-75, 1996. The Wang group (Yaming Wang, M.D., Zhong Yang, Ph.D., Q. Liu, M.D., W. Liu M.S., C. Lu) focuses its attention on gene therapy/cell therapy for Duchenne's muscular dystrophy (DMD). In addition to creating several novel hybrid HSV/AAV vectors which can integrate large cDNA sequences such as 14 kb full-length of dystrophin cDNA into human cells site specifically to be used for DMD gene therapy the Wang group has focused on why humans cannot behave like salamanders when they lose a limb or an eye? (salamanders grow a new one) Dr. Wang and her co-workers have shown that like the salamander, mammalian muscles can be made to dedifferentiate and create stem cells from fully differentiated muscle cells, by over expressing expressing msx1. Msx1 is a transcription factor that we share with the salamander, but is normally silent in humans after early embryogenesis. These cells can be derived from autologous muscle, a defect corrected using the integrating vector, and transplanted into the patient BUT with 100X more efficiency than normal myoblast transfer. In addition to its uses in gene therapy for muscle diseases, this technique may facilitate the use of muscle as a bioreactor to produce secreted proteins (e.g. factor 8 and factor 9 for hemophilia A and B). The Wang group is currently funded by NIH, and a BRI bridge grant and was previously funded by MDA and the Harvard Stem Cell Institute.  Selected Publications: Q. Liu, C. F. Perez, Y. Wang. Efficient site-specific integration of large transgenes by an enhanced herpes simplex virus/adeno-associated virus hybrid amplicon vector. J Virol. 2006; 80(4) 1672-9 Shen X, Franzini-Armstrong C, Lopez JR, Jones LR, Kobayashi YM, Wang Y, Kerrick WG, Caswell AH, Potter JD, Miller T, Allen PD, Perez CF. Triadins modulate intracellular Ca(2+) homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.J Biol Chem. 2007 Dec 28;282(52):37864-74. Epub 2007 Nov 2. The Westerman group (Karen Westerman Ph.D. and Ashley Penvose, B.S.) is devising new ways to deliver therapeutic cells to muscle in order to treat muscle diseases such as limb-girdle muscular dystrophy.Her work involves modifying myoblasts and stem cells to enhance their homing and transmigration through the vasculature to sites of injured muscle. In addition, Dr. Westerman also collaborates with the Vacanti Tissue Engineering Laboratory, isolating and characterizing sphere-derived stem cells, which are generated through the formation of myospheres (derived from skeletal muscle) and neurospheres (derived from brain and spinal cord) in culture.Dr. Westerman is funded by a NIH KO1 award, her KO1 mentors include Drs. Sean Colgan, Bill Luscinskas, and Paul Allen.   Selected Publications: Qiu HY, Fujimori Y, Nishioka K, Yamaguchi N, Hashimoto-Tamaoki T, Sugihara A, Terada N, Nagaya N, Kanda M, Kobayashi N, Tanaka N, Westerman KA, Leboulch P, Hara H.Postnatal neovascularization by endothelial progenitor cells immortalized with the simian virus 40T antigen gene.Int J Oncol. 2006. 28(4):815-21. Wazen RM, Moffatt P, Zalzal SF, Daniel NG, Westerman KA, Nanci A.Local gene transfer to calcified tissue cells using prolonged infusion of a lentiviral vector.Gene Ther. 2006. 13(22):1595-602. Kong T, Westerman KA, Faigle M, Eltzschig HK, Colgan SP.HIF-dependent induction of adenosine A2B receptor in hypoxia. FASEB J. 2006. 20(13):2242-50. Westerman KA, Ao Z, Cohen EA, Leboulch P.Design of a trans protease lentiviral packaging system that produces high titer virus.Retrovirology. 2007.Dec 28;4:96. The Samso group (Montserrat Samso, Ph.D., Youngha Hwang, Ph.D.) is studying the molecular structure of EC coupling proteins such as the RyR1 and the slow voltage gated Ca2+ channel (DHPR) using single particle cryo-electron microscopy techniques. In addition to the single particle work, this group has also focused on making 2D crystals of RyR1 embedded in a lipid bilayer to allow them to build an atomic map of RyR1 by electron crystallography. To date they have been able to obtain a 3D map of RyR1 at ~10 resolution, unveiling the structure of its ion pore, and make small 2D crystals. Dr. Samso is also collaborating with Drs. Kurt Beam and Claudio Perez to combine molecular biology, structural biology, and functional studies in order to map specific regions within the DHPR and RyR, and their site(s) of mutual interaction. The Samso Group is funded by the American Heart Association and in collaboration with Dr. Beam by an R01 from NIH.  Selected Publications: Meng, X., Samso, M., Koonce, M. A Flexible Linkage Between the Dynein Motor and its Cargo. J. Mol. Biol. 2006; 357:701-6. Samso, M, Shen X, Allen PD. Structural Characterization of the RyR1-FKBP12 Interaction. J Mol Biol. 2006 356:917-27. Cherednichencko G, Ward CW, Feng W, Cabrales E, Michaleson L, Samso, M, Lopez JR, Allen PD, Pessah IN (2008). Enhanced Excitation-Coupled Calcium Entry (ECCE) in Myotubes Expressing Malignant Hyperthermia Mutation R163C is Attenuated by Dantrolene. Molec. Pharm. 73:1203-1212. The Perez Group (C. F. Perez, Ph.D., J. Fox, R. Hirsch, M.S. and several summer and winter term Ph.D. and Medical Students) is identifying the specific relationships of RyR1 and the skeletal DHPR and determining the critical regions of both proteins that are associated with EC coupling, DHPR tetrad formation and bi-directional signaling. In a related Project, Dr. Perez and his associates are investigating whether or not cardiac EC coupling is exclusively supported by Ca2+ induced Ca2+ release (CICR) or whether part of the signal is external Ca2+ independent and the result of conformation coupling with the cardiac DHPR. In addition, Dr. Perez has been involved in characterizing the effects of the absence of skeletal Triadin and MG29 on Ca2+ signaling in skeletal muscle using single and double KO mice developed by the Allen group. The Perez group is currently funded by the American Heart Association and NIH K01 award (K01 mentors: Dr. G. Stahl, Ph.D., J.R. Lopez, M.D. and K. Beam Ph.D.) In addition Dr. Perez has active collaborations with Dr. P.D. Allen, M.D., Ph.D. and M. Samso Ph.D. at BWH and Dr. I. Pessah, Ph.D. at UC Davis. Selected Publications: Liu Q, Perez CF, Allen PD and Wang Y. (2006) Efficient site-specific integration of large transgenes by an enhanced Herpes Simplex Virus/Adeno-Associated Virus hybrid amplicon vector. J. Virol. 80: 1672-1676. Sheridan DC, Takekura H, Franzini-Armstrong C, Beam KG Allen PD and Perez CF. (2006). Bi-directional signaling between calcium channels of skeletal muscle requires multiple, direct and indirect, interactions. Proc. Natl. Acad. Science USA, 103:19760-19765. Shen X, Franzini-Armstrong C, Lopez JR, Jones LR, Kobayashi YM, Wang Y, Kerrick WG, Caswell AH, Potter JD, Miller T, Allen PD and Perez CF. (2007) Triadins modulate intracellular Ca2+ homeostasis but are not essential for excitation-contraction coupling in skeletal muscle. J Biol Chem. 282:37864-37874. Voss AA, Allen PD, Pessah IN and Perez CF. (2008) Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras. Biochem. Biophys. Res. Commun. 366:988-993. CENTER FOR TISSUE ENGINEERING Charles A. Vacanti, MD, Director At the Vacanti Laboratory for Tissue Engineering and Regenerative Medicine, researchers are currently developing several projects centered on the goal of placing tissue-engineered cells and scaffolds into the human body in order to regenerate tissue. The laboratory was founded by Dr. Charles Vacanti, M.D., the current Chairman of the Department of Anesthesia at Brigham & Women's Hospital. A world-renowned pioneer in tissue engineering, Dr. Vacanti contributed to many of the first published research papers on tissue-engineered cells and structures. The most easily recognized image of this milestone was published in 1997 when scientists and the public alike were amazed to see cartilage in the shape of a human ear grown on the back of a mouse. While the research involved in the process of growing cartilage has grown to be the foundation of tissue-engineering, researchers at the Vacanti Laboratory are moving beyond regenerating cartilage and into more complex tissues such as trachea, lung, blood vessel, ligament, spinal cord, brain, and pancreas. Currently in the Vacanti Laboratory, the research group consists of Dr. Kojima, the Scientific Director, two faculty members, research fellows, and a medical student. There is a continual influx of undergraduate students and research fellows from around the world learning the basics about tissue engineering. Recent work has focused on pancreatic islet cells as well as identification, culture, and characterization of spore-like cells from the lung, liver, adrenal gland, and nervous tissue. These spore-like cells, or "spheres", appear to be abundant in nearly every tissue in the body and may be a key for regeneration of injured or diseased tissue.  Tissue-engineered trachea The Vacanti Laboratory for Tissue Engineering and Regenerative Medicine welcomes any interest in this exciting and innovative field of medicine. For more information on the laboratory's most well-known and most recent publications, please follow the links below: Selected Publications Iwasaki K, Kojima K, Kodama S, Paz AC, Chamber M, Umezu M,Vacanti CA. Bioengineering three-layered robust and elastic artery utilizing hemodynamically-equivalent pulsatile bioreactor. Circulation.2008 [in press]. Zani BG, Kojima K, Vacanti CA, Edelman ER. Tissue Engineered Endothelial and Epithelial Implants Differentially and Synegistically regulate Airway Repair. Proc Natl Acad Sci USA. 2008 ; 105: 7046-7051. Vacanti CA.History of tissue engineering and a glimpse into its future. Tissue Eng. 2006 May;12(5):1137-42. Yasuda A, Kojima K, Tinsley KW, Yoshioka H, Mori Y, Vacanti CA.In vitro culture of chondrocytes in a novel thermoreversible gelation polymer scaffold containing growth factors.Tissue Eng. 2006 May;12(5):1237-45. Kojima K, Vacanti CA.Generation of a tissue-engineered tracheal equivalent. Biotechnol Appl Biochem. 2004 Jun;39(Pt 3):257-62. For further information, please contact Dr. Koji Kojima at kojima@zeus.bwh.harvard.edu. CENTER FOR REGENERATIVE MEDICINE Piero Anversa, MD, Director The research performed in our laboratory challenges the accepted but never proven paradigm that the adult heart is a post-mitotic organ composed of an irreplaceable number of parenchymal cells, which is established at birth. The common theme of our work is based on the premise that the heart is a self-renewing organ in which a stem cell compartment controls the physiologic turnover of cardiac cells and conditions myocardial aging and tissue regeneration in pathologic states. The long-term goal is the understanding of the origin and developmental control of cardiac progenitor cells (CPCs), their distribution in the heart and mechanisms of aging, the etiology of their death and senescence, and their therapeutic potential for the aged and infarcted heart. The recognition that CPCs are present in the heart imposes a reconsideration of the various theories of cardiac development, maturation and myocardial aging. The notion that cardiomyocytes age at the same pace, and the age of the cells, organ and organism coincides is no longer acceptable. We are trying to ascertain the origin of CPCs and, more specifically, whether they are remnants of the embryonic cardiogenic plates that remain in the myocardium or whether they derive from the bone marrow and colonize the heart through the circulation and continuously replenish the CPC pool. An important area of our activities is CPC senescence. The time-dependent decrease in the number of functionally competent CPCs mediated by critical shortening of telomeres and reduced telomerase activity may result in CPC aging with forced entry into an irreversible state of quiescence. The complex process of stem cell senescence is expected to involve loss of locomotion, growth and differentiation, limiting cell turnover and expanding the population of old poorly functioning myocytes. Thus, CPC senescence leads to the old heart phenotype. The ability to activate and mobilize CPCs from the site of storage to areas of damage and promote myocardial regeneration may postpone the remodeling of the aged-infarcted heart and the onset of terminal failure in the elderly. To accomplish our objectives, we need profound understanding of the biology of resident CPCs and we have to determine whether the CPC pool includes distinct classes of primitive cells which have powerful but distinct vasculogenic and myogenic properties. The recognition of a coronary vascular progenitor cell (VPC) that differentiates predominantly into smooth muscle cells and endothelial cells suggests that the heart has the ability to create the various portions of the coronary circulation, from conductive coronary arteries to capillary structures. Similarly, the characterization of a myocyte progenitor cell (MPC) that acquires prevalently the cardiomyocyte phenotype suggests that the opportunity exists to restore extensive losses of muscle mass. Various proportions of VPCs and MPCs may be utilized according to the needs of the organ and the uniqueness of the cardiac lesion. This possibility is examined in small animal models, which are particularly suitable for genetic manipulations relevant to the characterization of the effector pathways that regulate the activation and differentiation of CPC classes into specific cardiac cell lineages. Currently, the presence and therapeutic potential of VPCs and MPCs is being established in large animal models to obtain relevant preclinical data. Finally, we are investigating whether the decompensated human heart possesses functionally competent VPCs and MPCs and whether molecular strategies can be implemented to interfere with the fate of PC categories and enhance their regenerative capacity. If successful, this research will make the impossible dream of myocardial regeneration a feasible reality. Selected Publications: Urbanek K, Cesselli D, Rota M, Nascimbene A, Bearzi C, Hosoda T, Boni A, Bolli R, Kajstura J, Anversa P, Leri A. Cardiac stem cell niches. Proc Natl Acad Sci USA, 103:9226-9231, 2006. Anversa P, Leri A, Rota M, Bearzi C, Urbanek K, Kajstura J, Bolli R. Stem cells, myocardial regeneration and methodological artifacts. Stem Cells. 25:589-601, 2007. Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, LeCapitaine N, Cascapera S, Beltrami AP, D'Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P. Human cardiac stem cells. Proc Natl Acad Sci USA. 104:14068-14073, 2007. Rota M, Kajstura J, Hosoda T, Bearzi C, Vitale S, Esposito G, Iaffaldano G, Padin-Iruegas ME, Gonzalez A, Rizzi R, Small N, Muraski J, Alvarez R, Chen X, Urbanek K, Bolli R, Houser SR, Leri A, Sussman MA, Anversa P. Bone marrow cells adopt the cardiomyogenic fate in vivo. Proc Natl Acad Sci USA. 104:17783-17788, 2007. Tillmanns J, Rota M, Hosoda T, Misao Y, Esposito G, Gonzalez A, Vitale S, Parolin C, Yasuzawa-Amano S, Muraski J, De Angelis A, LeCapitaine N, Siggins RW, Loredo M, Bearzi C, Bolli R, Urbanek K, Leri A, Kajstura J, Anversa P. Formation of large coronary arteries by cardiac progenitor cells. Proc Natl Acad Sci USA. 105:1668-1673, 2008.
Rota M, SDF-1 axis and myocardial repair. Am J Physiol Heart Circ Physiol 299: H1307-H1308, 2010. First published doi:10.1152/ajpheart.00876.2010
Laboratory for Aging Neuroscience Deborah Culley, MD and Gregory Crosby, M.D. The Culley-Crosby Lab (aka the Laboratory for Aging Neuroscience) is focused on the aging brain and the impact general anesthesia has on it. Cognitive impairment lasting days to months after surgery and general anesthesia is a very common and distressing source of postoperative morbidity in the elderly. Our laboratory is testing the hypothesis that general anesthesia, which is controlled coma, contributes to this problem. This is of more than theoretical interest to the PIs in the lab (Drs. Crosby & Culley) because both are clinical anesthesiologists who see the benefits as well as adverse effects of the agents at the bedside. Using behavioral testing, we have demonstrated enduring spatial learning impairment in aged but not young rodents after general anesthesia with some, but not all, commonly used agents. (Culley DJ, Raghavan SV, Waly M, Baxter MG, Yukhananov RY, Deth RC, Crosby G. Nitrous oxide transiently decreases cortical methionine synthase and produces lasting memory impairment in aged rats. Anesth Analg 2007;105:83–8.) (Lee IH, Culley DJ, Baxter MG, Xie Z , Yukhananov RY, Tanzi RE, Crosby G. Propofol anesthesia does not impair spatial memory in aged rats. Anesth Analg 2008; In Press.) These learning deficits are not easily explained by incomplete clearance of the anesthetics, since the agents in question are rapidly eliminated. This led us to postulate that general anesthesia induces persistent changes in the molecular and cellular characteristics of the hippocampus, a brain region that mediates spatial working memory. As such, the main focus of the lab currently is to examine the neurobiological basis of the persistent memory dysfunction. To that end, we are focusing on two possibilities: 1. that general anesthesia induces neuroplastic changes in the aged brain; and 2. that general anesthesia damages the aged brain. With respect to the former, we have identified long-lasting, age-dependent molecular and synaptic changes in the hippocampus of old rats. (Culley DJ, Yukhananov RY, Xie Z, Galli R, Tanzi RE, Crosby G. Hippocampal gene expression is altered 48 h after general anesthesia in aged rats. European Journal of Pharmacology. 2006 Nov 7;549(1-3):71-8.) With respect to the latter, our lab has collaborated with colleagues in anesthesia and neurology at MGH to show that in a cell culture system at least one general anesthetic agent induces apoptosis and enhances formation of β amyloid, a protein strongly implicated in the pathogenesis of Alzheimer's disease. (Xie Z, Dong Y, Maeda U, Afille P, Culley DJ, Crosby G, Tanzi RE. The common inhalation anesthetic isoflurane induces apoptosis and increases Aβ levels. Anesthesiology. 2006 May;104(5):988-94.)( Zhang B, Dong Y, Zhang G, Moir RD, Xia W, Yue Y, Tian M, Culley DJ, Crosby G, Tanzi RE, Xie Z, The inhalation anesthetic desflurane induces caspase activation and increases amyloid beta-protein levels under hypoxic conditions.J Biochem 2008;283:11866-75.) Together, these data indicate that general anesthesia can produce ongoing neuronal dysfunction and / or toxicity in vitro and in vivo. Thus, contrary to standard teaching, it appears that general anesthesia leaves the brain different than it was before, implying the brain reacts to general anesthesia and is not just a passive bystander. Whether there is a relationship between the enduring cellular and molecular effects of general anesthesia in the aged brain and the postoperative cognitive morbidity observed commonly in elders after surgery and anesthesia remains to be determined but we have established collaborations with colleagues in geriatrics to begin to address that question. Our hope is that better understanding of the impact of perioperative events on the neurobiology of the aged brain will ultimately translate into improved cognitive outcome after surgery and anesthesia in elders. Names, degrees and funding of professional personnel who work in the Crosby Laboratory over the past 3 years
CROSBY LAB
COLLABORATORS Selected Publications: Culley DJ, Yukhananov RY, Crosby G. General anesthesia does not reduce life expectancy in aged rats. Anesth Analg. 2006 Mar;102(3):956-9. Xie Z, Dong Y, Maeda U, Moir R, Inouye S, Culley DJ, Crosby G, Tanzi RE. Isoflurane induced apoptosis:A potential pathologic link between delirium and dementia. J Gerontol A Biol Sci Med Sci. 2006 Dec;61(12):1300-6. Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE, The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Ab Accumulation. J Neurosci, 2007;27:124754. Baxter MG, Murphy KL, Crosby G, Culley DJ. Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia. Hippocampus 2008; 18:245-50. Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE. Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J Neurosci. 2008;28(17):4551-60. PAIN RESEARCH CENTER The mission of the Pain Research Center is to investigate the mechanisms and the behavior associated with chronic pain state, both in animal models and with human subjects, and to develop new therapeutic approaches for cure and prevention of pain.Chronic pain may arise from diseases, such as cancer, from nerve injury, from prolonged or intensely acute inflammation, or from unknown causes. Investigators in the Center integrate a range of methods, from molecular biology and cellular physiology, in vitro biochemistry and pharmacology, animal behavioral studies and clinical observations to find the common and divergent causes for chronic pain, and to develop better methods of treatment for prevention, amelioration and reversal of these conditions. The Pain Research Center is staffed by 8 Principal Investigators, 3 Senior Research Associates, 3 Visiting Professors (anesthesia), 5 Postdoctoral Fellows and 5 support staff, and its work is supported by 12 NIH-funded grants. Laboratory Research Peter Gerner, M.D. My overall research goal is the development of nociceptor/sensory-selective local anesthetics for the safe and specific treatment of pain. Local anesthetics may cause severe adverse effects due to systemic toxicity (including seizures and cardiac arrest) and local toxicity (from temporary nerve degeneration to permanent paraplegia). Development of several new promising drugs has been halted in late clinical stage due to toxicity. Currently I am examining the hypothesis that toxicity of local anesthetics can be minimized by exploiting specific pharmacological interactions that modulate the function of either the Na+ channel or the cellular signaling pathways activated by local anesthetics. Techniques employed in my laboratory to test this hypothesis range from electrophysiological recordings (patch-clamp technique) and immunohistochemistry to in vivo rat nerve block and rat pain models; in addition I have completed several phase I studies in volunteers. Our data demonstrate that systemic toxicity can be minimized by the use of novel agents that act synergistically on TRPV1 as well as Na+ channels and allow great reduction of the dosage of the local anesthetic. Of note, almost exclusive nociceptor/sensory blockade over motor blockade has been achieved in several animal models. We have also shown that local toxicity can be minimized by the use of neuroprotective drugs that prevent apoptotic changes induced locally by local anesthetics. Selected Publications: Gerner P. Postthoracotomy pain management problems. Anesthesiol Clin. 2008;26(2):355-67. Lirk P, Haller I, Colvin HP, Lang L, Tomaselli B, Klimaschewski L, Gerner P. In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity. Anesth Analg. 2008;106(5):1456-64. Gerner P, Strichartz GR. Sensory and motor complications of local anesthetics. Muscle Nerve. 2008;37(4):421-5. Gerner P, O'Connor JP. Impact of analgesia on bone fracture healing. Anesthesiology. 2008;108(3):349-50. Pomahac B, Zuhaili B, Kudsi Y, Bleiziffer O, Velander P, Eriksson E, Gerner P. Safety Evaluation of Topically Applied Amitriptyline in Porcine Full-Thickness Wounds. Reg Anesth Pain Med. 2007;32(5):377-381. Hung YC, Chen CY, Lirk P, Wang CF, Cheng JK, Chen CC, Wang GK, Gerner P. Magnesium sulfate diminishes the effects of amide local anesthetics in rat sciatic-nerve block. Reg Anesth Pain Med. 2007;32(4):288-95. Ru-Rong Ji,Ph.D. Sensory Plasticity Laboratory
Present members: Area of research Neural and glial regulation of chronic pain Chronic pain, such as neural injury-induced neuropathic pain and tissue injury-induced inflammatory pain, is a major public health problem worldwide. Current treatments have only produced limited success, due to our incomplete understanding of the mechanisms underlying the induction and maintenance of chronic pain. It is generally believed that chronic pain is caused by neural plasticity that occurs both in primary sensory neurons (peripheral sensitization) and spinal cord dorsal horn neurons (central sensitization). Accumulating evidence also suggests that glial cells (microglia and astrocytes) in the spinal cord play an important role in the development and maintenance of chronic pain. There are two major research projects in the lab. The first project is to investigate how MAP kinase (MAPK) signaling pathways regulate chronic pain. Our previous studies have demonstrated neuronal mechanisms of MAPKs (e.g., ERK activation in dorsal horn neurons and p38 activation in DRG neurons) are critical for the development of neural plasticity in the nociceptive system, leading to development of persistent pain. Our recent studies have shown that nerve injury differentially activates MAP kinases (ERK, p38, and JNK) in spinal microglia and astrocytes, which is required for the development and maintenance of neuropathic pain by producing pronociceptive mediators such as IL-1b. Very recently, we have shown that IL-1b can induce central sensitization by both increasing excitation and decreasing inhibition (disinhibition) in dorsal horn neurons. We are investigating (a) how MAPKs are activated in spinal glia, (b) whether anti-inflammatory and analgesic compounds act by blocking MAPK activation, and (c) how MAPKs regulate the synthesis of inflammatory mediators in spinal microglia and astrocytes. The second project is to investigate how matrix metalloproteases (MMPs) regulate chronic pain. Recently, we have shown that MMP-9 and MMP-2 play distinct roles in neuropathic pain development by regulating IL-1b activation, glial activation, and neuropathic pain in the early- and late-phase, respectively. Currently, we are investigating (a) whether MMP-9 and MMP-2 can actively cleave cytokines, chemokines, and synaptic proteins,(b) whether these MMPs can modulate synaptic plasticity in the dorsal horn, and (c) whether MMP-9 inhibition can prevent the development of chronic pain. We use histochemical, biochemical, electrophysiological, genetic, and behavioral approaches in intact animals and isolated spinal cord slices to investigate the neural and glial mechanisms of chronic pain. Our studies will greatly improve our understanding of molecular and cellular mechanisms underlying chronic pain and lead to novel therapies for the management of chronic pain. Selected Publications: Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ. Protein kinases as potential targets for the treatment of pathological pain. Handbook of Experimental Pharmacology, 2007; 177:359-389. Suter M, Ji RR (2007) Do glial cells control pain? Neuron Glia Biology, 2007, 3:255-268. Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med, 2008, 14:331-336 (Cover Story). Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: overlapping and distinct roles of proinflamamtory cytokines IL-1b, IL-6, and TNF-a in regulating synaptic and neuronal activity. J Neurosci, 2008, 28:5189-5194. Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008 Oct;33(10):1970-8. Igor Kissin, M.D., Ph.D. Dr. Kissin's interests are centered on the neurobehavioral pharmacology of anesthetics and analgesics. They have led to studies of anesthetic interactions resulting in a concept that general anesthesia is based not on a single general anesthetic action but on a spectrum of separate pharmacological actions, even if the anesthesia is produced by one drug. This led to a conclusion that the search for a reliable index of anesthetic depth should be transformed into a search for separate indices of different components of anesthesia. The other area of Dr. Kissin's investigations is preemptive analgesia. Preemptive analgesia is a treatment that prevents establishment of the altered sensory processing that amplifies post-operative pain. The treatment should cover the entire duration of high-intensity noxious stimulation that can lead to establishment of central (and peripheral) sensitization caused by incisional or inflammatory injuries (during surgery and the initial postoperative period). Two approaches have been used to reveal preemptive analgesia. One of them is to demonstrate a reduction in pain intensity and/or in analgesic use beyond the drug presence in the biophase. This approach is based on a study design comparing preoperative treatment and nontreatment groups (PRE versus NO). The other approach is to prove that a treatment applied before surgery is more effective than the same treatment provided at the end of surgery (PRE versus POST). The present direction of his investigations is to prove that full potential of preemptive analgesia can be revealed only with PRE versus NO approach. The other important condition to have the full effect of preemption is the completeness of interventions suppressing C and Aδ fibers central input. One of Dr. Kissin's projects is based on the idea to use vanilloid agonists for the blockade of peripheral nerves. Vanilloids bind to the transient receptor potential type channels (TRPV1) and cause nerve desensitization. He has shown that vanilloids can provide selective (C fibers and Aδ fibers) and long-lasting (days) neural blockade. Extension of the traditional local anesthetic blockade into the postoperative period presents a problem for early mobilization (rehabilitation) after surgery and when protective sensation is required. Vanilloid agonists have an advantage in this regard. They do not affect non-painful sensations to touch and pressure or motor function. Dr. Kissin's experiments demonstrated that perineural resiniferatoxin (vanilloid agonist) prevents hyperalgesia in a rat model of postoperative pain. His electron microscopy study in rats demonstrated that resiniferatoxin-induced sciatic nerve blockade may lead to morphological changes in C fibers but to a much smaller degree than those with the use of local anesthetics. This result may indicate a new direction in the treatment of pain--conduction analgesia.  Typical regions from cross-sections of rats' sciatic nerves 48 h after the perineural administration of RTX (0.001%, 0.1 mL). Note the normal appearance of unmyelinated fibers. Unmyelinated fibers are marked with arrows, myelinated fibers – mf, mitochondira – m, nuclei of the Schwann cells – n, horizontal bars – 500 nm. Selected Publications: Kissin I, Freitas CF, Bradley EL Jr. Perineural resiniferatoxin prevents the development of hyperalgesia produced by loose ligation of the sciatic nerve in rats. Anesth Analg 2007;104:1210-6. Kissin I, Freitas CF, Mulhern HL, DeGirolami U. Sciatic nerve block with resiniferatoxin: an electron microscopic study of unmyelinated fibers in the rat. Anesth Analg 2007;105:825-31. Yukhananov R, Kissin I. Persistent changes in spinal cord gene expression after recovery from inflammatory hyperalgesia: A preliminary study on pain memory. BMC Neuroscience 2008;9:32-46 Kissin I. Vanilloid–induced conduction analgesia: selective, dose-dependant, long-lasting, with a low level of potential neurotoxicity. Anesth Analg 2008;107:271-81. Persons involved: Kissin I, Yukhananov R, Langone J. Gary Strichartz, Ph.D. Principal Investigator Director, Pain Research Center Peripheral Neuropharmacology for Chronic Pain The Strichartz lab is actively investigating in two areas of persistent pain: 1. the role of receptors for endothelin-1 (ET-1) in abnormal pain from tissue injury, inflammation and cancer, and 2. the mechanisms of chronic post-operative pain. The G-protein coupled receptors for ET-1, an endogenous peptide, appear to be involved in several forms of acute and chronic pain. Our work has shown that injection of ET-1 in the paw or application directly on peripheral nerve causes immediate and transient pain in rats, induces spontaneous action potentials selectively in peripheral nociceptors in vivo, and causes increases in excitability,cellular [Ca+2] in and in the opening of a TTX-R voltage-gated Na+ channel found exclusively in nociceptors, as well as a depression of the currents carried by delayed-rectifier type K+ channels. All these effects are mediated by ETAreceptors for ET-1. In addition, acute ET-1 injection enhances the amount of both glutamate and CGRP in the epidermis, accounting for a rapid phase of nociceptor sensitization, and also enhances the expression of the transducing receptor TRPV-1, a molecule that senses noxious heat and the elevated [H+] that accompanies inflammation. The ETB receptor sub-type, in contrast, makes two different contributions to pain; ETB receptors on neurons are pro-algesic and sensitize nociceptors to mechanical stimuli to elevate pain behavior, whereas ETB receptors on keratinocytes, in the skin's epidermis, are anti-hyperalgesic, countering the effects of pain stimuli and sensitizers This anti-algesic action occurs, and which also differs in differentby the release of the opioid peptide β-endorphin from the keratinocytes that synthesize and store it. The ultimate likelihood that a nociceptor will generate afferent impulses to signal pain is substantially dependent on the dynamic interactions between pro-algesic neuronal ETA and ETB receptors and the anti-algesic ETB receptors on keratinocytes, a balance which changes after injury and inflammation, and which also differs between hairy skin and glabrous, hairless skin. The most recent work has focused on the role of the ET receptors in skin. Our lab has collaborated with the Skin Disease Research Center laboratory of Dr. James Rheinwald to grow basal keratinocytes and to differentiate them and study the effects of ET-1.Such cultures allow a degree of autonomy and manipulation that is difficult in vivo, and provides the opportunity to study basic cellular processes in keratinocytes that contribute to peripheral pain processing, by examining gene expression (RT-PCR), cellular physiology (Ca-imaging and whole cell voltage-clamp) and protein expression (Western blot and immunocytochemistry). 
Schematic of a generalized epidural keratinocyte shows the presence of signal transducing TRP channels (TRPA1, TRPV1, TRPV3 and TRPV4), of delayed rectifier potassium channel (K Channel) and of GPCRs for endothelins (ETA and ETB) as well as for certain cannabinoids (CB2). This simplified scheme also depicts the secretion of β-endorphin (known to be effected by activation of the ETB and CB2 receptors) and of ATP, glutamate (Glu) and the neuropeptides CGRP. Receptors for glutamate, ATP and CGRP are also known to be expressed by keratinocytes (not shown). Several intracellular signaling pathways are also shown; those for which there is direct evidence are indicated by solid arrows, those that are speculative by broken arrows. Chronic post-operative pain is an important clinical problem for many procedures, including thoracotomies, mastectomies, gynecological surgery, obstetrical surgery and most forms of amputation. Our laboratory has begun to study this problem by developing new animal models that mimic surgical procedures. Using the hairy skin of the rat we have found that skin incisions through the dorso-lumbar region cause both primary and secondary mechanical allodynia, but that this elevated pain can be prevented by pre-emptive application of local and systemic local anesthetics, apparently through an action on the CNS/spinal cord.Incisions through the medial thigh, followed by an hour-long retraction of the skin and muscle that entraps the saphenous nerve, leads to a profound and long-lasting (3-5 week) tactile allodynia of the ipsilateral plantar paw surface, a striking example of secondaryhyperalgesia since this region is not directly innervated by the saphenous nerve. Ongoing studies to document the absence of nerve damage at the retraction site and to examine the anatomical changes in the plantar skin, at the stimulation site, and of the DRG and spinal cord that process signals from nerves of the retraction and test sites will allow the identification of cells and structures involved in this prolonged hyperalgesia. In conjunction with Dr. Peter Gerner, of our department, we are investigating the ability of a block of sciatic nerve sensory function for 5-10 hours, by a synthetic matrix that slowly releases lidocaine, on the pain that develops after paw incision. Preliminary results suggest that such a block is able to prevent the post-incisional allodynia that usually lasts for 4-5 days after the incision.Further studies with this model and other surgical models will continue through 2008-2009. Selected Publications: Balonov K, Khodorova A, Strichartz, GR. Tactile allodynia initiated by local subcutaneous endothelin-1 is prolonged by activation of TRPV-1 receptors. Exp Biol Med 2006, 231:1165-70. Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 2006, 7 (Supplement 3): S1-S29. Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, Feinstein DL. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart.Regional Anesth Pain Med 2006, 31: 296-303. Mujenda FH, Duarte AM, Reilly EK, Strichartz GR. Cutaneous endothelin-A receptors elevate post-incisional pain.Pain 2007, 133:161-173. Sugimoto K, Kissin I and Strichartz GR.High concentrations of resiniferatoxin inhibit ion channel function in clonal neuroendocrine cells. Anesth Analg. 2008;107: 318-324. Strichartz GR. Novel ideas of local anaesthetic actions on various ion channels to ameliorate post-operative pain.Br J Anaesth 2008; doi: 10.1093/bja/aen101 Ging Kuo Wang, Ph.D. Molecular Pharmacology of Ion Channels The overall goals of Dr. Wang's laboratory are (1) to map the local anesthetic receptor within the voltage-gated Na+ channel and (2) to identify novel drugs that may be applicable as long-acting local anesthetics for prolonged nerve block. Local anesthetics are clinic drugs that block action potentials in excitable membranes reversibly. The primary target of local anesthetics is voltage-gated Na+ channels, which are responsible for the generation and propagation of action potentials. Prolonged nerve block by long-acting local anesthetics is desirable for alleviating postoperative pain. Local anesthetics are also used in pain management for chronic and cancer pain but their applications appear limited because of the short blocking action. Mammalian Na+ channels contain a large a-subunit (Nav1.1-1.9) and one or two small b-subunit (b1-b4). The primary structure of the a-subunit isoform consists of four homologous domains (D1-D4) each with six transmembrane segments (S1-S6). The local anesthetic receptor has been mapped to a cluster of residues at D1S6, D3S6, and D4S6 segments encircling the inner cavity of the Na+ channel. Dr. Wang's laboratory is working to identify the contact points of local anesthetics with the Na+ channel in order to understand how the Na+ permeation pathway is blocked by local anesthetics. Towards this goal, Dr. Wang is also collaborating with other theorists to construct an open Na+ channel model for in silico local anesthetic docking within the inner cavity. Such a model will be used to reveal and/or to confirm the contact points between local anesthetics and residues within the Na+ channel. With this model Dr. Wang's laboratory will be able to explore whether drugs can be identified as local anesthetics by the docking exercise and later tested in animal for their duration of nerve block. To identify novel drugs, Dr. Wang's laboratory is working to establish stable cell lines that express robust inactivation-deficient Na+ channels. Persistent late Na+ currents are likely the culprit that induces ecotopic high-frequency discharges in injured nerve. Such high-frequency discharges have been found as the cause for neuropathic pain. Cell lines that express robust inactivation-deficient Na+ channels are therefore valuable as screening tools to identify drugs that target persistent late Na+ currents. Two cell lines have now been established in Dr. Wang's laboratory: (1) inactivation-deficient rNav1.4-WCW mutant channels and (2) inactivation-deficient hNav1.4-CW mutant channels. Recent studies in Dr. Wang's laboratory regarding local anesthetic block, the establishment of cell lines expressing inactivation-deficient Na+ channels, and the construction of the open Na+ channel model are listed below in the published form. Personnel in Wang's laboratory included Dr. Peter Gerner, Dr. Thomas Eldrich, and Ms. Gabriella Russell. Selected Publications: Wang,G.K., T.Edrich, and S.Y.Wang. 2006. Time-Dependent Block and Resurgent Tail Currents Induced by Mouse b4154-167 Peptide in Cardiac Na+ Channels. J Gen. Physiol 127:277-289. Wang,S.-Y., J.Mitchell, and G.K.Wang. 2007. Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel. Pain 127:73-83. Wang,C.F., P.Gerner, S.-Y.Wang, and G.K.Wang. 2007. Bulleyaconitine A isolated from aconitum plant displays long-acting local anesthetic properties in vitro and in vivo. Anesthesiology 107:82-90. Wang,G.K., J.Calderon, and S.Y.Wang. 2008. State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine. Mol. Pharmacol 73:940-948. Wang,G.K., J.Mitchell, and S.Y.Wang. 2008. Block of Persistent Late Na+ Currents by Antidepressant Sertraline and Paroxetine. J Membr. Biol. 222:79-90. PAIN RESEARCH CENTER- Clinical Pain Research The Section of Clinical Pain Research within the Pain Research Center entails the work of Drs. Edwards, Jamison, and Wasan, whose individual research programs are described in more detail below.We have a clinical research program predominantly, with funding from NIH, industry, and private foundations. Our work concentrates on psychophysical pain testing (e.g. quantitative sensory testing), innovative pain assessments tools (such as the use of PDAs to monitor pain), and the role of psychiatric factors in pain treatment response (i.e., the impact of depression or anxiety on treatment outcome).We have done significant work on the role of catastrophizing in pain perception and evaluation of opioid therapy efficacy for noncancer pain. We have developed tools for patient selection for opioids, such as a validated measure rating the propensity for opioid misuse, and for monitoring opioid compliance. Most recently, our work in opioids is extending to a clinical trial of opioids in chronic low back pain, evaluating analgesic and functional efficacy in proposed subgroups of responders. We are also conducting a study to validate a bedside clinical exam for neuropathic pain. We collaborate with the Psychiatric Neuroimaging Group at MGH to explore neural correlates of chronic pain perception as seen on fMRI. Robert Edwards, Ph.D. Dr. Edwards is a licensed clinical psychologist with appointments in Anesthesiology and Psychiatry at Brigham & Women's Hospital. His research focuses on biopsychosocial aspects of the pain experience, including studies of how negative emotions may magnify the physiological impact of pain. In addition to studying the role of negative emotions in shaping the pain experience, Dr. Edwards' work focuses on evaluating individual differences in sensitivity to pain using psychophysical techniques to assess responses to a variety of noxious stimuli. He has established a psychophysical pain testing laboratory at Brigham & Women's Hospital (located adjacent to the Pain Management Center), in which quantitative sensory testing (QST) is used to study sensory responses in a controlled environment. In past work, Dr. Edwards has studied ethnic and sex differences in responses to pain, and some of the psychosocial variables which might explain such differences. More recently, his research has focused on factors such as emotional distress, pain-related catastrophizing, and disrupted sleep as important contributors to pain responses both inside and outside of the laboratory. Dr. Edwards is the recipient of several NIH and foundation awards, including: a K23 award from NIAMS, which includes the use of QST in patients with rheumatoid arthritis and osteoarthritis, an R21 from NCI, which includes the use of QST assessments in patients undergoing surgical procedures, and young investigator awards from the American College of Rheumatology and the Arthritis Foundation, which involve functional neuroimaging studies to identify the central nervous system substrates of pain-related catastrophizing.Dr. Edwards works closely with Drs. Wasan and Jamison, and ongoing projects in his laboratory use tools such as functional Magnetic Resonance Imaging (fMRI) to evaluate how the brain processes pain-related information. Additional projects include a laboratory-based study of how pain-related anxiety can alter the functioning of the immune system and stimulate an inflammatory response, as well as a study of the predictors of individual differences in post-surgical pain. Selected References: Edwards R, Haythornthwaite J, Max M, Tella P, Raja, S. Basal heat pain thresholds predict opioid analgesia in patients with post-herpetic neuralgia. Anesthesiology 2006;104:1243-8. Edwards R, Smith M, Kudel I, Haythornthwaite J. Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain 2006;126:272-9. Edwards R and Fillingim R. Self-reported pain sensitivity: Lack of correlation with pain threshold and tolerance. Eu J Pain 2007;11:594-8. Edwards R., Klick B, Buenaver L, Max, M. Symptoms of distress as prospective predictors of pain-related sciatica treatment outcomes. Pain 2007;130:47-55. Edwards R, Smith M, Klick B. Symptoms of depression and anxiety as unique predictors of pain-related outcomes following burn injury. Annals of Behavioral Medicine 2007;34:313-22. Edwards R, Almeida D, Klick B, Haythornthwaite J, Smith M.Duration of sleep contributes to next-day pain report in the general population. Pain 2008;137: 202-7. Robert N. Jamison, Ph.D. Pain Management Center, Department of Anesthesia, BWH Activities and Goals: Over the past few years the focus of Dr. Jamison's clinical research efforts have been directed toward three areas of study: 1) Development and implementation of computer and information technology in the assessment and treatment of chronic pain patients; 2) Assessment of addiction risk potential among patients prescribed opioids for pain; and 3) Examination of psychopathology and personality differences as predictors of treatment outcome among chronic pain patients. Areas of Research: Dr. Jamison is a licensed clinical psychologist with over 30 years' experience working with persons with chronic pain. As an Associate Professor at Harvard Medical School with appointments in the Departments of Anesthesiology, Perioperative and Pain Medicine, Psychiatry, and Physical Medicine and Rehabilitation, he has enjoyed balancing clinical duties with research and teaching. His primary clinical responsibility is as Chief Psychologist at the Pain Management Center of Brigham and Women's Hospital. His duties include assessment and treatment of new patients referred to the Pain Center. He also screens for candidacy for opioid therapy and implantable devices and offers behavioral medicine services to patients and their families. Dr. Jamison has many related areas of research that have included 1) developing valid and reliable electronic data entry software for pain patients, 2) establishing valid screening tools for addiction risk in chronic opioid therapy, and 3) creating computerized dynamic assessment of quality of life assessment of persons with chronic pain. He has also been an investigator on studies of 1) disease management for chronic pain, 2) neuropsychological effects of long-term opioid use in chronic pain patients, 3) the association between psychopathology and placebo analgesia in patients with discogenic low back pain, 4) use of cannabinoids for chronic pain patients and 5) motivational compliance monitoring and substance abuse treatment for high risk chronic pain patients on opioid therapy. He has collaborated with many of the staff members in the Pain Management Center including Ed Ross, MD, Ed Michna, MD JD, David Janfaza, MD, Sanjeet Narang, MD, Srdjan Nedeljkovic, MD, Diane Palombi, RN, Ajay Wasan, MD, Robert Edwards, Ph.D. as well as colleagues from other academic and private institutions. Importance of Research Contributions: Dr. Jamison has been predominantly involved in clinical trials that have practical application for pain patients and their clinicians. His research efforts have been clinically based with direct applicability in the assessment and management of persons with chronic pain. He has gained recognition for his contribution in the creation of screening tools and software programs for use by busy practitioners. The universal acceptance of the Screener and Opioid Assessment for Patients with Pain - Revised(SOAPP-R) and the Current Opioid Misuse Measure (COMM) in pain management centers has added to his notoriety. He has also co-developed and validated the Interactive Computerized Quality of Life (ICQOL) and the Pain Electronic Calendar (PEC) programs. He recently co-edited a special issue of Pain Medicine entitled "Computer and Information Technology in the Assessment and Management of Patients with Pain" designed to inform clinicians of new modalities to advance the treatment of pain patients. Dr. Jamison is committed to remaining active in clinical studies with the goal of continuing to improve the overall quality and outcomes of pain management among persons with acute and chronic pain. Selected Publications: Butler SF, Budman SH, Fernandez KC, Houle B, Benoit C, Katz N, Jamison RN. Development and validation of the Current Opioid Misuse Measure. Pain 2007;130:144-156. Marceau L, Carolan S, Schuth B, Jamison RN. Pain diaries as a tool to improve pain management: is there any evidence? Pain Med 2007;S3:101-109. Wasan AD, Butler SF, Budman SH, Benoit C, Fernandez K, Jamison RN. Psychiatric history and psychological adjustment as risk factors for aberrant drug-related behavior among patients with chronic pain. Clin J Pain. 2007;23:307-315. Narang S, Gibson D, Wasan AD, Michna E, Ross EL, Nedeljkovic SS, Jamison RN. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain, 2008;9:254-264. Butler SF, Budman SH, Fernandez K, Benoit C, Jamison RN. Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain, 2008;9:360-372 . Ajay D. Wasan, M.D., M.Sc. Assistant Professor of Anesthesiology and Psychiatry, Brigham and Women's Hospital and Harvard Medical School Research Summary: The research of Dr. Wasan is centered on understanding the great variability in treatment response in patients with chronic pain, seen in most populations with chronic painful illnesses. There is little understanding of which patients respond best or least to various medications, nerve block procedures, or rehabilitation programs for chronic pain, such as chronic low back pain. His research focuses on whether comorbid psychiatric illness (a highly prevalent comorbidity) is an important predictor of pain treatment and a predictor of the neural patterns of brain activation associated with processing painful stimuli. He also has an interest in developing standardized measures (patient surveys and physical exams) to quantitatively describe the variability in symptoms and signs in patients with neuropathic pain. Quantitative sensory testing and functional MRI are important tools of physiological investigation Dr. Wasan incorporates into his studies. In his studies he often combines quantitative measures with qualitative research to provide a detailed description of the phenomena he studies. He has ongoing studies examining predictors of opioid analgesia, prescription opioid misuse, and nerve block response.He is also validating a method for standardized examinations in neuropathic pain.He has begun work using fMRI to describe neural activations patterns in the brain associated with chronic low back pain.His work is funded by NIH, industry, and private foundations. Selected Publications: Wasan AD, Davar G, Jamison RN. The Association between Negative Affect and Opioid Analgesia in Patients with Discogenic Low Back Pain, Pain, 2005: 117: 450-61 Michna E, Jamison RN, Pham LD, Ross EL, Janfaza D, Nedeljkovic SS, Narang SS, Palombi R, Wasan AD. Urine Toxicology Screening Among Chronic Pain Patients on Opioid Therapy: Frequency and Predictability of Abnormal Findings, Clin. J. Pain, 2007, 23(2): p.173-179 Wasan AD, Butler SF, Budman SH, Benoit C, Fernandez K, Jamison RN. Psychiatric History and Psychological Adjustment as Risk Factors for Aberrant Drug-Related Behavior among Patients with Chronic Pain, Clin J Pain, 2007 23 (4): p. 307-15. Wasan AD, Fernandez E, Pham LD, Jamison RN, and Bhattacharyya N. The association between anxiety, depression, and reported disease severity in chronic rhinosinusitis, Annals of Otology, Rhinology, and Laryngology, 2007: 116 (7): 491-7 Wasan AD, Taubenberger SP, Robinson WM. Reasons for Participation in Pain Research: Can they Indicate a Lack of Informed Consent? Pain Medicine, 2008 (accepted for publication) CLINICAL RESEARCH Angela Bader, M.D. My current academic interests lie in the area of assessment and quality improvement, focusing specifically on strategies for the optimization of patient outcomes with appropriate risk assessment as well as efficient resource use. During the past three years I completed an MPH at the Harvard School of Public Health (graduating in June 2006) with a specific concentration in health care management to be bettered prepared to answer these questions. We have developed a small research group within the division to work together to address these issues and directly implement appropriate practices in our presurgical area. Recently published studies include a report of problems identified in the preop clinic that can impact operating room efficiency and a needs analysis for implementation of perioperative beta blockade protocols. We also are completing studies addressing the following issues: identifying risk factors warranting the ordering of preoperative electrocardiograms versus routine screening; determination of a preoperative screen that will be predictive of patients at risk for postoperative delirium, analysis of operational flow processes within the preoperative clinic to determine best practice; impact of systems improvement on patient satisfaction, and predictive value of ECG in vascular patients. I have also recently completed two book chapters on perioperative assessment for the second edition of the Handbook of Preoperative Assessment and Management as well as onefor the newest edition of Miller's textbook of anesthesia. I believe our activities have made the preoperative area within the department of Anesthesia, Pain and Perioperative Medicine at BWH into a prominent benchmarking unit. In an effort to improve the quality of preoperative practice on a national and international level, members of this division (Drs. Angela Bader, David Hepner, and Darin Correll) together with a group of national and international experts in this area formed the Society for Perioperative Assessment and Quality Improvement (SPAQI).Drs. Bader, Hepner, and Correll serve respectively as the founding President, Vice President and Secretary/Treasurer. SPAQI was formed in 2006 as a nonprofit, international organization with the goal of bringing together a variety of professionals in various disciplines to work together on all facets influencing optimal surgical outcomes. These elements include proper preoperative assessment and evaluation; optimization of pre-surgical status, appropriate and efficient resource use; integration of proper planning for postoperative pain management and appropriate use of alternative and complementary medicine techniques. The group plans to share best practices, promote research, and provide a pathway for communication. The first annual meetings were held in conjunction with the Cleveland Clinic in fall of 2007 and 2008 with an attendance of over 250 at each. The meeting presented the most up to date practices and also contained a research session and discussion of best abstracts and posters.This is the first attempt to bring a group of experts in this area together in a society that could have a positive impact both in communicating practice and research internationally as well as improving the quality of care in this area. Simon Body, M.D. CABG Genomics Program The CABG Genomics Program is a two-institution study (Brigham and Women's Hospital and the Texas Heart Institute) of the genomic influences upon adverse cardiac and non-cardiac outcomes after coronary artery bypass graft (CABG) surgery. The CABG Genomics Program was established with Departmental support as part of an NIH K23 grant awarded to Dr. Simon Body. Since August, 2001 patients undergoing primary CABG surgery at both institutions have been enrolled and followed for occurrence of adverse postoperative events both in-hospital and up to 5 years after surgery. Patient blood is collected prior to and during the 5 days after surgery to allow for subsequent genotyping and measurement of circulating biomarkers. To date over 1800 patients have been enrolled in the study and initial genotyping has been conducted on over 1000 patients. Perioperative biomarker measurements relevant to heart failure, renal dysfunction, coagulation, and myocardial injury have been measured in over 1400 enrolled patients. Within the specialty of Anesthesiology we have long known of familial inheritance of malignant hyperpyrexia and succinylcholine apnea. Recently, we have learnt of the importance of inherited forms of the long QT syndrome and drug-induced sudden death.Even more recently, we are appreciating that the adverse events from procedures and surgery may have a genetic basis. Because of this, a group of individuals in the Department of Anesthesiology is examining whether postoperative outcomes after CABG surgery are associated with genetic variation. Specifically, the Program seeks to identify the relationships between genetic variation and major adverse cardiac events (MACE), bleeding and other outcomes after CABG surgery. The CABG Genomics Project co-investigators include Simon Body, MBChB, MPH, Stanton Shernan, MD, Amanda Fox, MD (Brigham and Women's Hospital), and Charles D. Collard, MD (Texas Heart Institute). Drs. Jochen Muehlschlegel and Tjorvi Perry are participating in the CABG Genomics study as postdoctoral research fellows and are presently enrolled in Harvard Medical School's two year Scholars in Clinical Science Masters Degree Program. The CABG Genomics research staff include Kutjim Bodinaku, MD, Jai Madan, MD, Jochen Daniel Meuhlschlegel, MD, Jim Gosnell, RN, and Svetlana Gorbatov, MPH. To date multiple research efforts have been conducted within the CABG Genomics Program. These efforts have been spearheaded by different primary research interests amongst the CABG Genomics investigators, but all projects have focused on associations between genetic variants, biomarkers, and adverse outcomes. Some of the recent research efforts conducted within the CABG Genomics project is described below: 1. We have demonstrated an association between a haplotype of the complement protein mannose binding lectin (MBL) and perioperative myocardial infarction. This finding was published by us in 2007 in Circulation. MBL is an important component of the innate immune system, and activator of the lectin complement pathway. MBL functions as a pattern recognition molecule that recognizes carbohydrate structures on microorganism surfaces (e.g., bacteria, fungi, and parasites) and innate molecules mimicking carbohydrate structures. MBL opsonization in turn leads to activation of the LCP via MBL-associated serine proteases. Several lines of evidence suggest that increased MBL levels may be an important regulator of cardiovascular injury. The associated we identified between an MBL haplotype and myocardial infarction may lead to perioperative therapies that manipulate the lectin complement pathway. We are presently looking at how variants of MBL and complement associate with one another and with myocardial injury after CABG. 2. We have identified C-reactive protein (CRP) gene variants associated with CRP concentrations after CABG surgery. 3. We have assessed variants that were recently identified in the 4q25 chromosomal region as associated with increased incidence of ambulatory atrial fibrillation and have found these variants to also predict increased incidence of atrial fibrillation after CABG surgery. The mechanism for this association has yet to be elucidated. 4. We are assessing the value of serum neutrophil gelatinase-associated lipocalin for use as an early marker of acute kidney injury after CABG surgery. 5. We have demonstrated that elevated preoperative levels of B-type natriuretic peptide (BNP) are associated with increased likelihood of ventricular dysfunction and mortality after CABG surgery. These findings are in press with the Journal of Thoracic and Cardiovascular Surgery. We are presently evaluating the value of postoperative BNP concentrations for perioperative risk stratification. We have also evaluated variants within multiple genes related to the natriuretic peptide system and have identified independent associations between these variants and both perioperative BNP concentrations and postoperative ventricular dysfunction. 6. We have conducted a pilot whole genome association study to provide an unbiased approach to identifying genetic variants potentially associated with increased incidence of ventricular dysfunction after CABG surgery. 7. We have demonstrated an association between a haplotype of thrombomodulin and the risk of bleeding after CABG surgery. Thrombomodulin is an integral membrane protein expressed on the surface of vascular endothelial cells that binds to thrombin and act as a cofactor in the activation of protein C. In that fashion it acts as an anticoagulant by inactivation of coagulation factors Va and VIIIa. In a contrary fashion, the thrombomodulin-thrombin complex also activates thrombin-activatable fibrinolysis inhibitor (TAFI), thus inhibiting fibrinolysis. 8. We have found that plasma heart-type fatty acid binding protein (hFABP), a small cytosolic protein in myocardium, is an early peaking independent postoperative predictor of death after CABG surgery. We have also showed that postoperatice cardiac troponin I concentrations predict increased mortality and hospital lengths of stay after primary CABG surgery while diagnosis of MI according to postoperative electrocardiograms does not. 9.We are looking at variations within multiple candidate genes for association with increased myocardial injury after CABG surgery. Selected Publications: Collard CD, Body SC, Shernan SK, Wang S, Mangano DT; Multicenter Study of Perioperative Ischemia (MCSPI) Research Group, Inc; Ischemia Research and Education Foundation (IREF) Investigators. Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg. 2006; 132(2):392-400. Hindler K, Eltzschig HK, Fox AA, Body SC, Shernan SK, Collard CD.Influence of statins on perioperative outcomes. J Cardiothorac and Vasc Anesth. 2006; 20: 251-258. Walsh MC, Shaffer LA, Guikema BJ, Body SC, Shernan SK, Fox AA, Collard CD, Fung M, Taylor RP, Stahl GL. Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. J Immunol Methods 2007;323(2):147-59. Collard CD, Shernan SK, Fox AA, Bernig T, Chanock SJ, Vaughn WK, Takahashi K, Ezekowitz AB, Jarolim P, Body SC. The MBL2 "LYQA Secretor" Haplotype is an Independent Predictor of Postoperative Myocardial Infarction in Caucasians Undergoing Coronary Artery Bypass Graft Surgery. Circulation 2007; 116(11 Suppl):I106-12. Body SC, Schwinn DA. Limitations of genetic findings that are not in Hardy-Weinberg equilibrium. Anesthesiology. 2008 Feb;108(2):338 Muehlschlegel JD, Body SC. Impact of genetic variation on perioperative bleeding. Am J Hematol. 2008 Christopher Connor, M.D. Ph.D. (Resident) My current research interests deal with the optimization of patient monitoring and of the delivery of anesthetic agents through improved modeling of the interactions between human physiology and the anesthetic milieu. In conjunction with Dr.Ferrigno, I study the narcotizing and toxic effects of high pressure gases with a view to palliating these effects during escape from a submarine disabled at depth. Connor, Gohil and Harrison, "Six-sigma Systolic Arterial Pressure Alarms", European Society of Anesthesia Annual Meeting, Copenhagen, Denmark, June 2008. Connor and Philip, "The Severinghaus square root of time relationship for anesthetic uptake and its implications for the stability of compartmental pharmacokinetics", Physiological Measurment 29(5):685-701. Harrison and Connor, "Statistics-based alarms from sequential physiological measurements", Anaesthesia 62(10): 1015-1023, October 2007. Connor, "TivaMan 1.5 - software for interactive pharmacological simulation", available online at http://www.mit.edu/~cwc/tivaman Connor and Ferrigno, "Estimates of the risk of Nitrogen Narcosis and CNS Oxygen Toxicity During DISSUB Escapes from 600 to 1,000 ft", 2007 Undersea Medicine Combined Progress Review of the US Navy, Mystic CT, July 2007. Massimo Ferrigno, M.D., F.C.C.M. Physiology Laboratory Human breath-hold diving: The study of the cardiovascular and respiratory changes occurring during breath-hold diving has some important bearing on anesthesia practice.As an example, understanding what happens in the human body during a prolonged breath hold can help us in the care of a patient with a "difficult airway", who is rendered apneic and cannot be ventilated with a mask or intubated. Equally interesting, and clinically relevant, is a better understanding of the chest-wall mechanics during breath-hold dives to great depths (at present, several divers have dived to more than 500 ft) or during breathing maneuvers (glossopharyngeal breathing maneuvers, both insufflation and exsufflation) used by these elite divers. Recently, the Physiology Laboratory has organized a multidisciplinary study of four of these exceptional divers in Boston, focusing on the respiratory and cardiovascular effects of glossopharyngeal breathing maneuvers,putting together a large team of investigators including scientists and clinicians from Brigham and Women's Hospital, Harvard School of Public Health, Beth Israel Deaconess Medical Center (all in Boston) and Karolinska University in Stockholm, Sweden. Several manuscripts have either been published or are under preparation (see Selected Publications below). Heat exchange in the respiratory system: At present, there is no practical and effective non-invasive method to cool/rewarm patients. In the last few years, Dr. Ferrigno has developed, together with Dr. Yandong Jiang (MGH),three new noninvasive methods (either already patented or in the process) to cool or rewarm patients using the respiratory system for heat exchange. Having worked as a commercial diver, Dr. Ferrigno was familiar with the large respiratory heat loss during saturation diving, therefore he thought of using the respiratory system for heat exchange. This approach to cool/rewarm patients using the respiratory system could become a valuable clinical tool, allowing either induction of protective hypothermia or rewarming from accidental hypothermia even in the pre-hospital arena, where paramedics frequently perform intubation. Through CIMIT (Center for Integration of Medicine and Innovative Technology) and other extramural funding (AGA Healthcare, Sweden; and Gas Enabled Medical Innovation - GEMI Fund), cooling and rewarming with a dense gas (SF6), with a dense mist and with a combination of the two have been tested in a large swine model; also, cooling using latent heat of evaporation has been studied. Results from these studies are being written up as manuscript for publication. Risk of nitrogen narcosis and oxygen toxicity during submarine escape: This study was requested by the US Navy to evaluate feasibility of escape from a disabled submarine at depths ranging from 600 ft (the present depth limit) to 1000 ft. Theoretical calculations of the risks of nitrogen narcosis and oxygen toxicity have been performed by Dr. Ferrigno and Dr. Christopher Connor (an Anesthesia Resident) and they have been already submitted as a US Navy report; they are also being written up in manuscript format. Physiological effects of NOSCAR surgery: This study, in collaboration with Dr. Thompson, a gastroenterologist at BWH, was funded by a consortium of companies interested in this novel approach, in which surgical procedures are performed using endoscopes inserted through natural orifices (either the mouth or the anus; thus, the name NOTES, Natural Orifice Transluminal Endoscopic Surgery) and then advanced into the peritoneal cavity, through either the stomach or the distal sigmoid wall. The hypothesis of this study was that this approach causes less physiologic stress to the body compared to traditional laparoscopic surgery. We just completed the animal experiments and we are analyzing the results (including postoperative inflammatory response, respiratory function, wound healing and pain) to see whether the inflammatory response, postoperative respiratory function, wound healing and pain after NOSCAR are different compared to the laparoscopic approach through the abdominal wall. Increase DISSUB crew survival by reverse diazepam sedation: This study, funded by NAVSEA, will be conducted in the Hermann Rahn Environmental Physiology Laboratory in Buffalo, NY, using human subjects. The hypothesis is that prolonged sedation with benzodiazepines will cause a reduction in carbon dioxide production, whose build-up is a major problem for crew survival in a disabled submarine.Dr. Ferrigno will function not only as an Investigator, but also as Medical Officer for these experiments. Selected Publications: Jacobson FL, Loring SH, Ferrigno M.Pneumomediastinum after lung packing.Undersea and Hyperbaric Medicine 2006; 33(5):313-316. Loring SH, O'Donnell CR, Butler JP, Lindholm P, Jacobson F, Ferrigno M.Respiratory mechanics during glossopharyngeal breathing in competitive breath-hold divers.J Appl Physiol 2007; 102:841-846. Melanson S, Szymanski T, Rogers S, Jarolim P, Frendl G, Rawn J, Cooper Z, Ferrigno M. Utilization of arterial blood gas measurements in a large tertiary care hospital. Amer J Clin Pathology. 2007; 127 (4):604-609. Novalija J, Lindholm P, Loring SH, Diaz E, Fox JA, Ferrigno M.Cardiovascular aspects of glossopharyngeal insufflation and exsufflation.Undersea and Hyperbaric Medicine 2007:34(6):415-423. Binks, Vovk A, Ferrigno M, Banzett RB.The air hunger response of four elite breath-hold divers.Respiratory, Physiology and Neurobiology 2007; 159:171-177. Patents: Ferrigno M, inventor; "Noninvasive Method for Increasing or Decreasing the Body Temperature of a Patient" .U.S. Department of Commerce Patent#6,303,156; 2001 Ferrigno M, Jiang Y, inventors; "Method for Altering the Body Temperature of a Patient Using a Nebulized Mist" .U.S. Department of Commerce Patent #7,201,163; 2007 Amanda A. Fox, M.D. Research Focus: Identification of Genetic Variants and Biomarkers Predictive of Ventricular Dysfunction and Related Adverse Outcomes after Cardiac Surgery I have conducted my recent research efforts as a co-investigator in the CABG Genomics Research Study (collaborative study of primary CABG patients enrolled at Brigham and Women's Hospital and the Texas Heart Institute). One of my main interests within the CABG Genomics Study has been to identify genetic variants and plasma biomarkers that are associated with postoperative heart failure and related morbidities. In relation to this interest my colleagues within CABG Genomics and I have focused on several areas of research: 1. We have assessed the value of plasma natriuretic peptide concentrations for predicting adverse events after primary CABG surgery. B-type natriuretic peptide (BNP) is released by myocardial cells in response to stretch and ischemia and is an established biomarker for predicting adverse events in ambulatory cardiac patients. With data derived from the CABG Genomics primary CABG cohort we have recently shown that increased preoperative BNP concentrations predict adverse events after CABG surgery independently of other accepted clinical predictors such as preoperative left ventricular ejection fraction or myocardial injury. We have a manuscript in press with the Journal of Thoracic and Cardiovascular Surgery that describes the ability of preoperative BNP concentrations to predict postoperative in-hospital ventricular dysfunction as well as up to 5 year postoperative mortality. In this manuscript also describe the added benefit of considering preoperative BNP in conjunction with commonly used cardiac surgical risk scoring systems (such as the Cleveland Clinic Score, Euroscore, and Parsonnet Score) for predicting 5 year postoperative mortality. We are presently assessing the value of postoperative BNP concentrations for predicting long-term outcomes after CABG surgery. 2. We have assessed the relationship between variations within 7 genes related to the natriuretic peptide system and both perioperative BNP concentrations and occurrence of postoperative ventricular dysfunction and myocardial injury after primary CABG surgery. We have identified unique genetic associations with each of these outcomes. An abstract reporting associations between variants within the natriuretic peptide genes and incidence of postoperative ventricular dysfunction was recently accepted for presentation at the October, 2008 Annual Meeting of the American Society of Anesthesiologists in Orlando, Florida. 3. We conducted a whole genome association pilot study funded by a Foundation for Anesthesia Education and Research Research Starter Grant as a method of providing an unbiased approach to identifying genetic regions likely to be associated with postoperative ventricular dysfunction. We are presently in the process of fine-mapping and validating associations identified by this pilot study within the larger CABG Genomics cohort. Selected Publications: Walsh MC, Shaffer LA, Guikema BJ, Body SC, Shernan SK, Fox AA, Collard CD, Fung M, Taylor RP, Stahl GL. Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. J Immunol Methods 2007;323(2):147-59. Collard CD, Shernan SK, Fox AA, Bernig T, Chanock SJ, Vaughn WK, Takahashi K, Ezekowitz AB, Jarolim P, Body SC. The MBL2 "LYQA Secretor" Haplotype is an Independent Predictor of Postoperative Myocardial Infarction in Caucasians Undergoing Coronary Artery Bypass Graft Surgery. Circulation 2007; 116(11 Suppl):I106-12. Hindler K, Eltzschig HK, Fox AA, Body SC, Shernan SK, Collard CD.Influence of statins on perioperative outcomes. J Cardiothorac and Vasc Anesth. 2006; 20: 251-258. Joseph M. Garfield, M.D. Research in Professionalism, Medical Education, Clinical Decision Making & Quality Improvement
Departmental Co-Investigators: Dr. Garfield's recent research activities have focused on professionalism. Our group just completed a study investigating how academic physicians in differing medical specialties view the attributes of a medical professional and its implications for training programs. This work has been submitted for publication. Future research directions include: Adherence to practice guidelines and the evolution of clinical decision making during residency training and as an attending physician The effects of fast and slow cognition on clinical decision making The effects of length of practice on professional values Assessment of decision making processes in selecting candidates for medical school admission and for residency training programs An evaluation of how departmental members view electronic instruments for reporting anesthesia complications in terms of compliance and comparison to previous non-electronic reporting methodologies Selected Publication: Garfield JM, Garfield FB et al.Academic physicians differ in their emphasis on professional attributes: Implications for training programs.Submitted for publication. Philip M. Hartigan, M.D. Thoracic Anesthesia Division Overview: Directions of inquiry in thoracic anesthesia at BWH have, to date, been largely aligned with those of thoracic surgery. Thoracic surgery at BWH is of a volume and complexity, which is largely unrivaled nationally or internationally, and as such provides a rich environment for clinical trials. There exists enviable collegial interdependence among the players, with a sense of coordinated forward progress against some of the most vexing problems in the field. Pleural Mesothelioma: BWH is an international magnet for patients with this asbestos-related cancer of the lining of the lung, which heretofore had been rapidly, and virtually uniformly fatal.Significant inroads and survival benefits are being achieved at BWH by the novel technique of intra-operative infusion of heated chemotherapy into the open chest cavity following surgical tumor debulking (extrapleural pneumonectomy or pleurectomy). This attempts to "mop up" residual cancer cells with higher chemo doses at the site of action than would be achievable by the toxicity-limited doses of systemic chemotherapy. While the concept is rightfully credited to the surgeons, many logistical hurdles of the initiative, including renal protection protocols, continue to evolve with the integral involvement of thoracic anesthesiologists. Lung-Volume Reduction Surgery (LVRS): End-stage emphysematous patients represent another desperate population due to the inadequacy of medical treatments and the insufficient availability of lung transplant donors. The strategy of LVRS is to surgically remove limited amounts of nonfunctional lung, providing room for improved expansion of remaining lung, and improved respiratory mechanics. Controversy swirled around this procedure because of the high perioperative risks of chest surgery in such respiratory cripples. BWH was an important center in the National Emphysema Treatment Trial (NETT), which ultimately established efficacy, and identified the appropriate subgroup in which the benefits outweighed the risks. The development of safe anesthetic techniques allowing for one-lung anesthesia and immediate extubation of such patients was integral to the success. Reviews on this topic, authored by this group, have been sought-after and well received. Bronchoscopic LVRS is an alternative, which attempts to collapse portions of the lung by bronchoscopically depositing bioactive reagents in targeted lung regions.Trials have recently been underway at BWH testing the safety and efficacy of this noninvasive approach. Spearheaded by a pulmonologist, this program evolved from collaboration with thoracic anesthesiologists and surgeons. Technical Aspects of Thoracic Anesthesia: The sheer surgical volume and considerable technical challenges of thoracic anesthesia at BWH have driven the development of certain innovations and techniques by thoracic anesthesiologists.A patent for a novel bronchial blocker is in process to improve the technique of lung isolation.Bronchoscopic examination (by anesthesiologists) of bronchial resection margins intra-operatively to help guide surgeons is underway with the hope of reducing the incidence of stump dehiscence and bronchopleural fistulae following pneumonectomy. Lung Transplantation:Collaboration is underway between thoracic anesthesiologists and surgeons to address the need for a means of improving the preservation of donor lungs, and for better evaluating the suitability of donor lungs for transplantation. Selected Publications: Ng J and Hartigan PM. Anesthetic strategies for patients undergoing extrapleural pneumonectomy for mesothelioma. Curr Opin Anesthesiol 2008, 21:21-27. Richards WG, Zellos L, Bueno R, Jaklitsch MT, Janne PA, Chirieac LR, Yeap BY, Dekkers RJ, Hartigan PM, Capalbo L, Sugarbaker DJ. Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.J Clin Oncol. 2006; 24(10):1561-7. Lee A. Kearse, Jr. M.D., Ph.D., MBA Dr. Kearse's research interests have concerned the use of neurophysiologic technologies for two purposes: (1) to prevent intra-operative neurological injury such as cerebral stroke or spinal cord damage to patients undergoing surgery in which those neural structures were put at direct risk; and (2) to determine features of electroencephalography capable of delineating stages of anesthesia coma as guides for intra-operative medical management. More recently, Dr. Kearse has begun a series of research projects in collaboration with the Departments of Radiology and Psychiatry, using magnetic resonance imaging (MRI) and quantitative EEG (qEEG) technologies. These projects include the following: (1) Functional magnetic resonance imaging (fMRI) Feedback for Stroke Rehabilitation; and (2) Modular Real-Time fMRI Neuro-Feedback and qEEG for Controlling Nicotine Cravings in Smokers. The former project has been submitted for RO1 NIH funding; and the latter has been submitted for R21 NIH funding. In the first study, patients are trained in the fMRI scanner to activate the motor brain area contralateral to the damaged, affected extremity in order to increase blood flow to the damaged brain. Under a rigid protocol conducted at Spaulding Rehabilitation Hospital, exact measurements detecting motor improvements in the extremity's strength are correlated with the extent of blood oxygen level dependent (BOLD) activation. In the second study, a similar process is used to activate specific subcortical neuronal centers associated with addictive behaviors in order to inhibit nicotine craving. Dr. Kearse is a co-investigator for both studies. Dr. Kearse is the principal investigator in the third project that has two phases. The first phase consists of Computer-Based Evaluation of Post-operative Cognitive Abilities. In this phase, eligible young and older subjects will take neuropsychological tests involving working memory and executive functions before and after surgery to assess any change in their processing speed and accuracy. The results of these tests will be used to determine the regions of interests to be evaluated in a second group of patients for the second phase who will undergo the same tests conducted during MRI imaging to assess mechanisms of brain function during the tests before and after surgery. Bhavani Shankar Kodali M.D. This period was mostly spent on the airway evaluation in pregnancy, evaluation of coagulation after termination of low molecular weight heparins. The most notable publication was on how the changes evolve in the upper airway anatomy in pregnant patients undergoing labor and delivery. This study was undertaken in two different study protocols. However, for the sake of publication, they were bonded together into one single publication as the two methods used in this study, though different, show similar end results. In a way the results compliment each other and thus reinforcing the findings. There are no prospective studies that evaluated airway changes during labor. The purpose of this study was to evaluate airway changes in women undergoing labor and delivery. METHODS: Two studies were undertaken to evaluate airway changes during labor. The first study used the conventional Samsoon modification of the Mallampati airway class. The airway was photographed at the onset and the end of labor. Women with class 4 airways were excluded from initial participation. In the second study, upper airway volumes were measured using acoustic reflectometry at the onset and the conclusion of labor. Acoustic reflectometry software computed the values for the components of upper airway, oral volume, and pharyngeal volume. RESULTS: In study 1 (n = 61), there was a significant increase in airway class from prelabor to postlabor (P < 0.001). The airway increased one grade higher in 20 (33%) and two grades higher in 3 (5%) after labor. At the end of labor, there were 8 parturients with airway class 4 (P < 0.01) and 30 parturients with airway class 3 or class 4 (P < 0.001). In study 2 (n = 21), there were significant decreases in oral volume (n = 21; P < 0.05), and pharyngeal area (P < 0.05) and volume (P < 0.001) after labor and delivery. No correlation was observed between airway changes during labor and duration of labor, or fluids administered during labor in either study. CONCLUSION: Airways can change during labor. Therefore, a careful airway evaluation is essential just before administering anesthesia during labor rather than obtaining this information from prelabor data. There is increasing number of patients coming to labor and delivery who are on low molecular weight heparins. There is substantial controversy on the safe interval following the last dose of low molecular weight heparins when epidurals can be placed for labor analgesia. We used Thromboelastography studies to determine the status of coagulation with varying levels of heparin added to the blood samples in-vitro. This study was awarded Gerrtie Marx research competition award to one of our residents. The purpose of this study is to determine if Anti Xa level estimation is reliable in assessing the declining levels of low molecular weight heparins. Thromboelastography is also being used in another ongoing study to determine the coagulation status of the blood that is injected into the epidural space to treat postpartum headaches. In another ongoing study, we are evaluating the physiological dead space changes that are likely to occur during aortic cross clamping in patients undergoing aortic aneurysm surgery. A Respironics cardiac output monitor is being used for this purpose that determines cardiac output noninvasively from carbon dioxide output. Selected Publications: Felbinger TW, Posner, M, Eltzschig HK, Kodali BS. Laparoscopic splenectomy in a pregnant patient with immune thrombocytopenic purpura. International J Obst Anesth. 2007; 16:281-3. O'Rourke N, McElrath T, Baum R, Camann W, Tuomala R, Stuebe A, Kodali BS. Cesarean delivery in the interventional radiology suite: A novel approach to obstetric hemostasis. Anesth Analg. 2007; 104(5)1193-4. Kodali BS, Chandrasekhar S, Bulich L, Topulos G, Datta S. Airway changes during labor. Anesth. 2008;108(3):57-62. Harnett M, Kodali BS. Thromboelastography assessment of coagulation status in patients with lupus anticoagulant receiving heparin therapy. Int J Obstet Anaesth. 2006; 15(2):177-8. Srinivasa V, Kodali BS. Caution when using colorimetry to confirm endotracheal intubation. Anesth Analag. 2007; 104(3):738-9. Srinivasa V, Kodali BS. Video on orotracheal intubation. N Engl J Med. 2007; 357(6):620. K. Annette Mizuguchi, M.D., Ph.D. Acute renal failure necessitating renal replacement therapy is a serious complication following cardiopulmonary bypass and is associated with high morbidity and mortality. Therefore, as a cardiac anesthesiologist I am interested in focusing my academic career on developing prevention and treatment strategies for acute kidney injury (AKI).I have, chosen to work with Joseph Bonventre MD, PhD, BWH Renal Division, former Co-Director of Harvard-MIT Science Technology Program, as my senior mentor and Gyorgy Frendl, MD, PhD, Director of STAR (Surgical ICU Translational Research) Center and Susrut Waikar, MD, MPH, BWH Renal Division as my co-mentors on a collaborative project where the main goal of my project is to identify early biomarkers for AKI and to develop kidney protection strategies from injurious effects of cardiopulmonary bypass (CPB). My ultimate goal is to develop into an independent clinical researcher. Although I have formal training in basic science research, my main interest is clinical. I believe that physicians in academia are in the optimal position to do translational and clinical research because they can act as a bridge between basic science and clinical medicine. However, I also believe that it is important to have a sound fund of knowledge to guide me through clinical and translational research projects. I have been accepted into the Scholars for Clinical Science Program to start July 1, 2008. Currently I do not have any publications to report regarding my research but we are working on several projects and hope to have a few publications this year. Jochen Daniel Muehlschlegel, M.D. Dr. Jochen Daniel Muehlschlegel is currently a first-year scholar in the Scholars in Clinical Science Program at Harvard Medical School and mentee of Dr. Simon Body in the CABG Genomics Program. He is working on three projects. Genetic variation in the Platelet Receptor and functional analysis First, Dr. Muehlschlegel is examining the effect of genetic variation in platelet receptors upon the frequency of perioperative myocardial infarction (PMI) after primary CABG surgery. A complete haplotype-based analysis of the platelet receptor genome was performed and from this analysis, a significant and novel association between variants of the PAR4 receptor (gene abbreviation F2RL3) and peak postoperative levels of cTnI was observed, even after adjusting for important clinical predictors of myocardial injury. The protease-activated receptors (PAR)-1 and 4 are thrombin-activated receptors on the platelet and endothelial cell surface, responsible for platelet and endothelial activation, contributing to both normal hemostasis and disease states such as coronary thrombosis and atherosclerosis. The important role of PAR receptors in platelet-mediated thrombosis and vascular endothelial function is a vital area of research. Dr. Muehlschlegel's aim in year two of his Bayer Fellowship in Blood Conservation Grant and in year one of the SCA Starter Grant is to establish the functional role of PAR4 gene polymorphisms upon platelet PAR4 receptor expression and thrombin-mediated platelet activation. Definition of Perioperative Myocardial Infarction Second, Dr. Muehlschlegel has been working on developing a clinical prediction model of PMI. Biochemical definitions derived in ambulatory populations are not relevant to perioperative populations. Cardiac enzyme release associated directly with myocardial ischemia and reperfusion injury may be obscured by measurable enzyme release due to inherent surgical trauma. Furthermore, ECG definitions of MI derived from ambulatory populations have low specificity in cardiac surgical populations who are subjected to a pericardiotomy and often experience a variety of postoperative dysrhythmias. Heart-type fatty acid binding protein and myocardial injury Lastly, Dr. Muehlschlegel is examining a relatively new biomarker of myocardial injury. Heart-type fatty acid binding protein (hFABP) is a small cytosolic protein abundantly present in the myocardium that is the key carrier of the fatty acid carrier proteins. It is released into the circulation in the early phase of myocardial injury. Previous studies in the ambulatory setting have associated hFABP with an increased risk of death and major cardiac events. Its prognostic utility in the cardiac surgical population has not been established. The CABG Genomics group has been able to show that hFABP is an earlier marker of myocardial injury, and an independent predictor of death and hospital length of stay after coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). Selected Publications Abstract selected for Expert Review of Best Abstracts at the 30th Annual Meeting of the Society of Cardiovascular Anesthesia, Vancouver, BC. Muehlschlegel JD, Perry TE, Fox AA, Collard CD, Liu KY, Shernan SK, Body SC. Heart-Type Fatty Acid Binding Protein is an Early-Peaking and Independent Predictor of Death after Coronary Artery Bypass Graft Surgery. Anesth Analg. 2008; 106 (SCA Suppl): 24 Muehlschlegel JD, Body SC, Genetic Causes of Perioperative Bleeding, Am J Hematol, 2008, Sep;83(9):732-7. Perry TE*, Muehlschlegel JD*, Body SC, Genomics: risk and outcomes in cardiac surgery, Cardiac Anesthesia: Today and Tomorrow, Anesthesiology Clinics 2008 Sep;26(3):399-417. (*both authors contributed equally to the work) Platform presentation at the AHA Scientific Sessions 2008, Nov. 8-12, 2008, New Orleans, LA. Muehlschlegel JD, Liu KY, Perry TE, Fox AA, Collard CD, Body SC, Shernan SK. Variants in CDKN associated with Perioperative Myocardial Injury after Cardiac Surgery. Tjorvi E Perry, M.D. Tjorvi E Perry, MD holds a postgraduate position with Dr. Simon C Body, MBChB, MPH. Dr. Perry is examining the effects of inflammatory mediators on adverse postoperative outcomes following adult cardiac surgery with cardiopulmonary bypass. Concurrently, Dr. Perry is in the second of 2 years of his Masters of Science degree at the Harvard School of Public Health and Harvard Medical School. Dr. Perry's most recent work has includes the following: Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury after adult cardiac surgery. Acute kidney injury following cardiac surgery is associated with significant morbidity and mortality. Traditional markers of kidney injury, namely serum creatinine, do not increase until late in the postoperative period. The thrust of recent investigation has been to identify early markers of kidney injury after cardiac surgery. We demonstrated serum NGAL to be predictive of postoperative kidney injury and extended hospital length of stay, but because serum NGAL is elevated in the majority of patients immediately after separating from cardiopulmonary bypass, it is a non-specific marker. We foresee that serum NGAL might be useful in anuric patients where measuring urinary NGAL is not an option, or as part of a panel of markers of postoperative kidney injury. C-reactive protein (CRP) gene variants are associated with altered postoperative CRP levels following cardiac surgery. Baseline CRP level is a well-recognized risk factor for developing cardiovascular-associated disease in the non-surgical population. Recently, CRP gene variants have been shown to be associated with baseline CRP levels in this same population. We explored the influence of CRP gene variants on postoperative CRP levels following cardiac surgery, and found that, after accounting for clinical covariates of interest and multiple comparisons, the rs1800947 polymorphism was significantly associated with lower postoperative CRP levels. This work validates in a novel cohort of cardiac surgical patients, what has been described in the ambulatory population. The results of this study will contribute to our efforts of disease pathway discovery and patients risk stratification. Future work will focus on the influence of complement gene variants on both complement system activation, and adverse outcomes following cardiac surgery.
Beverly K. Philip, M.D. The goals of anesthesia for ambulatory surgery are to provide control of surgical stimuli and a patient-chosen level of consciousness during the procedure, followed by rapid recovery with minimal side effects, so that the patient can return to normal function as soon as possible. In order to identify the most appropriate drugs for ambulatory anesthesia practice, we study the use of drugs currently available and drugs under development. Agents under investigation have included sedatives, analgesics, inhalants, and antiemetics. We study hemodynamic and respiratory responses to the drugs during anesthesia and in the early postoperative period, subjective and objective measures of psychomotor recovery, nausea/vomiting and patient satisfaction with anesthetic techniques. We evaluate the use of these drugs in a range of applications for general anesthesia and sedation, such as inhalation anesthesia, intravenous bolus administration and administration by continuous infusion. Related projects include studies in the pharmacokinetics of these drugs in ambulatory surgical patients. Ambulatory Anesthesia research also addresses Patient Outcomes, and Leadership and Management. Topic areas in this field include leadership, negotiation, management/business, efficiency, and quality improvement. This research program encompasses single-site to multi-national, commercially sponsored projects. We utilize the active ambulatory surgery service in the Day Surgery Unit and operating rooms, with involvement from the Anesthesia Bioengineering Group. Members of the Ambulatory Research Team include Drs. Richard Urman, Robert Knapp, Naila Moghul, James Philip and McCallum Hoyt, and James Gosnell, RN. Selected Publications: Diemunsch P, Gan TJ, Philip BK, et al. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind Phase III trial in patients undergoing open abdominal surgery. BJA Advance Access May 30, 2007; 99: 202-11. Diemunsch P, Apfel C, Gan TJ, Candiotti K, Philip BK et al. Preventing postoperative nausea and vomiting: post hoc analysis of pooled data from two randomized active-controlled trails of aprepitant. CMRO 2007; 23: 2559-65. Gan TJ, et al. [Philip BK, consensus panel member]. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting.Anesth Analg 2007; 105 :1615-28. James H. Philip, M.E.E. , M.D. , C.C.E. Bioengineering Laboratory
Present members:
Recent Elective Residents: Goal, Objectives, and History The goal of the Brigham and Women's hospital (BWH) Anesthesia Bioengineering Laboratory is to increase effectiveness and decrease cost of anesthesia care by effectively and appropriately applying engineering principles. There are several major areas of ongoing research in the BWH Bioengineering Laboratory. These include basic science research, device definition and development, and testing. Specific areas include Fluid Infusion, Inhalation Anesthesia Administration, and Patient Monitoring. In each area, techniques and devices have been and continue to be developed while clinical practice reaps the benefits on a daily basis. There is close collaboration among a multi-disciplinary group of clinicians, scientists, and engineers. The BWH operating rooms are equipped with numerous devices to facilitate quantitative patient care and study. Numerous publications and products have emerged from this environment. Other projects not listed include various diagnostic, monitoring, and therapeutic devices. Fluid infusion into veins and tissues Research involves the physics and physiology of fluid infusion into veins (IV therapy) and other tissues (nerve blocks, etc.). Mathematical models predict system behavior under different clinical conditions. Techniques for detecting intravenous and other fluid infusion administration problems are in progress. One Patent submitted and two Abstracts published in the past year describe a self-contained hydraulic impedance measurement system. Computer assisted inhalation drug administration A computer simulation and textbook, GAS MAN¨Understanding Anesthesia Uptake and Distribution, has been developed and published. A nonprofit corporation, Med Man Simulations Inc. has been formed as a distribution channel for this educational tool. The Laboratory is closely affiliated with this nonprofit corporation. Gas Man teaches the pharmacokinetics of inhalation anesthesia from several different perspectives. It utilizes computer simulation and graphics to produce a learning environment that serves as an anesthesia administration laboratory. Learners develop mental models that help them create effective drug administration profiles. Computer-designed drug administration profiles are applied and tested every day in clinical practice. All BWH operating rooms have multi-channel gas monitors capable of testing hypotheses generated with the computer simulation. Anesthetic techniques such as closed circuit liquid injection are often employed using the models and the measurement. Control of anesthetic depth assisted by CO2 administration A dominant parameter limiting inhalation anesthetic control is ventilation. Addition of CO2 to inspired gas allows increased breathing (hyperpnea) to be accomplished without excessive CO2 elimination (eucapnea). The theory and application of eucapnic hyperpnea led our colleagues at another university (University of Utah) to develop a CO2-rebreathing, Anesthetic-agent-scrubbing adapter to facility emergence from anesthesia. We will study this device in the next year. Patient monitoring A Calculus of Monitoring has been developed, published, and is being utilized in research and clinical practice. This was accomplished by merging clinical practice and physiology with system modeling, mathematics, and human factors engineering. This research area will define and implement monitoring systems to optimize short and long term outcome measures. Several commercial products resulted from this undertaking. The first product, LifewatchTM, provided a continuous qualitative C02 waveform incorporated in the Perkin Elmer and Marquette multiplexed mass spectrometer system. Alert Zones, implemented in PPG SARA, Datascope Multinex, and Ohmeda Central Display Anesthesia Monitor alert clinicians to clinically significant patient changes which occur long before an alarm should sound Brain monitoring during anesthesia As part of our Patient monitoring work, we identified the need for a better monitor of brain function during anesthesia. To that end, we created a technique whereby any existing brain monitor (EBM) can be used to monitor the response to repetitive stimuli that are capable of eliciting a response from an unanesthetized brain. The relationship between the EBM response and the stimulus is the new brain monitor (NBM). A patent was issued on this invention in 2005. Anesthesia clinical technology resident and fellow training In this clinical rotation, anesthesiology residents and fellows are taught to apply quantitative techniques to monitor and manage clinical anesthesia. Research is merged with clinical practice. They are brought into the Bioengineering Laboratory to test hypotheses they develop. Selected Publications: Kaimal AS, Philip JH, Greenberg JA.How Much Pressure Does a Pressure Dressing Press?A Pilot Study Quantifying the effects of a pressure Dressing on the Post-Cesarean Section Incision.Wounds 2006;18:51-53. Connor CW, Philip JH.The Severinghaus Square Root of Time Relationship for Anesthetic Uptake and its Implications for the Stability of Compartmental Pharmacokinetics.Physiol. Meas. 2008;29:685-701.
Christine N. Sang, M.D., M.P.H. Our clinical translational laboratory systematically evaluates novel potential analgesics in human subjects and patients to target selective mechanisms of pain and establish dose‑responses for analgesia, and to identify appropriate indications and optimize the clinical doses used later in drug development. Our long-range goal is to improve the medical management of patients with chronic refractory pain states, such as that following peripheral nerve or spinal cord damage resulting from tumors, vascular lesions, inflammation, and traumatic events. Our studies fall within two broad categories: Neuropharmacology of central and peripheral neuropathic pain states: Clinical development of novel compounds and new drug delivery systems in Phases Ia/First-in-Man to II using novel trial designs and analyses, in various experimental and clinical neuropathic pain states. Development of biomarkers and surrogate endpoints in patients with central neuropathic pain following spinal cord injury: Advancing new clinical trial methodologies (in Phases I and IIa) and discovery of potential biomarkers to assess mechanisms in experimental and chronic peripheral and central neuropathic pain and development and validation of noninvasive sensory tools as clinical biomarkers in analgesic clinical trials.
Staff of Translational Research Program Selected Publication:
Campen RB, Sang CN, Duncan LM. A 41-year-old woman with painful subcutaneous nodules. N Engl J Med 355:714-722, 2006. Lawrence Tsen, M.D. Research in Obstetric Anesthesia My research interests are centered within obstetric anesthesia and perioperative medicine, and are primarily clinical, although some of our work is almost entirely lab based. For patients undergoing assisted reproductive technologies, our group has focused on improving the quality and safety of anesthetic options on reproductive outcomes; more specifically, we are just beginning to explore the impact of intravenous anesthetic agents on meiosis and mitosis. Some of our successes to date have enabled drug substitutions or dose reductions for oocyte retrieval processes and have become the standard of practice at a number of institutions. For parturients undergoing labor and delivery, our focus is on augmenting pharmacologic and non-pharmacologic alternatives to the regimens currently in use and understanding the mechanisms of intended and non-intended anesthetic effects. One of our landmark papers demonstrated the salutary effects of combined spinal epidural techniques on the progress of labor. Currently, we are investigating the proteomic expression of preeclampsia in spinal fluid and mechanisms by which epidural analgesia has an effect on maternal temperature. Finally, in terms of preoperative assessment, our group has focused on improving algorithms for perioperative care and practitioner education. My current work focuses on improving labor analgesia (including the novel Dural Puncture Epidural Technique), and evaluating the effect of anesthetics on oocytes, embryos and fetuses. Selected Publications: Panni MK, Camann WR, Tsen LC.Resident training in obstetric anesthesia in the United States. Int J Obstet Anesth. 2006;15:284-9. Tsen LC, Hepner DL.History of Spinal Needles.Expert Review of Medical Devices.2006 Jul; 3(4):499-508. Practice Guidelines for Obstetric Anesthesia:An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia:Anesthesiology 2007;106 (4):843-63. Tsen LC. Neuraxial techniques for labor analgesia should be placed in the lateral position.Int J Obstet Anesth 2008; 17(2):146-9. Egan B, Racowsky C, Hornstein MD, Martin R, Tsen LC. Anesthetic Impact of Body Mass Index in Patients Undergoing Assisted Reproductive Technologies. J Clin Anesth 2008 (In Press). Cappiello E, O'Rourke N, Segal S, Tsen LC.Randomized trial of dural puncture epidural technique compared to standard epidural technique for labor analgesia.Anesth Analg 2008 (In Press). REGIONAL AND ORTHOPEDIC ANESTHESIA Kamen V Vlassakov, M.D. Overview: Research, innovation and advanced training in regional anesthesia at the BWH have been historically aligned with the clinical practice of the orthopedic anesthesia group. Orthopedic surgery at BWH provides the volume, complexity and diversity of cases, necessary for clinical trials and training. In addition, our regional anesthesia experts are available for consultation, direct help and teaching in the other sectors, whenever the need for advanced peripheral nerve block techniques arises. Orthopedic Trauma and Geriatric Surgery: The multitude of trauma and geriatric orthopedic cases that are inherent to our field, in combination with the frequent option to avoid general anesthesia, provide a great potential for studying the effects of inhalation agents, pathophysiological stress, trauma and inflammation on the aging brain, in particular. Collaboration with the Laboratory for Aging Neuroscience (Drs. Crosby and Culley) is established and clinical trials are being planned. Orthopedic Oncology:Orthopedic anesthesiologists, acute postoperative pain service and orthopedic oncology surgeons are collaborating to improve preemptive pain management and phantom-limb pain prevention. Regional Anesthesia and Pain Management: Anesthesiologists from both the Regional/Orthopedic Anesthesia and Chronic/Oncology Pain teams (Drs. Vlassakov, Janfaza, Narang) are collaborating in treating extremely complex cases of intractable cancer pain with palliative nerve/plexus blocks – some of these blocks have become safely feasible only after the introduction of ultrasound guidance into our regional anesthesia practice. In addition, first clinical trials are planned/being developed with the research group of Dr. Gerner, to test drugs and combinations of drugs for producing differentially prolonged sensory block and pain relief. Closer cooperation in this regard with the Pain Clinic (Drs. Ross and Edwards) is being established. A personal ambition of mine as director of our division is to provide the logistic basis for building a strong and productive working relationship between our experimental researchers and our daily clinical practice through relevant clinical research. Technical Aspects of Regional Anesthesia: The complexity of some orthopedic cases and their specific challenges has inspired innovations and modifications of existing techniques by our anesthesiologists. This year, a new modified ultrasound-guided brachial plexus block has been introduced by Drs. Vlassakov and Janfaza. It offers an alternative approach when patient anatomy and/or function are significantly altered by disease or injury. Regional Anesthesia Education: Finally, our group has always focused on improving algorithms for regional anesthesia education and training. Our current work focuses on improving regional anesthesia learning process, in particular, when ultrasound guidance is used. Developing a combined simulation and clinical practice based teaching curriculum is under way in collaboration with the new BWH STRATUS center. Selected Publications: "Ultrasound-Guided Retroclavicular Approach to the Brachial Plexus Cords" Vlassakov K, Janfaza D. ASRA Annual Meeting - May 1, 2008, Playa del Carmen, Mexico  A picture of an ulltrasound guided retroclavicular brachial plexus block. MaxwellWeinmann, M.D. Principal Investigator Active Projects: Natriuretic Peptides and Acute Renal Failure The project is in collaboration with the Depts of Surgery and Nephrology, using an animal model to evaluate the Urodilatin response in acute renal ischemia. Present evidence implicates Urodilatin in renal vascular regulation, which is a first. Also, that Urodilatin is a potential biomarker of ischemic renal injury (paper presented at the American Clinical Pharmacology Meeting 2008). Part 2 of this project consists of assessing the effects of ultra low dose regimens of IV BNP on renal recovery and endogenous Urodilatin secretion. Part 3 consists of re examining dose response relationship between renal function and IV BNP in ischemic rat model. Heat Shock Protein response to ischemic renal injury in animal model.Research is active and in collaboration with the Department of Surgery. Chemiluminescent Medical Devices: This uses chemiluminescent technology to develop and test new medical devices from laryngoscopes, through to endotracheal tubes.Prototypes of the laryngoscopes are currently in production with Cyalume Inc, MA. The next phase is testing in a simulator lab and humans. Pending/Applied for: Near Infra Red Spectroscopy (NIRS) NIRS uses light wavelengths which penetrate deeply into tissue and allow measurement of O2 tension in cytochromes. This therefore provides real time metabolic mapping of cellular O2 dynamics.The models developed are both animal and human in the following settings: i) Prediction of renal graft function using NIRS at time of engraftment (human).Evaluation of organ perfusion and O2 dynamics in an animal model of hemorrhagic shock. This also includes an interventional arm, using various pressor agents, etc. a)Evaluation of organ perfusion and O2 dynamics during coronary artery bypass (humans) b)Cerebral O2 Dynamics following acute ischemic injury (humans) ii) The application of xigris in non septic inflammatory conditions in an animal model of decompression sickness. Selected Publications: Hutchens M, Weinmann M.Renal protection with recombinant B-type natriuretic peptide in a burn patient with rhabdomyolysis. Burns.2006, 32:128-131. Hutchens M, Weinmann M. Use Of Recombinant B-Type Natriuretic Peptide In A Patient With Severe Sepsis: Renoprotective?. The Internet Journal of Emergency and Intensive Care Medicine. 2007. Volume 10 Number 2. Weinmann M. Evidenced Based Weaning from Mechanical Ventilation. In , Essential Clinical Anesthesia, publisher - Cambridge University press, ed. Charles A. Vacanti, M.D. and Scott Segal, Scheduled for publication 2008. Weinmann M. Congestive cardiac failure in the Intensive Care Unit. In, Essential Clinical Anesthesia, publisher - Cambridge University press, ed. Charles A. Vacanti, M.D. and Scott Segal, Scheduled for publication 2008. Weinmann M. Septic shock and sepsis syndromes. In, Essential Clinical Anesthesia, publisher - Cambridge University press, ed. Charles A. Vacanti, M.D. and Scott Segal, Scheduled for publication 2008. RESEARCH PUBLICATIONS OF THE DEPARTMENT OF ANESTHESIOLOGY, PERIOPERATIVE AND PAIN MEDICINE: 2006-2008 CLINICAL RESEARCH PUBLICATIONS FOR 2006 Akbik H, Butler SF, Budman SH, Fernandez K, Katz NP, Jamison RN. Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP). J Pain Symptom Manage 2006;32:287-93. Collard CD, Body SC, Shernan SK, Wang S, Mangano DT; Multicenter Study of Perioperative Ischemia (MCSPI) Research Group, Inc; Ischemia Research and Education Foundation (IREF) Investigators. Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2006; 132:392-400. Correll DJ, Bader AM, Hull MW, Hsu C, Tsen LC, Hepner DL. Value of preoperative clinic visits in identifying issues with potential impact on operating room efficiency. Anesthesiology 2006; 105:1254-9. Foyouzi N, Norwitz ER, Tsen LC, Buhimschi CS, Buhimschi IA. Placental growth factor in the cerebrospinal fluid of women with preeclampsia. Int J Gynaecol Obstet 2006; 92:32-7. Harnett MJ, Carabuena JM, Tsen LC, Kodali BS. Anesthesia for interventional radiology in parturients at risk of major hemorrhage at cesarean section delivery. Anesth Analg 2006; 103:1329-30. Harnett M and Kodali BS. Thromboelastography assessment of coagulation status in patients with lupus anticoagulant receiving heparin therapy. Int J Obstet Anaesth 2006; 15:177-8. Hindler K, Eltzschig HK, Fox AA, Body SC, Shernan SK, Collard CD.Influence of statins on perioperative outcomes. J Cardiothorac and Vasc Anesth 2006; 20: 251-8. Jacobson FL, Loring SH, Ferrigno M. Pneumomediastinum after lung packing.Undersea and Hyperbaric Medicine 2006; 33:313-6. Jamison RN, Raymond SA, Slawsby EA, McHugo GJ, Baird JC. Pain assessment in patients with low back pain: comparison of weekly recall and momentary assessment of pain.J Pain 2006;7:192-9. Kaimal AS, Philip JH, Greenberg JA.How much pressure does a pressure dressing press?A pilot study quantifying the effects of a pressure dressing on the post-cesarean section incision.Wounds 2006;18:51-3. O'Rourke N, Lee C, Kodali BS, Harnett M. Thromboelastographic monitoring of the efficacy of recombinant factor VIIa administration in a parturient with factor VII deficiency. Can J Anaesth 2006; 53:528-9. Panni MK, Camann WR, Tsen LC.Resident training in obstetric anesthesia in the United States. Int J Obstet Anesth 2006;15:284-9. Richards WG, Zellos L, Bueno R, Jaklitsch MT, Janne PA, Chirieac LR, Yeap BY, Dekkers RJ, Hartigan PM, Capalbo L, Sugarbaker DJ. Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.J Clin Oncol 2006; 24:1561-7. Tsen LC and Hepner DL.History of spinal needles.Expert Review of Medical Devices2006; 3:499-508. Wasan AD, Kaptchuk TJ, Davar G, Jamison RN. The association between psychopathology and placebo analgesia in patients with discogenic low back pain. Pain Med 2006;7:217-28. LABORATORY RESEARCH PUBLICATIONS FOR 2006 Amaya F, Shimosato G, Kawasaki Y, Hashimoto S, Tanaka Y, Ji RR, Tanaka M. Induction of CB(1) cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB(1) agonist. Pain 2006; 124:175-83. Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 2006; 7 (Supplement 3): S1-S29. Anversa P, Kajstura J, Leri A, Bolli R. Life and death of cardiac stem cells: a paradigm shift. Circulation 2006;113:1451-63. Anversa P, Leri A, Kajstura J. Cardiac regeneration. J Am Coll Cardiol 2006; 47:1769-76. Arita M, Oh SF, Chonan T, Hong S, Elangovan S, Sun Y-P, Uddin J, Petasis NA, Serhan CN. Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J Biol Chem. 2006; 281:22847-54 (Epub June 6). Ariel A, Fredman G, Sun Y-P, Kantarci A, Van Dyke TE, Luster AD, Serhan CN. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution via modulation of CCR5 expression. Nat Immunol 2006; 7:1209-16 (doi 10.1038/ni1392; Epub October 1). Beloeil H, Ji RR, Berde CB. Effects of bupivacaine and tetrodotoxin on carrageenan-induced hind paw inflammation in rats (Part 2): cytokines and p38 mitogen-activated protein kinases in dorsal root ganglia and spinal cord. Anesthesiology 2006; 105:139-45. Balonov K, Khodorova A, Strichartz GR. Tactile allodynia initiated by local subcutaneous endothelin-1 is prolonged by activation of TRPV-1 receptors. Exp Biol Med 2006; 231:1165-70. Ceonzo K, Gaynor A, Shaffer L, Kojima K, Vacanti CA, Stahl GL. Polyglycolic acid-induced inflammation:Role of hydrolysis and resulting complement activation.Tissue Engineering 2006; 12:301-8. Chiang N, Hurwitz S, Ridker PM, Serhan CN. Aspirin has a gender-dependent impact on anti-inflammatory 15-epi-lipoxin A4 formation: a randomized human trial. Arterioscler Thromb Vasc Biol 2006; 26:14-7 (Epub November 17). Chiang N and Serhan CN. Cell-cell interaction in the transcellular biosynthesis of novel omega-3-derived lipid mediators. In: Colgan SP, ed. Cell-Cell Interactions: Methods and Protocols. Totowa, NJ: Humana, 2006:227-50 (Methods in Molecular Biology, Walker JM, ed., vol. 341). Chiang N and Serhan CN. New mechanism for an old drug: aspirin triggers anti-inflammatory lipid mediators with gender implications. Compr Ther. 2006; 32:150-7. Chiang N, Serhan CN, Dahl S-E, Drazen JM, Hay DWP, Rovati GE, Shimizu T, Yokomizo T, Brink C. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev. 2006; 58:463-87. Clish CB, Serhan CN. Lipidomic analysis of plasma and tissues: lipid-derived mediators of inflammation and markers of disease. In: Burczynski ME, Rockett JC, eds. Surrogate Tissue Analysis: Genomic, Proteomic and Metabolomic Approaches. Boca Raton, FL: Taylor & Francis, 2006:185-202. Costa C, Zhao L, Shen Y, Su X, Hao L, Colgan SP, Stahl GL, Zhou T, Wang Y. Role of complement component C5 in cerebral ischemia/reperfusion injury. Brain Research 2006; 1100:142-51 Culley DJ, Yukhananov RY, Crosby G. General anesthesia does not reduce life expectancy in aged rats. Anesth Analg. 2006 Mar;102(3):956-9. Davis ME, Hsieh PCH, Takahashi T, Song Q, Zhang S, Kamm RD, Grodzinsky AJ, Anversa P, Lee RT. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc Natl Acad Sci USA. 103:8155-8160, 2006. Dawn B, Guo Y, Rezazadeh A, Huang Y, Stein A,B, Hunt G, Tiwari S, Varma J, Gu Y, Prabhu SC, Kajstura J, Anversa P, Ilstad ST, Bolli R. Postinfarct cytokine therapy regenerates cardiac tissue and improves left ventricular function. Circ Res. 98:1098-1105, 2006. Duffield JS, Hong S, Vaidya V, Lu Y, Fredman G, Serhan CN, Bonventre JV. Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol. 2006; 177:5902-11. Edwards, R, Haythornthwaite, J, Max, M, Tella, P, Raja, S. (2006). Basal heat pain thresholds predict opioid analgesia in patients with post-herpetic neuralgia. Anesthesiology, 104:1243-8. Edwards, R, Smith, M, Kudel, I, Haythornthwaite, J. (2006). Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain, 126:272-9. Edwards, R, Smith, M, Stonerock, G, Haythornthwaite, J. (2006). Pain-Related Catastrophizing in Healthy Women is Associated with Greater Temporal Summation of and Reduced Habituation to Thermal Pain. Clinical Journal of Pain, 22:730-7 Faustman DL., Tran SD., Kodama S., Lodde BM., Szalayova I., Key S., Toth ZE., Mezey E. Diabetes reversal in NOD mice. Science 314(5803):1243, 2006. Gude N, Muraski J, Rubio M, Kajstura J, Schaefer E, Anversa P, Sussman MA. Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res. 99:381-388, 2006. Hudert CA, Weylandt KH, Wang J, Lu Y, Hong S, Dignass A, Serhan CN, Kang JX. Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc Natl Acad Sci USA 2006; 103:11276-81. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, and Decosterd I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2006, 2:259-269. Ji RR, Wen YR. Neural-glial interaction in the spinal cord for the induction and maintenance of nerve injury-induced neuropathic pain. Drug Development Research, 2006; 66:1-8. Kong T, Westerman KA, Faigle M, Eltzschig HK, Colgan SP. HIF-dependent induction of adenosine A2B receptor in hypoxia.FASEB J. 2006.20(13):2242-50. Kajstura J, Bolli R, Sonnenblick EH, Anversa P, Leri A. Cause of death: suicide. J Mol Cell Cardiol. 40:425-437, 2006. Kajstura J, Leri A, Bolli R, Anversa P. Endothelial progenitor cells: neovascularization and more. J Mol Cell Cardiol. 40:1-8, 2006. Kajstura J, Rota M, Urbanek K, Hosoda T, Bearzi C, Anversa P, Bolli R, Leri A. The telomere-telomerase axis and the heart. Antioxid Redox Signal. 8:2125-2141, 2006. Kawasaki Y, Kohno T, Ji RR. Different effects of opioid and cannabinoid on C-fiber-induced ERK activation in dorsal Horn neurons in normal and spinal nerve-ligated Rats. Journal of Pharmaceutical and Experimental Therapeutics, 2006; 316:601-607. Leri A, Hosoda T, Kajstura J, Anversa P. Heart failure and regenerative cardiology. Regenerative Med. 1:153-159, 2006. Li Q, Wu S, Li SY, Lopez FL, Du M, Kajstura J, Anversa P, Ren J. Cardiac specific overexpression of insulin-like growth factor-1 (IGF-1) attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol. 292:H1398-403, 2006. Q. Liu, C. F. Perez, Y. Wang. Efficient site-specific integration of large transgenes by an enhanced herpes simplex virus/adeno-associated virus hybrid amplicon vector. J Virol. 2006; 80(4) 1672-9 Liu W, Cao D, Oh SF, Serhan CN, Kulmacz RJ. Divergent cyclooxygenase responses to fatty acid structure and peroxide level in fish and mammalian prostaglandin H synthase. FASEB J. 2006; 20:1097-108. Lu Y, Hong S, Gotlinger K, Serhan CN. Lipid mediator informatics and proteomics in inflammation-resolution. TheScientificWorldJOURNAL 2006; 6:589-614. Machado FS, Johndrow JE, Esper L, Dias A, Bafica A, Serhan CN, Aliberti J. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2-dependent. Nature Med. 2006; 12:330-34 (Epub January 15). McMullen ME, Hart ML, Walsh MC, Buras J, Takahashi K, Stahl GL. Mannose binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology 2006; 211:759-66 (Epub July 28, 2006) (cover issue) Meng, X., Samso M., Koonce, M. A Flexible Linkage Between the Dynein Motor and its Cargo. J. Mol. Biol. 2006; 357:701-6. Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, Esposito G, Vitale S, Urbanek K, Casarsa C, Giorgio M, Luscher TF, Pelicci PG, Anversa P, Leri A, Kajstura J. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res 99:42-52, 2006. Samso M, Shen X, Allen PD. Structural Characterization of the RyR1-FKBP12 Interaction. J Mol Biol. 2006 356:917-27 Schwab JM, Serhan CN. Lipoxins and new lipid mediators in the resolution of inflammation. Curr Opin Pharmacol. 2006; 6:414-20 (Epub June 5). Serhan CN. Bengt Samuelsson and the discovery of the leukotrienes. J Allergy Clin Immunol. 2006; 118:972-76. Serhan CN. Novel chemical mediators in the resolution of inflammation: resolvins and protectins. Anesthesiol Clin N Am. 2006; 24:341-64. Serhan CN. Resolvins and protectins: novel lipid mediators in anti-inflammation and resolution. In: Proceedings of NAFA Conference 2006. Scand J Food Nutr. 2006; 50(S2):68-78. Serhan CN, Chiang N. Putting the brakes on neutrophils. Blood 2006; 107:1742-43. Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J Immunol. 2006; 176:1848-59. Serhan CN, Hong S, Lu Y. Lipid mediator informatics-lipidomics: novel pathways in mapping resolution. AAPS J. 2006; 8:E284-97. Serhan CN, Levy BD. Lipid mediators: lipoxins. In: Laurent GJ, Shapiro SD, eds. Encyclopedia of Respiratory Medicine, vol. 2. Oxford: Elsevier, 2006:594-606. Sheridan DC, Takekura H, Franzini-Armstrong C, Beam KG, Allen PD, Perez CF. Bidirectional signaling between calcium channels of skeletal muscle requires multiple direct and indirect interactions. Proc Natl Acad Sci U S A. 2006 103:19760-5. Epub 2006 Dec 15. Tjonahen E, Oh SF, Siegelman J, Elangovan S, Percarpio KB, Hong S, Arita M, Serhan CN. Resolvin E2: Identification and anti-inflammatory actions: Pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem Biol. 2006; 13:1193-202 (doi: 10.1016/j.chembiol.2006.09.011). Tsujita Y, Muraski J, Shiraishi I, Kato T, Kajstura J, Anversa P, Sussman MA. Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc Natl Acad Sci USA. 103:11946-11951, 2006. Tyce GM, Hunter LW, Kristensen EW, Chritton SL, and Rorie DK, Release of DOPA from Dog Peripheral Tissues.In: Yoshimi Misu and Yoshio Goshima, editors. Neurobiology of DOPA as a Neurotransmitter. Boca Raton: CRC Press, 2006. Urbanek K, Cesselli D, Rota M, Nascimbene A, Bearzi C, Hosoda T, Boni A, Bolli R, Kajstura J, Anversa P, Leri A. Cardiac stem cell niches. Proc Natl Acad Sci USA, 103:9226-9231, 2006. Vacanti CA.History of tissue engineering and a glimpse into its future. Tissue Eng. 2006 May;12(5):1137-42. Van Dyke TE, Serhan CN. A novel approach to resolving inflammation. Sci Am. Oral and Whole Body Health 2006; 42-45. Wada K, Arita M, Nakajima A, Katayama K, Kudo C, Kamisaki Y, Serhan CN. Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation. FASEB J. 2006; 20:1785-92 (issue cover). Wang,G.K., T.Edrich, and S.Y.Wang. 2006. Time-Dependent Block and Resurgent Tail Currents Induced by Mouse b4154-167 Peptide in Cardiac Na+ Channels. J Gen. Physiol 127:277-289. Wang PF, Sha H, Ji RR, Zhao ZQ, Zhang YQ. Is endogenous d-serine in the rostral anterior cingulate cortex necessary for pain-related negative affect? Journal of Neurochemistry, 2006; 96:1636-47. Wazen RM, Moffatt P, Zalzal SF, Daniel NG, Westerman KA, Nanci A. Local gene transfer to calcified tissue cells using prolonged infusion of a lentiviral vector.Gene Ther. 2006. 13(22):1595-602. Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, Feinstein DL. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart.Regional Anesth Pain Med 2006, 31: 296-303. Xia S, Lu Y, Wang J, He C, Hong S, Serhan CN, Kang JX. Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids. Proc Natl. Acad Sci USA 2006; 103:12499-12504 (Epub August 3). Xie Z, Dong Y, Maeda U, Moir R, Inouye S, Culley DJ, Crosby G, Tanzi RE. Isoflurane induced apoptosis:A potential pathologic link between delirium and dementia. J Gerontol A Biol Sci Med Sci. 2006 Dec;61(12):1300-6. Yang T, Riehl J, Esteve E, Matthaei KI, Goth S, Allen PD, Pessah IN, Lopez JR. Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. Anesthesiology. 2006 105:1164-75. Yanagidate F and Strichartz GR. Bupivacaine inhibits activation of neuronal spinal extracellular receptor activated kinase through selective effects on ionotropic receptors. Anesthesiology2006, 104: 805-814. Yasuda A, Kojima K, Tinsley KW, Yoshioka H, Mori Y, Vacanti CA. In vitro culture of chondrocytes in a novel thermoreversible gelation polymer scaffold containing growth factors.Tissue Eng. 2006 May;12(5):1237-45. Zhuang ZY, Wen YR, Zhang DR, Tiziana B, Christhophe B, Strichartz GR, Decosterd I, Ji RR (2006) A peptide JNK inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. Journal of Neuroscience, 2006; 26:3551-3560. CLINICAL RESEARCH PUBLICATIONS FOR 2007 Binks, Vovk A, Ferrigno M, Banzett RB.The air hunger response of four elite breath-hold divers.Respiratory, Physiology and Neurobiology 2007; 159:171-177. Butler SF, Budman SH, Fernandez KC, Houle B, Benoit C, Katz N, Jamison RN. Development and validation of the Current Opioid Misuse Measure. Pain 2007;130:144-156. Collard CD, Shernan SK, Fox AA, Bernig T, Chanock SJ, Vaughn WK, Takahashi K, Ezekowitz AB, Jarolim P, Body SC. The MBL2 ÒLYQA SecretorÓ Haplotype is an Independent Predictor of Postoperative Myocardial Infarction in Caucasians Undergoing Coronary Artery Bypass Graft Surgery. Circulation 2007; 116(11 Suppl):I106-12. Connor, "TivaMan 1.5 - software for interactive pharmacological simulation", available online at http://www.mit.edu/~cwc/tivaman Connor and Ferrigno, "Estimates of the risk of Nitrogen Narcosis and CNS Oxygen Toxicity During DISSUB Escapes from 600 to 1,000 ft", 2007 Undersea Medicine Combined Progress Review of the US Navy, Mystic CT, July 2007. Diemunsch P, Apfel C, Gan TJ, Candiotti K, Philip BK et al. Preventing postoperative nausea and vomiting: post hoc analysis of pooled data from two randomized active-controlled trails of aprepitant. CMRO 2007; 23: 2559-65. Diemunsch P, Gan TJ, Philip BK, et al. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind Phase III trial in patients undergoing open abdominal surgery. BJA Advance Access May 30, 2007; 99: 202-11. Felbinger TW, Posner, M, Eltzschig HK, Kodali BS. Laparoscopic splenectomy in a pregnant patient with immune thrombocytopenic purpura. International J Obst Anesth. 2007; 16:281-3. Gan TJ, et al. [Philip BK, consensus panel member]. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting.Anesth Analg 2007; 105 :1615-28. Harrison and Connor, "Statistics-based alarms from sequential physiological measurements", Anaesthesia 62(10): 1015-1023, October 2007. Jamison RN, Fanciullo GJ, McHugo GJ, Baird JC. Validation of the short-form interactive computerized quality of life scale (ICQOL-SF). Pain Med 2007;8:243-250.
Marceau L, Carolan S, Schuth B, Jamison RN. Pain diaries as a tool to improve pain management: is there any evidence? Pain Med 2007;S3:101-109. Melanson S, Szymanski T, Rogers S, Jarolim P, Frendl G, Rawn J, Cooper Z, Ferrigno M. Utilization of arterial blood gas measurements in a large tertiary care hospital.Amer J Clin Pathology. 2007; 127 (4):604-609. Michna E, Jamison RN, Pham LD, Ross EL, Janfaza D, Nedeljkovic SS, Narang SS, Palombi R, Wasan AD. Urine Toxicology Screening Among Chronic Pain Patients on Opioid Therapy: Frequency and Predictability of Abnormal Findings Clin. J. Pain, 2007, 23(2): p.173-179 Novalija J, Lindholm P, Loring SH, Diaz E, Fox JA, Ferrigno M.Cardiovascular aspects of glossopharyngeal insufflation and exsufflation.Undersea and Hyperbaric Medicine 2007:34(6):415-423. O'Rourke N, McElrath T, Baum R, Camann W, Tuomala R, Stuebe A, Kodali BS. Cesarean delivery in the interventional radiology suite: A novel approach to obstetric hemostasis. Anesth Analg. 2007; 104(5)1193-4. Provenzano DA, Fanciullo GJ, Jamison RN, McHugo GJ, Baird JC. Computer assessment and diagnostic classification of chronic pain patients. Pain Med 2007;S3:167-175. Srinivasa V, Kodali BS. Caution when using colorimetry to confirm endotracheal intubation. Anesth Analag. 2007; 104(3):738-9. Srinivasa V, Kodali BS. Video on orotracheal intubation. N Engl J Med. 2007; 357(6):620. Walsh MC, Shaffer LA, Guikema BJ, Body SC, Shernan SK, Fox AA, Collard CD, Fung M, Taylor RP, Stahl GL. Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. J Immunol Methods 2007;323(2):147-59. Wasan AD, Butler SF, Budman SH, Benoit C, Fernandez K, Jamison RN. Psychiatric history and psychological adjustment as risk factors for aberrant drug-related behavior among patients with chronic pain. Clin J Pain. 2007;23:307-315. Wasan AD, Fernandez E, Jamison RN, Bhattacharyya N. The association of anxiety and depression with reported disease severity in patients undergoing evaluation for chronic rhinosinusitis. Ann Otol, Rhinol, Laryngol, 2007;116:491-497. Practice Guidelines for Obstetric Anesthesia:An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia:Anesthesiology 2007;106 (4):843-63. LABORATORY RESEARCH PUBLICATIONS FOR 2007 Anversa P, Kajstura J, Leri A. If I can stop one heart from breaking. Circulation. 115:829-832, 2007. Anversa P, Leri A, Rota M, Bearzi C, Urbanek K, Kajstura J, Bolli R. Stem cells, myocardial regeneration and methodological artifacts. Stem Cells. 25:589-601, 2007. Anversa P, Sonnenblick EH, Frishman WH. Conclusions – future directions. In: Cardiovascular Regeneration and Stem Cell Therapy. Edited by Annarosa Leri, Piero Anversa and William H. Frishman. Blackwell Publishing, Malden, Mass. 2007, 221-224. Anversa P, Urbanek K, Bearzi C, De Angelis A, Rota M. Cardiac stem cells and the failing heart. In: Cardiovascular Regeneration and Stem Cell Therapy. Edited by Annarosa Leri, Piero Anversa and William H. Frishman. Blackwell Publishing, Malden, Mass. 2007, 201-220. Ariel A, Serhan CN. Resolvins and protectins in the termination program of acute inflammation. Trends Immunol. 2007; 28:176-83 (Epub March 6; doi:10.1016/j.it.2007.02.007). Arita M, Ohira T, Sun Y-P, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 2007; 178:3912-17. Arita M, Serhan CN. Novel chemical mediators in the resolution of inflammation. Tanpakushitsu Kakusan Koso. 2007; 52:348-354 (Japanese). Ashton AW, Mukherjee S, Nagajyothi FNU, Huang H, Braunstein VL, Desruisseaux MS, Factor SM, Lopez L, Berman JW, Wittner M, Scherer PE, Capra V, Coffman TM, Serhan CN, Gotlinger K, Wu KK, Weiss LM, Tanowitz HB. Thromboxane A2 is a key regulator of pathogenesis during Trypanosoma cruzi infection. J Exp Med. 2007; 204:929-40. Bannenberg G, Arita M, Serhan CN. Endogenous receptor antagonists: resolving inflammation. The ScientificWorld Journal 2007; 7:1440-62 (doi: 10.1100/tsw.2007.188). Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, LeCapitaine N, Cascapera S, Beltrami AP, D'Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P. Human cardiac stem cells. Proc Natl Acad Sci USA. 104:14068-14073, 2007. Bolli R, Anversa P. Stem cells and cardiac aging. In: Cardiovascular Regeneration and Stem Cell Therapy. Edited by Annarosa Leri, Piero Anversa and William H. Frishman. Blackwell Publishing, Malden, Mass. 2007, 171-182. Campbell EL, Louis NA, Tomassetti SE, Canny GO, Arita M, Serhan CN, Colgan SP. Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. FASEB J. 2007; 21:3162-70 (Epub May 11; doi: 10.1096/fj.07-8473com). Chen X, Wilson RM, Kubo H, Beretta RM, Harris DM, Zhang X, Jaleel N, MacDonnell SM, Bearzi C, Tillmanns J, Trofimova I, Hosoda T, Mosna F, Cribbs L, Leri A, Kajstura J, Anversa P, Houser SR. The adolescent feline heart contains a population of small proliferative venricular myocytes with immature physiological properties. Circ Res. 100:536-544, 2007. Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem NN Jr., Serhan CN, Smith LEH. Increased dietary intake of w-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nature Med. 2007; 13:868-73 (issue cover; published online 6/24/07; doi:10.1038/nm1591). Edwards, R. and Fillingim, R. (2007). Self-reported pain sensitivity: Lack of correlation with pain threshold and tolerance. European Journal of Pain, 11:594-8. Edwards, R., Klick, B., Buenaver, L., Max, M., et al. (2007). Symptoms of distress as prospective predictors of pain-related sciatica treatment outcomes. Pain, 130:47-55. Edwards, R, Smith, M, Klick, B, et al. (2007). Symptoms of depression and anxiety as unique predictors of pain-related outcomes following burn injury. Annals of Behavioral Medicine, 34:313-22. El Kebir D, J—zsef L, Khreiss T, Pan W, Petasis NA, Serhan CN, Filep JG. Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation. J Immunol. 2007; 179:616-22. Feng W, Tu J, Pouliquin P, Cabrales E, Shen X, Dulhunty A, Worley PF, Allen PD, Pessah IN. Dynamic regulation of ryanodine receptor type 1 (RyR1) channel activity by Homer 1. Cell Calcium. 2008 43:307-14. Epub 2007 Aug 17. Fridrich P, Colvin HP, Zizza A, Wasan AD, Lukanich J, Lirk P, Saria A, Zernig G, Hamp T, Gerner P. Phase 1A safety assessment of intravenous amitriptyline. J Pain. 2007;8(7):549-55 Fritz N, Morel JL, Jeyakumar LH, Fleischer S, Allen PD, Mironneau J, Macrez N. RyR1-specific requirement for depolarization-induced Ca2+ sparks in urinary bladder smooth muscle. J Cell Sci. 2007 120:3784-91. Ganter MT, Brohi K, Cohen MJ, Shaffer LA, Walsh MC, Stahl GL, Pittet JF.Role of the alternative pathway in the early complement activation following major trauma. Shock; 2007, 28:29-34 Griffin RS, Costigan M, Brenner GJ, Ma CHE, Scholz J, Moss A, Allchorne AJ, Stahl GL, Woolf CJ. Complement induction in spinal cord microglia results in anaphylatoxin C5a mediated pain hypersensitivity. Journal of Neuroscience 2007; 27:8699-708 (cover issue) Haas-Stapleton EH, Lu Y, Hong S, Arita M, Favoreto S, Nigam S, Serhan CN, Agabian N. Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator Resolvin E1. PLoS ONE 2007; 2:e1316 (doi:10.1371/journal.pone.0001316). Haller I, Lirk P, Keller C, Wang GK, Gerner P, Klimaschewski L. Differential neurotoxicity of tricyclic antidepressants and novel derivatives in vitro in a dorsal root ganglion cell culture model. Eur J Anaesthesiol. 2007;24(8):702-8. Hasturk H, Kantarci A, Goguet-Surmenian E, Blackwood A, Andry C, Serhan CN, Van Dyke TE. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J Immunol. 2007; 179:7021-29 (issue cover). Hirakawa S., Brown LF., Kodama S., Paavonen K., Alitalo K., Detmar M. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109(3):1010-7, 2007. Hong S, Lu Y, Yang R, Gotlinger KH, Petasis NA, Serhan CN. Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms. J Am Soc Mass Spectrom. 2007; 18:128-44. Hung YC, Chen CY, Lirk P, Wang CF, Cheng JK, Chen CC, Wang GK, Gerner P. Magnesium sulfate diminishes the effects of amide local anesthetics in rat sciatic-nerve block. Reg Anesth Pain Med. 2007;32(4):288-95. Ikeda S, Kong SW, Lu J, Bisping E, Zhang H, Allen PD, Golub TR, Pieske B, Pu WT. Altered microRNA expression in human heart disease. Physiol Genomics. 2007 31:367-73. Epub 2007 Aug 21. Ji RR, Kawasaki Y, Wen YR, Zhuang ZY, and Zhang YQ. Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol. 2007; (177):359-89. Kajstura J, LeCapitaine N, Loredo M., Giorgio M, Mitchell TS, Valentini S, Rotatori F, Pelicci PG. Cardiac stem cells and diabetic cardiomyopathy. In: Cardiovascular Regeneration and Stem Cell Therapy. Edited by Annarosa Leri, Piero Anversa and William H. Frishman. Blackwell Publishing, Malden, Mass. 2007, pp 161-169. Kato G, Kawasaki Y, Ji RR, Strassman AM. Differential wiring of local excitatory and inhibitory synaptic inputs to islet cells in rat spinal lamina II demonstrated by laser scanning photostimulation. Journal of Physiology, 2007; 580:815-33. Kissin I, Freitas CF, Bradley EL Jr. Perineural resiniferatoxin prevents the development of hyperalgesia produced by loose ligation of the sciatic nerve in rats. Anesth Analg 2007;104:1210-6. Kissin I, Freitas CF, Mulhern HL, DeGirolami U. Sciatic nerve block with resiniferatoxin: an electron microscopic study of unmyelinated fibers in the rat. Anesth Analg 2007;105:825-31. Lee EH, Allen PD. Homo-dimerization of RyR1 C-terminus via charged residues in random coils or in an alpha-helix. Exp Mol Med. 2007 Oct 31;39:594-602. Leri A, Boni A, Siggins R, Nascimbene A, Hosoda T. Cardiac stem cells niches. In: Cardiovascular Regeneration and Stem Cell Therapy. Edited by Annarosa Leri, Piero Anversa and William H. Frishman. Blackwell Publishing, Malden, Mass. 2007, 87-94. Levy BD, Kohli P, Gotlinger K, Haworth O, Hong S, Kazani S, Israel E, Haley KJ, Serhan CN. Protectin D1 is generated in asthma and dampens airway inflammation and hyper-responsiveness. J Immunol. 2007; 178:496-502. Levy BD, Lukacs NW, Berlin AA, Schmidt B, Guilford WJ, Serhan CN, Parkinson JF. Lipoxin A4 analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J. 2007; 21:3877-84 (Epub July 11; doi: 10.1096/fj.07-8653com). Lu Y, Hong S, Yang R, Uddin J, Gotlinger KH, Petasis NA, Serhan CN. Identification of endogenous resolvin E1 and other lipid mediators derived from eicosapentaenoic acid via electrospray low-energy tandem mass spectrometry: spectra and fragmentation mechanisms. Rapid Commun Mass Spectrom. 2007; 21:7-22. Masoodi M, Mir AA, Petasis NA, Serhan CN, Nicolaou A. Simultaneous lipidomic analysis of three families of bioactive lipid mediators leukotrienes, resolvins, protectins and related hydroxy-fatty acids by liquid chromatography/electrospray ionisation tandem mass spectrometry. Rapid Commun. Mass Spectrom. 2007; 22:75-83 (Epub Dec. 4). Mujenda FH, Duarte AM, Reilly EK, Strichartz GR. Cutaneous endothelin-A receptors elevate post-incisional pain.Pain 2007, 133:161-173. Muraski JA, Rota M, Misao Y, Fransioli J, Cottage C, Gude N, Esposito G, Delucchi F, Arcarese M, Alvarez R, Siddiqi S, Emmanuel GN, Wu W, Fischer K, Martindale JJ, Glembotski CC, Leri A, Kajstura J, Magnuson N, Berns A, Beretta RM, Houser SR, Schaefer EM, Anversa P, Sussman MA. Pim-1 regulates cardiomyocyte survival downstream of Akt. Nat Med. 13:1467-1475, 2007. Murata K, Fox-Talbot K, Qian Z, Takahashi K, Stahl GL, Baldwin WM, Wasowska BA. Synergistic deposition of C4d by complement-activating and nonactivating antibodies in cardiac transplants.American Journal of Transplantation 2007; 7:2605-14 Paolini C, Quarta M, Nori A, Boncompagni S, Canato M, Volpe P, Allen PD, Reggiani C, Protasi F. Reorganized stores and impaired calcium handling in skeletal muscle of mice lacking calsequestrin-1. J Physiol. 2007 583:767-84. Phimister AJ, Lango J, Lee EH, Ernst-Russell MA, Takeshima H, Ma J, Allen PD, Pessah IN. Conformation-dependent stability of junctophilin 1 (JP1) and ryanodine receptor type 1 (RyR1) channel complex is mediated by their hyper-reactive thiols. J Biol Chem. 2007 282(:8667-77. Epub 2007 Jan 19. Pomahac B, Zuhaili B, Kudsi Y, Bleiziffer O, Velander P, Eriksson E, Gerner P. Safety Evaluation of Topically Applied Amitriptyline in Porcine Full-Thickness Wounds. Reg Anesth Pain Med. 2007;32(5):377-381. Rota M, Hosoda T, De Angelis A, Arcarese ML, Esposito G, Rizzi R, Tillmanns J, Tugal D, Musso E, Rimoldi O, Bearzi C, Urbanek K, Anversa P, Leri A, Kajstura J. The young mouse heart is composed of myocytes heterogeneous in age and function. Circ Res. 101:387-399, 2007. Rota M, Kajstura J, Hosoda T, Bearzi C, Vitale S, Esposito G, Iaffaldano G, Padin-Iruegas ME, Gonzalez A, Rizzi R, Small N, Muraski J, Alvarez R, Chen X, Urbanek K, Bolli R, Houser SR, Leri A, Sussman MA, Anversa P. Bone marrow cells adopt the cardiomyogenic fate in vivo. Proc Natl Acad Sci USA. 104:17783-17788, 2007. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 2007; 447:869-74. Serhan CN. Nonclassical actions of aspirin: omega-3 and resolvins. In: Libby P, Knappertz V, eds. Inflammation, Atherosclerosis, & Aspirin: New Insights. Morristown: Bayer HealthCare, 2007:33-40. Serhan CN. Resolution phases of inflammation: novel endogenous anti-inflammatory and pro-resolving lipid mediators and pathways. Annu Rev Immunol. 2007; 25:101-37 (doi: 10.1146/annurev.immunol.25.022106.141647; Epub 11/6/06). Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O'Neill LAJ, Perretti M, Rossi AG, Wallace JL. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007; 21:325-32 (epub 12/13/06; fj.06-7227com). Serhan CN, Chiang N. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. Br J Pharmacol. 2007; 153:S200-S215 (published on-line October 29; doi: 10.1038/sj.bjp.0707489). Serhan CN, Lu Y, Hong S, Yang R. Mediator lipidomics: search algorithms for eicosanoids, resolvins and protectins. In: Brown HA, ed. Lipidomics and Bioactive Lipids: Mass-Spectrometry-Based Lipid Analysis. San Diego: Elsevier, 2007:275-317 (Methods in Enzymology, vol. 432). Shen X, Franzini-Armstrong C, Lopez JR, Jones LR, Kobayashi YM, Wang Y, Kerrick WG, Caswell AH, Potter JD, Miller T, Allen PD, Perez CF. Triadins modulate intracellular Ca(2+) homeostasis but are not essential for excitation-contraction coupling in skeletal muscle.J Biol Chem. 2007 Dec 28;282(52):37864-74. Epub 2007 Nov 2. Sun Y-P, Oh SF, Uddin J, Yang R, Gotlinger K, Campbell E, Colgan SP, Petasis NA, Serhan CN. Resolvin D1 and its aspirin-triggered 17R epimer: stereochemical assignments, anti-inflammatory properties and enzymatic inactivation. J Biol Chem. 2007; 282:9323-34 (published on-line on January 23, 2007; http://www.jbc.org/cgi/doi/10.1074/ jbc.M609212200). Suter M, Ji RR. Do glial cells control pain? Neuron Glia Biology, 2007, 3:255-268. Svensson CI, Zattoni M, Serhan CN. Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J Exp Med. 2007; 204:245-52 (published on-line on January 22, 2007; doi: 10.1084/jem.20061826). *Tran SD., *Kodama S., Lodde BM., Szalayova I., Key S., Khalili S., Faustman DL., Mezey E (*T.S. & S.K. contributed equally to this work.) Reversal of Sjšgren's-like syndrome in non-obese diabetic mice. Ann Rheum Dis 66(6): 812-4, 2007. Walsh MC, Shaffer LA, Guikema BJ, Body SC, Shernan SK, Fox AA, Collard CD, Fung M, Taylor RP, Stahl GL. Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. Journal of Immunological Methods 2007; 323:147-59 Wang CF, Gerner P, Wang SY, Wang GK. Bulleyaconitine A isolated from aconitum plant displays long-acting local anesthetic properties in vitro and in vivo. Anesthesiology. 2007;107(1):82-90. Wang,S.-Y., J.Mitchell, and G.K.Wang. 2007. Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel. Pain 127:73-83. Wen YR, Suter M, Kawasaki Y, Wang J, Pertin M, Khono T, Berde C, Decosterd I, Ji RR. Conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve Injury model. Anesthesiology, 2007, 107:312-321. Westerman KA, Ao Z, Cohen EA, Leboulch P.Design of a trans protease lentiviral packaging system that produces high titer virus.Retrovirology. 2007.Dec 28;4:96. Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE, The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Ab Accumulation. J Neurosci, 2007;27:124754. Yacoubian S, Serhan CN. New endogenous anti-inflammatory and pro-resolving lipid mediators: implications for rheumatic diseases. Nat Clin Pract Rheumatol. 2007; 3:570-79. Yang T, Allen PD, Pessah IN, Lopez JR. Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. J Biol Chem. 2007 282:37471-8. Epub 2007 Oct 16. Yang T, Esteve E, Pessah IN, Molinski TF, Allen PD, Lopez JR. Elevated resting [Ca(2+)](i) in myotubes expressing malignant hyperthermia RyR1 cDNAs is partially restored by modulation of passive calcium leak from the SR. Am J Physiol Cell Physiol. 2007 292:C1591-8. Epub 2006 Dec 20. Zhang H, Cang CL, Kawasaki Y, Liang LL, Zhang YQ, Ji RR, Zhao ZQ. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. Journal of Neuroscience, 2007, 27:12067-77. Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain, Behavior & Immunity, 2007, 21:642-651. CLINICAL RESEARCH PUBLICATIONS FOR 2008 Body SC, Schwinn DA. Limitations of genetic findings that are not in Hardy-Weinberg equilibrium. Anesthesiology. 2008 Feb;108(2):338 Cappiello E, O'Rourke N, Segal S, Tsen LC.Randomized trial of dural puncture epidural technique compared to standard epidural technique for labor analgesia.Anesth Analg 2008 (In Press). Connor, Gohil and Harrison, "Six-sigma Systolic Arterial Pressure Alarms", European Society of Anesthesia Annual Meeting, Copenhagen, Denmark, June 2008. Connor CW, Philip JH.The Severinghaus Square Root of Time Relationship for Anesthetic Uptake and its Implications for the Stability of Compartmental Pharmacokinetics.Physiol. Meas. 2008;29:685-701. Egan B, Racowsky C, Hornstein MD, Martin R, Tsen LC. Anesthetic Impact of Body Mass Index in Patients Undergoing Assisted Reproductive Technologies. J Clin Anesth 2008 (In Press). Fox AA, Shernan SK, Collard CD, Liu K, Aranki SF, DeSantis SM, Jarolim P, Body SC. Preoperative B-type natriuretic peptide independently predicts ventricular dysfunction and mortality after primary coronary artery bypass grafting. J Thorac Cardiovasc Surg 2008 (in press) Garfield JM, Garfield FB et al.Academic physicians differ in their emphasis on professional attributes: Implications for training programs.Submitted for publication. Kodali BS, Chandrasekhar S, Bulich L, Topulos G, Datta S. Airway changes during labor. Anesth. 2008;108(3):57-62. Muehlschlegel JD, Body SC. Impact of genetic variation on perioperative bleeding. Am J Hematol. 2008 Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, Jamison RN. Efficacy of dronabinol as an adjunct treatment for chronic pain patients on opioid therapy. The J Pain. 2008;9(3):254-264. Narang S, Wasan AD, Ross EL, Michna E, Chen JY, Jamison RN.Patients with chronic pain on opioid therapy taking dronabinol: incidence of false negatives using radioimmunoassay.J Opioid Manag. 2008;21-26. Ng J and Hartigan PM. Anesthetic strategies for patients undergoing extrapleural pneumonectomy for mesothelioma. Curr Opin Anesthesiol 2008, 21:21-27. Tsen LC.Neuraxial techniques for labor analgesia should be placed in the lateral position.Int J Obstet Anesth 2008; 17(2):146-9. Wasan AD, Taubenberger SP, Robinson WM, "Reasons for Participation in Pain Research:Can they Indicate a Lack of Informed Consent?" Pain Medicine, 2008 (accepted for publication) LABORATORY RESEARCH PUBLICATIONS FOR 2008 Baxter MG, Murphy KL, Crosby G, Culley DJ. Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia. Hippocampus 2008; 18:245-50. Berta T, Poirot O, Pertin M, Ji RR, Kellenberger S, Decosterd I (2008) Transcriptional and functional profiles of voltage-gated Na(+) channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain. Molecular and Cellular Neuroscience, 37:196-208. Busche MN, Walsh MC, McMullen ME, Guikema BJ, Stahl GL.Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes. Diabetologia 2008; in press Butler SF, Budman SH, Fernandez K, Benoit C, Jamison RN. Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain, 2008;9:360-372 . Cherednichenko G, Ward CW, Feng W, Cabrales E, Michaelson L, Samso M, Lopez JR, Allen PD, Pessah IN. Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene. Mol Pharmacol. 2008 73:1203-12. Epub 2008 Jan 2. Chiang N, Schwab JM, Fredman G, Kasuga K, Gelman S, Serhan CN. Anesthetics impact the resolution of inflammation. PLoS ONE 2008; 3:e1879. Constantin CE, Mair N, Sailer CA, Andratsch M, Xu ZZ, Blumer MJ, Scherbakov N, Davis JB, Bluethmann H, Ji RR, Kress M. Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. Journal of Neuroscience, 2008, 28:5072-5081. Csencsitsa K, Burrell BE, Lu G, Eichwald EJ, Stahl GL, Bishop DK. The classical complement pathway in transplantation:Unanticipated protective effects of C1q and role in inductive antibody therapy. American Journal of Transplantation 2008; in press Lidocaine inhibits NIH-3T3 cell multiplication by increasing expression of cyclin- depenedent kinase inhibitor 1A (p21). Desai SP., Kojima K., Vacanti CA., *Kodama S. (*Correspondence) Anesth Analg 2008 (In Press), [Accepted MS#: AA-D-08-00134R1] Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy. Circ Res. 102:1319-1330, 2008. Dona M, Fredman G, Schwab JM, Chiang N, Arita M, Goodarzi A, Cheng G, von Andrian UH, Serhan CN. Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets. Blood 2008; prepublished online 5/14/08 (doi: 10.1182/blood-2007-11-122598). Edwards, R, Almeida, D, Klick, B, Haythornthwaite, J, Smith, M. (2008). Duration of sleep contributes to next-day pain report in the general population. Pain; 137: 202-7. Gach MP, Cherednichenko G, Haarmann C, Lopez JR, Beam KG, Pessah IN, Franzini-Armstrong C, Allen PD. Alpha2delta1 dihydropyridine receptor subunit is a critical element for excitation-coupled calcium entry but not for formation of tetrads in skeletal myotubes. Biophys J. 2008 94:3023-34. Gao YJ, Ji RR. Activation of JNK pathway in persistent pain. Neuroscience Letter, 2008, 437:180-183. Gerner P. Postthoracotomy pain management problems. Anesthesiol Clin. 2008;26(2):355-67. Gerner P, O'Connor JP. Impact of analgesia on bone fracture healing. Anesthesiology. 2008;108(3):349-50. Gerner P, Strichartz GR. Sensory and motor complications of local anesthetics. Muscle Nerve. 2008;37(4):421-5. Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Muller P, Esposito G, Bearzi C, Vitale S, Dawn B, Math S, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A. Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res. 102:597-606, 2008. Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin-23, interferon-gamma and lipoxin A4 to promote resolution of allergic airway inflammation. Nat Immunol. 2008; published on-line 6/22/08 (doi: 10.1038/ni.1627). Hong S, Porter TF, Lu Y, Oh SF, Pillai PS, Serhan CN. Resolvin E1 metabolome in local inactivation during inflammation-resolution. J Immunol. 2008; 180:3512-19. Bioengineered three-layered robust and elastic artery utilizing hemodynamically equivalent pulsatile bioreactor. Iwasaki K., Kojima K., Kodama S., Paz AP., Chamber M., Umezu M., Vacanti CA. Circulation 2008 (In Press), [Accepted MS#: CIRCULATIONAHA/2007/757369] Iwasaki K, Kojima K, Kodama S, Paz AC, Chamber M, Umezu M,Vacanti CA. Bioengineering three-layered robust and elastic artery utilizing hemodynamically-equivalent pulsatile bioreactor. Circulation.2008 [in press]. Kajstura J. Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res. 2008 Jun 12. [Epub ahead of print] Kajstura, J, Urbanek K,, Rota M, Bearzi C, Hosoda T, Bolli R, Anversa,Leri A. Cardiac stem cells and myocardial disease. J Mol Cell Cardiol. In press, 2008. Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nature Medicine, 2008, 14:331-336 (Cover Story). Kawasaki Y, Zhang L, Cheng JK, Ji RR. Cytokine mechanisms of central sensitization: overlapping and distinct roles of proinflamamtory cytokines IL-1b, IL-6, and TNF-a in regulating synaptic and neuronal activity. Journal of Neuroscience, 2008, 28:5189-5194. Kissin I. Vanilloid–induced conduction analgesia: selective, dose-dependant, long-lasting, with a low level of potential neurotoxicity. Anesth Analg 2008;107:271-81. Kohno T, Wang H, Amaya F, Brenner G, Cheng JK, Ji RR, Woolf CJ. Bradykinin enhances AMAP and NMDA current via activation of multiple protein kinases in dorsal horn neurons. Journal of Neuroscience, 2008, 14:331-336. La Bonte LR, Davis-Gorman G, Stahl GL, McDonagh PF. Complement inhibition reduces injury in the type 2 diabetic heart following ischemia and reperfusion. American Journal of Physiology 2008; in press Leri A, Hosoda T, Rota M, Kajstura J, Anversa P. Myocardial regeneration by exogenous and endogenous progenitor cells. Drug Discovery Today: Disease Mechanisms 4:197-203, 2008. Leri A, Kajstura J, Anversa P, Frishman WH. Myocardial regeneration and stem cell repair. Curr Probl Cardiol. 33:91-153, 2008. Lirk P, Haller I, Colvin HP, Lang L, Tomaselli B, Klimaschewski L, Gerner P. In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity. Anesth Analg. 2008;106(5):1456-64. The promise of Hox11+ stem cells of the spleen for treating autoimmune diseases. Lonyai A., Kodama S., Burger D., Davis M., Faustman DL. Horm Metab Res 40(2):137-46, 2008. Fetal Hox11 expression patterns predict defective target organs: A novel link between developmental biology and autoimmunity. Lonyai A., Kodama S., Burger D., Faustman DL. Immunol Cell Biol 86(4): 301-9, 2008. Machado FS, Esper L, Dias A, Madan R, Gu YY, Hildeman D, Serhan CN, Karp C, Aliberti J. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6. J Exp Med. 2008; 205:1077-86 (published on-line 4/14/08; doi: 10.1084/jem20072416). Marcantonio E, Fong T, Culley DJ, Alsop D, Jones R, Culley DJ, Crosby G, Inouye S. Maximizing clinical research participation in frail older persons; identification of barriers and motivators. J Am Geriatrics Soc 2008; In Press. Merched A, Ko K, Gotlinger KH, Serhan CN, Chan L. Atherosclerosis: Evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 2008; published on-line 6/17/08 (doi: 10.1096/fj.08-112201). Muraski JA, Fischer KM, Wu W, Cottage CT, Quijada P, Mason M, Din S, Gude N, Alvarez R, Rota M, Kajstura J, Schaefer E, Chen X, MacDonnel S, Magnuson N, Houser SR, Anversa P, Sussman MA. Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload. Proc Natl Acad Sci USA. In press, 2008. Narang S, Gibson D, Wasan AD, Michna E, Ross EL, Nedeljkovic SS, Jamison RN. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain, 2008;9:254-264. Narang S, Wasan AD, Ross EL, Michna E, Chen JY, Jamison RN. Chronic pain patients on opioid therapy taking dronabinol: incidence of false negative using radioimmunoassay. J Opioid Manage 2008;4:21-26. Petasis NA, Keledjian R, Sun Y-P, Nagulapalli KC, Tjonahen E, Yang R, Serhan CN. Design and synthesis of benzo-lipoxin A4 analogs with enhanced stability and potent anti-inflammatory properties. Bioorg Med Chem Lett. 2008; 18:1382-87 (doi:10.1016/j.bmcl.2008.01.013). Poulsen RC, Gotlinger KH, Serhan CN, Kruger MC. Identification of inflammatory and pro-resolving lipid mediators in bone marrow and their profile alteration with ovariectomy and omega-3 intake. Am J Hematol. 2008; 83:437-45 (doi: 10.1002/ajh.21170). Ren J, Duan J, Thomas DP, Yang X, Sreejayan N, Sowers JR, Leri A, Kajstura J, Gao F, Anversa P. IGF-1 alleviates diabetes-induced rhoA activation, eNOS uncoupling and myocardial dysfunction. Am J Physiol. 294:R793-802, 2008. Rota M, Padin-Iruegas ME, Misao Y, De Angelis A, Maestroni S, Ferreira-Martins J, Fiumana E, Rastaldo R, Arcarese ML, Mitchell TS, Boni A, Bolli R, Urbanek K, Hosoda T, Anversa P, Leri A, Rudolph JL, Maracntonio ER, Culley DJ, Silverstein JH, Crosby G, Inouye SK. Delirium is associated with early postoperative cognitive dysfunction, Anaesthesia 2008; In Press. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008; 8:249-61 (issue cover). Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and pro-resolving lipid mediators. In: Abbas AK, Galli SJ, Howley PM, eds. Annu Rev Pathol Mech Dis. 2008; 3:279-312. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008; 8:249-61 (issue cover). Serhan CN. Novel lipid mediators in resolution and their aspirin triggered epimers: lipoxins, resolvins, and protectins. In: Rossi AG, Sawatzky DA, eds. The Resolution of Inflammation. Basel: Birkhauser Verlag AG, 2008:93-117 (Progress in Inflammation Research, Parnham MJ, ed.). Siddiqi S, Gude N, Hosoda T, Muraski J, Rubio M, Emmanuel G, Fransioli J, Vitale S, Parolin C, D'Amario D, Schaefer E, Kajstura J, Leri A, Anversa P, Sussman M. Myocardial induction of nucleostemin in response to postnatal growth and pathological challenge. Circ Res. 2008 Jun 2. [Epub ahead of print]. Strichartz GR. Novel ideas of local anaesthetic actions on various ion channels to ameliorate post-operative pain.Br J Anaesth2008; doi: 10.1093/bja/aen101 Sugimoto K, Kissin I and Strichartz GR.High concentrations ofresiniferatoxin inhibit ion channel function in clonal neuroendocrine cells. Anesth Analg. 2008;107: 318-324. Tillmanns J, Rota M, Hosoda T, Misao Y, Esposito G, Gonzalez A, Vitale S, Parolin C, Yasuzawa-Amano S, Muraski J, De Angelis A, LeCapitaine N, Siggins RW, Loredo M, Bearzi C, Bolli R, Urbanek K, Leri A, Kajstura J, Anversa P. Formation of large coronary arteries by cardiac progenitor cells. Proc Natl Acad Sci USA. 105:1668-1673, 2008. Voss AA, Allen PD, Pessah IN, Perez CF. Allosterically coupled calcium and magnesium binding sites are unmasked by ryanodine receptor chimeras. Biochem Biophys Res Commun. 2008 366:988-93. Epub 2007 Dec 26. Wang,G.K., J.Calderon, and S.Y.Wang. 2008. State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine. Mol. Pharmacol 73:940-948. Wang,G.K., J.Mitchell, and S.Y.Wang. 2008. Block of Persistent Late Na+ Currents by Antidepressant Sertraline and Paroxetine. J Membr. Biol. 222:79-90. Woo JS, Kim do H, Allen PD, Lee EH.TRPC3-interacting triadic proteins in skeletal muscle.Biochem J. 2008 411:399-405. Yukhananov R, Kissin I. Persistent changes in spinal cord gene expression after recovery from inflammatory hyperalgesia: A preliminary study on pain memory. BMC Neuroscience 2008;9:32-46. Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE. Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J Neurosci. 2008;28(17):4551-60. Zani BG, Kojima K, Vacanti CA, Edelman ER. Tissue Engineered Endothelial and Epithelial Implants Differentially and Synegistically regulate Airway Repair. Proc Natl Acad Sci USA. 2008 ; 105: 7046-7051. |
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