1
ANNUAL RESEARCH REPORT (draft, final, 01.30.13)
2011-2012
Brigham & Women's Hospital Department of Anesthesiology, Perioperative and
Pain Medicine
2
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 focused
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 and restoration,
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 35 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 twenty years the department's research activities have increased more than sixfold. The following passages describe in more detail the resources and organization of
departmental research, and the activities and accomplishments of individual laboratories
and Principal Investigators.
Resources and Productivity
3
In 2012 research in the Anesthesiology Department was supported by 37 NIH
grants and sub-contracts, of which 27 were individual investigator (R-01)grants, 3 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 34,220 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 2012 there were 32 faculty conducting independent laboratory research and clinical
research. Publications for the 2011 calendar year (those for 2012 are still being collected)
included 50 original basic research reports, 32 clinical research reports and 27
educational reviews and book chapters. In addition, faculty published 11 editorials, case
reports, and letters to the editor. 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.
Gary Strichartz, PhD
Vice-Chairman for Research
4
RESEARCH REPORTS
This section first contains overviews of each of the 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 compilation of publications by departmental researchers for 20102011.
LABORATORY RESEARCH
CENTER FOR EXPERIMENTAL THERAPEUTICS AND REPERFUSION INJURY
Charles N. Serhan, Director
Opportunities in Multi-Disciplinary and Human Translational Cellular & Molecular
Research: This basic research Center for Experimental Therapeutics and Reperfusion
Injury was founded by Professor Simon Gelman and continues to offer many
opportunities for discovery research and fellowship training in topics that are of interest
in internal medicine, surgery, pathology and their respective specialties.
This research Center is devoted to multidisciplinary research efforts with a cluster of
highly talented faculty members and affiliated faculty members that have unique
scientific expertise and perspective that are focused on defining key molecular events of
importance in the pathogenesis 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 focal clinical sequelae such as periodontal disease. In addition to these clinical
disease points, the underlying interactions between white blood cells and vascular &
mucosal tissues evoke local acute inflammatory responses that can be initiated within the
host by way of surgical stress local inflammatory mediators and persist in the
perioperative arena and beyond.
The perioperative arena provides a wide, unmet clinical challenge and need for
development of novel therapeutics that, if achieved, can shorten the duration of
perioperative holding times 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 cellular events can provide us with a wealth of new information that
could have wide-ranging implications for the medical specialties and our appreciation of
host defense, preventative medicine and novel therapeutics to diseases associated with
inflammation and chronic pain.
Scope of Research in 2012 and beyond
The research programs within the Center take multidisciplinary team approaches to solve
unexplored terrains relevant in human diseases. 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
5
representatives from each discipline focused on elucidating key components in ischemia
and reperfusion injury. This provides a unique opportunity for discovery and program
development with a balanced training environment. This is evidenced by the substantial
number of trainees and the strong extramural support for this Center over a dozen years.
Importantly, a significant number of faculty and alumni fellows are PIs and faculty at
prestigious institutions around the world.
Mission Statements & Goals of the CET&RI
An interdisciplinary research team of experienced as well as new investigators are
assembled within the Center with the following general mission statements:
"To identify novel targets and pathways critical in regulating acute inflammation and
its natural resolution and to establish the templates for physiologic small molecule
resolution-based interventions."
and
"To elucidate the molecular mechanisms underlying reperfusion injury and identify
novel therapeutic interventions that can prevent cell injury."
From these two broad mission statements we created a platform for discovery and
interweaving of molecular definition and a focus on structural elucidation, molecular
physiology and pharmacology as they merge in systems biology 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.
To accomplish our objectives, the Center environment and organizational structure
provides a platform that brings together a group of investigators and faculty members
who have recognized expertise in the areas of biochemistry, resolution-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, within inflammatory exudates as well as mucosal lining of the airway, eye
and gastrointestinal. Hence, one focal strength of the Center is its multidisciplinary
approach to the well-appreciated diseases associated with aberrant neutrophil activation
and uncontrolled host-defense/infection that can occur during collateral tissue damage
and local inflammation in a wide range of clinical scenarios as well as in ischemiareperfusion injury or reflow tissue injury as in the operating room.
The individual research report narratives of the Center's faculty (see following pages of
individual labs) indicate the research focus in each principal investigator's laboratory and
their recent discoveries that are funded by several extramural research sources. Current
support includes grants obtained from the National Institutes of Health, American Heart
Association, Arthritis Foundation, Fulbright Scholars Program and the Crohn's and
Colitis Foundation, to name a few of the extramural supporting agencies of this center’s
6
research mission. As a research cluster of very talented investigators in a strategic
alliance to solve problems of fundamental importance in the biomedical sciences, the
Center is placed in a highly unique position to rapidly translate basic research discoveries
at the molecular and cellular level into potentially novel approaches and new treatments
by shaping new thoughts regarding the pathobiology of human disease.
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 in the Greater Longwood Medical Area
This Center’s laboratories and offices of our faculty members are located in the Harvard
Institutes of Medicine, 8th Floor. This campus 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 Harvard Medical and greater Longwood
Area constellation of world class research teams.
Director and Principal Investigator
& NIH Program Project Program Director/PI,
Professor Charles N. Serhan, Ph.D., Director, Center for Experimental
Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and The
Simon Gelman Professor of Anaesthesia (Biochemistry & Molecular
Pharmacology), Harvard Medical School and Professor of Oral Medicine, Infection
and Immunity at Harvard School of Dental Medicine
Current Personnel in the Serhan Lab 2012-2013:
Nan Chiang, Ph.D. Assoc. Pharmacologist and Asst. Professor, Harvard Med. Sch.
Hildur Arnardottir, Ph.D. Post-Doctoral Fellow
Chien-Yee C. Cheng Lab Manager & Research Staff
Romain Colas, Ph.D. Post-Doctoral Fellow
Jesmond Dalli, Ph.D. Instructor, Harvard Medical School & Research Associate
Norma De La Cruz Office Administrator
Bin Deng, Ph.D.
Post-Doctoral Fellow
Jon Fitzgerald Research Staff
Fei Gao, Ph.D. Research Associate
Megumi Kibi, M.D. Post-Doctoral Fellow
Boyd Lever Research Staff
Yongsheng Li, Ph.D., M.D. Post-Doctoral Fellow
Masakazu Shinohara, Ph.D., M.D. Post-Doctoral Fellow
7
Mary Small Research Administrator
Chin-wei Wang, D.D.S. Research Fellow
Jason Wu
Research in the Serhan laboratory focuses on structural elucidation of bioactive
molecules. Dr. Serhan's overall mission is "To identify novel bioactive mediators,
pathways, and cellular targets critical in activating 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 Program Project grant, Resolution Mechanisms in Acute Inflammation:
Resolution Pharmacology. He is also Principal Investigator on the NIH research grant
entitled Blood Cell Lipoxygenase Products: Formation and Action, funded since 1987
and receiving a MERIT Award. He also serves as mentor for post-doctoral fellowships
including the Arthritis Foundation Fellowship awarded to Dr. Kie Kasuga (2006-2008).
Jan Schwab, M.D, Ph.D. was the recipient of a Deutsche Forschungsgemeinschaft
Fellowship (2005-2006). Dr. Matthew Spite received an NIH NRSA Fellowship (20082011). Dr. Lucy Norling received the Arthritis Research Campaign Fellowship (U.K.;
2008-2010).
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 mechanism(s) that
govern endogenous anti-inflammation and resolution mechanisms in inflammation. From
his research program, 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 biology 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 chemical 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, proresolving 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, protectins, and most recently the maresins. 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-
8
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 antiinflammatory 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 CET&RI discoveries have already provided 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, protectins and maresins. Knowledge of these pro-resolving
biochemical circuits and previously unknown novel 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 the inflammatory response in the perioperative stage and the
pain associated with chronic inflammation and post-surgical events are of increasing
importance in the practice of anesthesia and pain management. Dr. Serhan's research
provides new avenues to control inflammation and its natural resolution pathways with
precision. These ongoing studies now open the new field of resolution pharmacology and
its potential uses in human disease.
Select Recent Publications:
Chiang N, Fredman G, Bäckhed F, Oh SF, Vickery T, Schmidt BA, Serhan CN. Infection
regulates pro-resolving mediators that lower antibiotic requirements.
Nature 2012; 484:524-28 (doi: 10.1038/nature11042).
Featured in “Research Highlights”, Nat Rev Drug Discov. 2012; 11:441 (doi:
10.1038/nrd3760)
Xu Z-Z, Zhang L, Liu T, Park J-Y, Berta T, Yang R, Serhan CN, Ji R-R. Resolvins RvE1
and RvD1 attenuate inflammatory pain via central and peripheral actions.
Nat Med. 2010; 16:592-7 (Epub April 11; doi:10.1038/nm.2123).
Serhan CN, Dalli J, Karamnov S, Choi A, Park CK, Xu ZZ, Ji RR, Zhu M, Petasis NA.
Macrophage pro-resolving mediator maresin 1 stimulates tissue regeneration and controls
pain.
FASEB J. 2012; 26:1755-65 (Epub 1/17/12; doi: 10.1096/fj.11-201442).
Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes:
Microparticles stimulate macrophage efferocytosis and pro-resolving mediators.
Blood 2012; 120:e60-72 (Epub Aug 17; doi: 10.1182/blood-2012-02-413021).
9
Serhan CN. Review: Novel lipid mediators resolution mechanisms in acute inflammation:
to resolve or not?
Am J Pathol. 2010; 177:1576-91 (Epub Sept. 2; doi: 10.2353/ajpath.2010.100322).
Hongwei Gao, MD, PhD
Laboratory Members:
Hanna Tang, MD, PhD, Research Fellow
Wei Zhang, MD, PhD, Research Associate
Chunguang Yan, BS, MS, PhD Graduate Student
The research activities in Gao’s laboratory are focusing on revealing the molecular
mechanisms that regulate inflammatory events during acute lung injury, sepsis, and
inflammatory bone diseases. Specially, we are identifying the function of complements
and their receptors in acute lung injury, sepsis, and inflammatory bone diseases. We are
dissecting the function of transcription factors, cytokines and their networks of
interaction, which underlie the inflammatory process in airway injury and bone.
One project we developed is determining the role of transcription factors including
pneumonia. We have demonstrated that STAT3 plays a complex role in acute lung
injury. We show that transcription factor C/EBP
of STAT3. Furthermore, our study suggests that STAT3 acetylation seems to regulate its
activities. We are currently testing the hypothesis that STAT3 exerts its regulatory
function during acute lung injury by activating multiple target genes, which differentially
- and TLR4-mediated inflammatory responses in the lung. In
collaborating with Professor Charles Serhan’s group, we are determining the role of lipid
mediators in acute lung injury. Our studies have been supported by two NIH grants from
NHLBI.
Another project that we are working on is characterization of the roles of SOCS3
signaling and the C5a receptors, C5aR and C5L2, in the inflammation-associated bone
diseases. We have demonstrated that osteoblasts express both C5aR and C5L2, and
unexpectedly, we found that C5a down-regulated LPS-induced IL-6 release from
osteoblasts. Our hypothesis is that osteoblasts can exert their functions like macrophages
during inflammation, and C5a/C5aRs signaling may play an important role in
inflammatory bone diseases by regulating TLR-mediated inflammatory responses.
Furthermore, our recent work demonstrated that SOCS3 plays an important regulatory
role in osteoblast inflammatory response.
Selected Recent Publications:
Yan, C., Cao, J., Wu, M., Zhang, W., Jiang, T., Yoshimura, A., Gao, H. Suppressor of
cytokine signaling 3 inhibits LPS-induced IL-6 expression by suppressing
10
CCAAT/enhancer-binding protein β activity. J. Biol. Chem. 2010; 285(48):37227-39.
Wu, M., Huang, H., Zhang, W., Skannan, S., Weaver, A., Mckibben, M., Herington, D.,
Zeng, H., Gao, H. Host DNA repair proteins in response to P. aeruginosa in lung
epithelial cells and in mice. Infection and Immunity 2011; 79(1):75-87.
Yuan, K, Huang, C, Fox, J, Gaid, M, Weaver, A, Li, GP, Singh, BB, Gao, H, Wu, M.
Elevated inflammatory response in Caveolin-1 deficient mice with P. aeruginosa
infection is mediated by STAT3 and NF-{kappa}B. J. Biol. Chem. 2011;
286(24):21814-25.
Tang, H., Yan, C., Sarma, J.V., Haura, E.B., Wu, M., Gao, H. An essential role for Stat3
in regulating IgG immune complex-induced pulmonary inflammation. FASEB J. 2011,
Dec;25(12):4292-300.
C5a-regulated CCAAT/enhancer binding protein β and -δ are essential in Fcγ receptormediated inflammatory cytokine and chemokine production in macrophages. Yan C, Zhu
M, Staiger J, Johnson PF, Gao H. J Biol Chem. 2012 Jan 27;287(5):3217-30.
Yuan, K., Huang, C., Zhang, B., Yin, Q., Fox III, J., Laturnus, D., Carlson, E., Gao, H.,
Wu, M. Autophagy plays an essential role in the clearance of P. aeruginosa by alveolar
macrophages. J Cell Sci. 2012, 15;125(Pt 2):507-15.
Yan C, Wang X, Cao J, Wu M, Gao H. CCAAT/Enhancer-Binding Protein gamma Is a
Critical Regulator of IL-1beta-Induced IL-6 Production in Alveolar Epithelial Cells.
PLoS One 2012, 7:e35492.
Guo, Q., Shen, N., Yuan, K., Li, J., Wu, H., Zeng, Y., FoxIII, J., Bansal, AK, Singh, B.,
Gao, H., Wu, M. Caveolin-1 plays a critical role in host immunity against Klebsiella
pneumoniae by regulating STAT5 and Akt activity. European Journal of Immunology.
2012, 42:1-13.
Yan, C., Wu, M., Cao J., Tang, H., Zhu, M., Johnson, P.F. Gao, H. Critical Role for
CCAAT/Enhancer Binding Protein β in Immune Complex-Induced Acute Lung Injury.
J Immunol. 2012 Aug 1;189(3):1480-90.
Gregory L. Stahl, Ph.D.
Gregory L. Stahl's lab investigates 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
in mediating inflammation and tissue injury.
11
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
complement activation, tissue injury and inflammation following ischemia/reperfusion.
Current studies and recent publications by Dr, Stahl’s lab have investigated the
importance of MBL in coagulation abnormalities, as well as acute hyperglycemia and its
role in the cardiomyopathies associated with diabetes mellitus.
Selected Publications:
Takahashi K, Chang W-C, Takahashi M, Pavlov V, Ishida Y, La Bonte L, Shi L, Fujita T,
Stahl GL*, Van Cott EM* (*co-senior authors). Mannose-binding lectin and its
associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in
developing complications from infection, including disseminated intravascular
coagulation. Immunobiology 2011; 216:96-102 PMCID: PMC2912947 (cover issue)
Zou, C, La Bonte LR, Pavlov VI, Stahl GL. Murine hyperglycemic vasculopathy and
cardiomyopathy: whole-genome gene expression analysis predicts cellular targets and
regulatory networks influenced by mannose binding lectin. Frontiers in Immunology
2012; 3:15. doi: 10.3389/fimmu.2012.00015 PMC3286603
van de Pol P, Schlagwein N, van Gijlswijk DJ, Berger SP, Roos A, Bajema IM, de Boer
HC, de Fijter JW, Stahl GL, Daha MR, van Kooten C. A crucial role for mannan-binding
lectin in renal ischemia/reperfusion injury. American Journal of Transplantation 2012;
12:877-87
La Bonte LR, Pavlov VI, Tan YS, Takahashi K, Takahashi M, Banda NK, Fujita T, Stahl
GL. MBL-associated serine protease -1 (MASP-1) is a significant contributor to
coagulation in a murine model of occlusive thrombosis. Journal of Immunology 2012;
188:885-91 PMC3253146
Pavlov VI, La Bonte LR, Baldwin WM, Markiewski M, Lambris J, Stahl GL. Absence
of mannose-binding lectin prevents hyperglycemic cardiovascular complications.
American Journal of Pathology 2012; 180:104-112 PMC3338344
Pavlov VI, Skjoedt M-O, Tan YS, Rosbjerg A, Garred P, Stahl GL. Endogenous and
natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis.
Circulation 2012; 126:2227-35
Orsini F, Villa P, Parrella S, Zangari R, Zanier ER, Gesuete R, Stravalaci M, Fumagalli
S, Ottria R, Reina JJ, Paladini A, Micotti E, Ribeiro-Viana R, Rojo J, Pavlov VI, Stahl
GL, Bernardi A, Gobbi M, De Simoni M-G. Targeting mannose binding lectin confers
long lasting protection with a surprisingly wide therapeutic window in cerebral ischemia.
Circulation 2012; 126:1484-94
12
Stahl GL, Shernan SK, Smith PK, Levy JH. Complement activation and cardiac surgery:
A novel target for improving outcomes. Anesthesia and Analgesia (Invited Review)
2012; 115:759-71
Gorsuch WB, Chrysanthou E, Schwaeble WJ, Stahl GL. The complement system in
ischemia-reperfusion injuries. Immunobiology (Invited Review) 2012; 217:1026-33
Lectin pathway
Classical pathway
(C1q)
MAP-1
C2
MASP-1
Kallikrein-kinin system
(hmw kininogen)
MAP-1
MASP-2
C4
Coagulation system
MASP-3
C3b
(Prothrombin, fibrinogen, and FXIII)
MASPs
MAP-1
MAP-1
(Alternative pathway)
(Factor B and D)
C5a
C5
MAC
(C5b-9)
Altered self or pathogen surface
Figure 1.
A model of the recognition molecules MBL and the ficolins in association with the
MBL/ficolin associated serine proteases (MASPs) are shown. The possible roles of
the MASPs in activation of the complement system and other cascade systems and
subsequent MBL/ficolin associated protein-1 (MAP-1) inhibition are indicated.
Hmw = high molecular weight.
CENTER FOR MUSCLE RESEARCH
This Research Center focuses on the pathophysiology of skeletal muscle. The Center is
composed of 3 collaborative laboratories each headed by a Faculty PI. The focus of these
laboratories includes Excitation Contraction Coupling (skeletal and cardiac), calcium
metabolism in skeletal muscle, and the involvement of adhesion molecules and stem cells
in remodeling of injured muscle.
The Westerman group (Karen Westerman, Ph.D., Takeshi Aoba, M.D., Ph.D., and
Siddharth Ramshankar, M.S.) has been characterizing a unique type of muscle stem cell,
13
referred to as myosphere cells. These cells form non-adherent spheres in culture and can
maintained in a primitive ‘pre-myogenic’ state for long periods of time. In characterizing
these cells we became interested in adhesion molecules that maintain these cells as
spheres in culture. Our most recent research involves interaction of GPI anchored protein
Sca-1 and adhesion molecule αVβ3 integrin. We discovered that cells expressing Sca-1
interact adhesively with αVβ3 integrin and that this adhesiveness is enhanced when Sca-1
and β3 integrin are expressed within the same cell, indicating these molecules interact by
both trans and cis mechanisms. The importance of this interaction is that the activation of
αVβ3 integrin is involved in the repair and remodeling of injured tissues, indicating that
perhaps purpose of Sca-1 expression by stem cells is to aid in the response to injury. In
addition, the Westerman lab maintains an interest in tissue engineering and collaborates
with the Tissue Engineering Laboratory (Dr. Charles Vacanti’s group). Our most recent
tissue engineering project involves studying cell and polymer combinations to produce a
more stable tissue engineered ear. This research has been supported by grants from
NIAMS (KO1 AR052372-01) and Regenear.
Dr. Westerman is also the organizer of the Longwood Muscle Stem Cell Group, which is
composed of 63 researchers from Brigham and Women’s Hospital, Children’s Hospital,
Joslin Diabetes Center, Dana Farber Cancer Institute, Mass General, MIT, Boston
University, Tufts, and the BBRI. This group meets once a month to present stem cell and
muscle related research. If you interested in joining this group contact Karen Westerman
at kwest@zeus.bwh.harvard.edu.
Selected publications:
Westerman KA, Ao Z, Cohen EA, Leboulch P., Design of a trans protease lentiviral
packaging system that produces high titer virus. Retrovirology. 2007. 4:96.
Westerman KA, Penvose A, Yang Z, Allen PD, Vacanti CA., Adult muscle 'stem' cells
can be sustained in culture as free-floating myospheres. Exp Cell Res. 2010. 316:196676.
Obokata H, Kojima K, Westerman K, Yamato M, Okano T, Tsuneda S, Vacanti CA., The
potential of stem cells in adult tissues representative of the three germ layers. Tissue Eng
Part A. 2011. 17:607-15.
Penvose, A. and Westerman, K., Sca-1 is involved in the adhesion of myosphere cells to
αVβ3 integrin. Biology Open (2012) 1:839-847.
14
The Fessenden laboratory (currently, James D. Fessenden,
Ph.D., Mohana Mahlingam, Ph.D., and Tanya Girgenrath,
M.S.) studies fundamental Ca2+ signaling mechanisms in
skeletal muscle through structural analysis of the type 1
ryanodine receptor (RyR1), an enormous intracellular Ca2+
release channel which plays a pivotal role in skeletal muscle
excitation contraction (EC) coupling. In this process, muscle
fiber depolarization detected by the Cav1.1 voltage-gated
Ca2+ channel activates
RyR1, thereby releasing Ca2+ stored in the sarcoplasmic
reticulum (SR), which in turn activates muscle contraction.
In humans, single missense mutations in RyR1 can cause the
skeletal muscle disorders malignant hyperthermia (MH) and
central core disease (CCD). Virtually nothing is known as to
how these point mutations affect the structure of RyR1 nor
how these structural changes in the protein lead to these
debilitating skeletal muscle disorders.
We have developed a method to measure structural changes
in RyR1 using fluorescence resonance energy transfer
Figure 1: (Top) Structure of
(FRET), a technique which has been used as a “molecular
Cy3NTA bound to His tag.
ruler” to measure distances within or between proteins. A
(Bottom) FRET based method
prerequisite first step in these studies is to site-specifically
used in our lab. Cy3NTA binds
label RyR1 with the fluorophores required for FRET
to a His10 tag introduced into
primary sequence of RyR1
measurements. The method we have adapted for these
(black bar), thereby quenching
studies takes advantage of the strong interaction between
fluorescence of nearby fused
Ni2+/nitrilotriacetic acid (NTA) complexes and
GFP. RyR1 activation shortens
polyhistidine “tags” used for protein purification. By
the distance between donor and
coupling NTA to the fluorophore, Cy3 (Figure, top), the
acceptor, increasing FRET.
resulting compound (Cy3NTA) can be specifically targeted
to His tags engineered into RyR1 containing a fused GFP to act as a fluorescence donor.
FRET can then be measured as a decrease in GFP fluorescence when Cy3NTA is bound
to a nearby His tag. Thus, both static FRET measurements, to provide low resolution
topological information about RyR1, and changes in FRET after RyR modulation, to
measure conformational changes in the protein (Figure, bottom), can potentially be
conducted using this assay system.
Selected publications:
Fessenden, J.D. (2009). Forster resonance energy transfer measurements of ryanodine
receptor type 1 structure using a novel site-specific labeling method. PLoS One. 4, pp.
e7338.
Raina, S. A., Tsai, J., Samso, M. and Fessenden, J.D. (2012) FRET-based localization of
fluorescent protein insertions within the ryanodine receptor type 1. PLoS One. 7(6), pp.
e38594.
15
Geldart, A., Fessenden, J.D., Arons, E., Mitsialis, A., Kourembanas, S. and Christou, H.
(2012) Extracellular acidosis alters the metabolic phenotype and susceptibility to
apoptosis of pulmonary artery smooth muscle cells. Clin. and Exp. Med. Sci. vol. 1, pp.
141-160 (In press).
The Perez Group (C. F. Perez, Ph.D.,
Siddharth Ramshankar, M.S.) is focused in
understanding the molecular mechanisms that
control Ca2+ release and Ca2+ homeostasis in
striated muscles under normal and myopathic
conditions. Our studies primarily concentrate
in two major Ca2+ channels (ryanodine
receptor-RyRs and dihydropyridine receptorDHPR) and the role of their endogenous
protein modulators in channel function. Our
studies involve the extensive use of unique
knockout mice and myogenic cell line null for
key Ca2+ regulatory proteins including: RyRs,
and calsequestrin as well as double
Fig. 1. Protein-protein interactions involved in
triadin/junctin null mice. These studies have
RyR1 regulation in skeletal muscle. RyR1
revealed how different modulators of RyRs
channel activity is modulated by both plasma
regulate its function through specific
membrane (dihydropyridine receptor) and SR
functional and/or structural interaction. In
membrane proteins (Triadin, Junctin and
addition these studies have allowed the
Calsequestrin-1).
identification of the critical molecular
determinants of RyRs and DHPR involved in the bidirectional signaling process that
takes place during excitation-contract coupling.
In another line of research we are also studying the regulation of RyRs by disease-linked
mutations. RyR mutations associated with Ca2+ dysfunction have been linked to several
debilitating and deadly myopathies including Malignant Hyperthermia (MH), Central
Core Disease, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and
Sudden Unexplained Death. Using our RyR-null system we have initiated a
comprehensive structural/functional study that focuses on understanding the mechanism
by which these mutations affect Ca2+ binding sensitivity and channel activity of the
diseased receptors. These studies have revealed a novel calcium-binding site at the core
of a mutational hot spot associated with MH and CVPT. This line of research seeks to
generate the molecular basis for future development of new therapeutic approaches that
target a wide range of myopathies regardless of their etiology.
The lab maintains active collaboration with Dr. P.D. Allen, UC. Davis; Dr. Isaac N.
Pessah, UC. Davis; Dr. Clara Franzini-Armstrong, University of Pennsylvania; Dr.
Montserrat Samso, Virginia Commonwealth University and Dr. Jenny J. Yang, Georgia
State University. The group has been supported by American Heart Association is
currently funded by NIH.
16
Selected Publications:
Pessah I, Lehmler HJ, Robertson L, Perez CF, Cabrales E, Bose D, Feng W (2009)
Enantiomeric Specificity of (-)-2,2’,3,3’,6,6’-Hexachlorobiphenyl ((-)-PCB 136) towards
ryanodine receptor types 1 and 2. Chem. Res. Toxicol. 22(1):201-207.
Chopra N, Yang T, Asghari P, Moore ED, Huke S, Akin B, Cattolica RA, Perez CF,
Hlaing T, Knollmann-Ritschel BE, Jones LR, Pessah IN, Allen PD, Franzini-Armstrong
C, Knollmann BC. (2009) Ablation of triadin causes loss of cardiac Ca2+ release units,
impared excitation-contraction coupling and cardiac arrhythmias. Proc. Natl. Acad. Sci.
USA 106(18):7636-7641.
Eltit JM, Wei F, Lopez JR, Padilla IT, Pessah IN, Molinski TF, Fruen BR, Allen PD,
Perez CF (2010) Ablation of skeletal muscle triadin impairs FKBP12/RyR1 channel
interactions essential for maintaining resting cytoplasmic Ca2+. J Biol Chem. 285(49):
38453-38462.
Eltit JM, Szpyt J, Li H, Allen PD, Perez CF (2011) Reduced gain of excitationcontraction coupling in triadin-null myotubes is mediated by the disruption of
FKBP12/RyR1 interaction. Cell Calcium 49(2):128-135.
Perez CF (2011) On the footsteps of triadin and its role in skeletal muscle. World J Biol.
Chem. 2(8) 177-183.
Boncompagni S, Thomas M, Lopez JR, Allen PD, Yuan Q, Kranias EG, FranziniArmstrong C, Perez CF (2012). Triadin/Junctin double null mouse reveals a differential
role for Triadin and Junctin in anchoring CASQ to the jSR and regulating Ca2+
homeostasis. PLoS One. 7(7): e39962.
Szpyt J, Lorenzon N, Perez CF, Norris E, Allen PD, Beam K, Samso M (2012). 3D
Localization of the Alpha and Beta Subunits and of the II-III loop in the Skeletal Muscle
L-type Ca2+ Channel. J Biol Chem. Nov. 1. PMID: 23118233
CENTER FOR TISSUE ENGINEERING AND REGENERATIVE MEDICINE
Charles A. Vacanti, MD, Director
Dr. Charles Vacanti, M.D., the current Chairman of the Department of Anesthesia at the
Brigham & Women's Hospital, is a world-renowned pioneer in tissue engineering. Dr.
Vacanti contributed to many of the first published research papers on tissue engineering
and regenerative medicine. 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
17
more complex tissues such as lung, spinal cord, ligaments, tendons, kidneys and adrenal
glands.
Currently, the full-time research faculty at the Vacanti Laboratory consists of Scientific
Director Koji Kojima M.D. PhD, and postdoctoral research fellow Haruko Obokata PhD.
In addition, there is a continuous flux of medical, graduate, and undergraduate students in
the laboratory, as well as several visiting research fellows from around the world learning
the basics of tissue engineering.
One of the most important and successful tissue engineering projects being carried out in
our laboratory is examining the feasibility of creating an autologous trachea. This study
strives to provide a method for treating patients with injuries to the trachea using a
patients’ own cells seeded on biodegradable structures to engineer a tracheal replacement.
Positive results along with numerous publications led to FDA approval to attempt the
procedure in a child with a life-threatening tracheal condition. This story, the world’s first
autologous tissue engineered trachea in a human, was featured on an episode of ABC’s
Grey’s Anatomy. Additionally, our laboratory is working on projects within the field of
Orthopedic tissue engineering, looking at ways to improve clinical treatments for the
regeneration and repair of injuries to bone, articular cartilage, and the anterior cruciate
ligament.
While various adult stem cells have been reported to exist in different tissues, our recent
work has focused on pluripotent adult stem cells. Debate continues as to whether Oct4expressing stem cells naturally exist in the adult body, with a majority of the scientific
community believing that Oct4+ cells only exist during embryonic development.
Recently, our group has discovered isolation methods for spheres of pluripotent adult
stem cells from adult tissues derived from all tissue germ layers. However, it is important
to note that the cells described above were propagated as non-adherent spheres, which are
not known to exist in vivo. The in vitro behavior of the cells contained in these spheres is
likely to be very different from cells that reside in vivo. Our research group has been
investigating how these stem cells are harbored in the adult body, and how they can exert
their potential. We are focusing on gene fluctuations caused by external stimuli, such as
environmental changes. We believe that our studies suggest a novel aspect of mammalian
cells; one that cannot be explained only with knowledge from developmental studies.
References:
Vacanti, Charles A., et al. "Replacement of an avulsed phalanx with tissue-engineered
bone." New England Journal of Medicine 344.20 (2001): 1511-1514.
Kojima, Koji, and Charles A. Vacanti. "Generation of a tissue‐ engineered tracheal
equivalent." Biotechnology and Applied Biochemistry 39.3 (2004): 257-262.
Zani, Brett G, Kojima, Koji, Vacanti, CA, Edelman, ER. "Tissue-engineered endothelial
and epithelial implants differentially and synergistically regulate airway repair."
Proceedings of the National Academy of Sciences 105.19 (2008): 7046-7051.
18
Obokata, Haruko, et al. "The potential of stem cells in adult tissues representative of the
three germ layers." Tissue Engineering Part A 17.5-6 (2010): 607-615.
Canseco, Jose A., et al. "Effect on Ligament Marker Expression by Direct-Contact Coculture of Mesenchymal Stem Cells and Anterior Cruciate Ligament Cells." Tissue
Engineering Part A (2012).
CENTER FOR REGENERATIVE MEDICINE
Piero Anversa, MD, Director
Annarosa Leri, MD
Jan Kajstura, PhD
The research performed in our center 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 of our studies is
understanding the origin and developmental control of cardiac stem cells (CSCs), their
distribution in the heart, the etiology of their death and senescence, and their therapeutic
potential for the aged and infarcted heart.
The recognition that CSCs are present in the heart imposes a reconsideration of the
various theories of cardiac development, maturation and myocardial aging. Two major
controversial issues have been raised in the cardiovascular scientific community: the
magnitude of myocyte turnover and the origin of the newly formed cardiomyocytes. Two
opposite views of cardiac growth are currently held; one views the heart as a static organ
characterized by a large number of cardiomyocytes that are present at birth and live as
long as the organism, and the other views the heart a highly plastic organ in which the
myocyte compartment is restored several times during the course of life. The average age
of cardiomyocytes, vascular endothelial cells (ECs), and fibroblasts and their turnover
rates were measured by retrospective (14)C birth dating of cells in normal hearts and in
explanted failing hearts. The human heart was found to be characterized by a significant
turnover of ventricular myocytes, ECs, and fibroblasts, physiologically and
pathologically. Myocyte, EC, and fibroblast renewal is very high shortly after birth,
decreases during postnatal maturation, remains relatively constant in the adult organ, and
increases dramatically with age. From 20 to 78 years of age, the adult human heart
entirely replaces its myocyte, EC, and fibroblast compartment ~8, ~6, and ~8 times,
respectively. Myocyte, EC, and fibroblast regeneration is further enhanced with chronic
heart failure. These observations document that the human heart is a highly dynamic
organ that retains a remarkable degree of plasticity throughout life and in the presence of
chronic heart failure.
19
Several experimental assays have been implemented introduced to document that
cardiomyocytes derive entirely from the activation and commitment of CSCs and do not
originate from the re-entry in the cell cycle of terminally differentiated cells. It is
important to mention two of these multiple approaches. The formation of new
myocardium in the infarcted region following administration of clonal CSCs derived
from a single founder cells provides unequivocal evidence of the origin of
cardiomyocytes and coronary vessels in the context of tissue damage. To establish
whether this mechanism is operative physiologically, we have introduced viral marking
and genetic tagging. Storage sites of CSCs at the atrioventricular groove and apex of the
mouse heart were infected with a lentivirus carrying EGFP and the destiny of the tagged
cells was determined 1-5 months later. A common integration site was identified in
isolated CSCs, cardiomyocytes, endothelial cells (ECs) and fibroblasts, documenting the
multipotentiality of CSCs and the clonal origin of the differentiated cells. This strategy is
superior to fate mapping protocols, which establish a lineage relationship between
ancestors carrying the reporter gene and their descendents, but do not provide
information on the self-renewing property and clonogenicity of progenitor cells or clonal
origin of the daughter cells. Because of these intrinsic limitations, viral gene-tagging
remains the most powerful and accurate strategy for in vivo clonal analysis of stem-cells.
By this approach, c-kit-positive CSCs were found to possess the three fundamental
properties of stem cells in vivo: they are self-renewing, clonogenic, and multipotent.
Based on our experimental findings, we undertook a phase 1 trial (Stem Cell Infusion in
Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment
of heart failure resulting from ischemic heart disease. Patients with post-infarction LV
dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were
consecutively enrolled in the treatment and control groups. One million autologous CSCs
were administered by intracoronary infusion at a mean of 113 days after surgery; controls
were not given any treatment. Although the study was open label, the echocardiographic
analyses were masked to group assignment. The primary endpoint was short-term safety
of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This
study is registered with ClinicalTrials.gov, number NCT00474461. In 14 CSC-treated
patients who were analyzed, LVEF increased from 30•3% before CSC infusion to 38•5%
at 4 months after infusion. By contrast, in seven control patients, during the
corresponding time interval, LVEF did not change. Importantly, the salubrious effects of
CSCs were even more pronounced at 1 year. In the seven treated patients in whom
cardiac MRI could be done, infarct size decreased from 32•6 g by 7•8 g at 4 months and
9•8 g at 1 year. These initial results in patients are very encouraging. They suggest that
intracoronary infusion of autologous CSCs is effective in improving LV systolic function
and reducing infarct size in patients with heart failure after myocardial infarction, and
warrant further, larger, phase 2 studies.
An additional important area of our research aims at the documentation that c-kit-positive
CSCs constitute a functionally heterogeneous compartment. We are currently searching
for the most powerful CSCs with high regenerative potential. This objective has led us to
the identification of a pool of CSCs that during division selectively segregate
chromosomes carrying the old template DNA. A small class of human CSCs retains
20
during replication the mother DNA and generates 2 daughter cells, which carry the old
and new DNA, respectively. Human CSCs (hCSCs) with immortal DNA form a pool of
non-senescent cells with longer telomeres and higher proliferative capacity. In vivo
transplantation of this CSC subset in the infarcted heart results in the formation of a
chimeric organ, composed of spared rat and regenerated human cardiomyocytes and
coronary vessels, leading to a remarkable restoration of cardiac structure and function.
The impressive recovery in ventricular hemodynamics and anatomy mediated by clonal
hCSCs carrying the "mother" DNA underscores the clinical relevance of this stem cell
class for the management of heart failure in humans.
Figure Legend. Transverse section of an extensive myocardial infarct in a rat sacrificed
15 days after coronary occlusion and implantation of hCSCs carrying the immortal DNA
21
strand. Prior to injection in the border zone, hCSCs were infected with a lentivirus
carrying EGFP. The band of regenerated myocardium (arrowheads) replaces almost
entirely the scarred tissue. Newly formed myocytes are identified by the red fluorescence
of α-sarcomeric actin (central panel: α-SA, red). The human origin of these cells was
demonstrated by the detection of EGFP (upper panel; green). EGFP-negative α-SApositive cardiomyocytes reflect surviving myocardium; two layers of spared
cardiomyocytes are present at the epicardial and endocardial surfaces.
Selected Publications:
Bolli R, Chugh AR, D'Amario D, Loughran JH, Stoddard MF, Ikram S, Beache GM,
Wagner SG, Leri A, Hosoda T, Sanada F, Elmore JB, Goichberg P, Cappetta D, Solankhi
NK, Fahsah I, Rokosh DG, Slaughter MS, Kajstura J, Anversa P. Cardiac stem cells in
patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1
trial. Lancet. 2011;378:1847-1857.
Kajstura J, Bai Y, Cappetta D, Kim J, Arranto C, Sanada F, D'Amario D, Matsuda A,
Bardelli S, Ferreira-Martins J, Hosoda T, Leri A, Rota M, Loscalzo J, Anversa P.
Tracking chromatid segregation to identify human cardiac stem cells that regenerate
extensively the infarcted myocardium. Circ Res. 2012;111:894-906.
Kajstura J, Rota M, Cappetta D, Ogórek B, Arranto C, Bai Y, Ferreira-Martins J, Signore
S, Sanada F, Matsuda A, Kostyla J, Caballero MV, Fiorini C, D'Alessandro DA, Michler
RE, Del Monte F, Hosoda T, Perrella MA, Leri A, Buchholz BA, Loscalzo J, Anversa P.
Cardiomyogenesis in the aging and failing human heart. Circulation 2012;126:18691881.
D'Amario D, Cabral-Da-Silva MC, Zheng H, Fiorini C, Goichberg P, Steadman E,
Ferreira-Martins J, Sanada F, Piccoli M, Cappetta D, D'Alessandro DA, Michler RE,
Hosoda T, Anastasia L, Rota M, Leri A, Anversa P, Kajstura J. Insulin-like growth
factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic
potential for myocardial regeneration. Circ Res. 2011;108:1467-81.
Cesselli D, Beltrami AP, D’Aurizio F, Marcon P, Bergamin N, Toffoletto B, Pandolfi M,
Puppato E, Marino L, Signore S, Livi U, Verardo R, Piazza S, Marchionni L, Fiorini C,
Schneider C, Hosoda T, Rota M, Kajstura J, Anversa P, Beltrami CA, Leri A. Effects of
age and heart failure on human cardiac stem cell function. Am J Pathol. 2011;179:34966.
Hosoda T, Zheng H, Cabral-de-Silva M, Sanada F, Ide-Iwata N, Ogórek B, FerreiraMartins J, Arranto C, D’Amario D, del Monte F, Urbanek K, D’Alessandro D, Michler
RE, Anversa P, Rota M, Kajstura J, Leri A. Human cardiac stem cell differentiation is
regulated by a mircrine mechanism. Circulation 2011;123:1287-96.
Goichberg P, Bai Y, D’Amario D, Ferreira-Martins J, Fiorini C, Zheng H, Signore S, del
Monte F, Ottolenghi S, D’Alessandro D, Michler RE, Hosoda T, Piero Anversa, Kajstura
22
J, Rota M, Leri A. The ephrin A1-EphA2 system promotes cardiac stem cell migration
after infarction. Circ Res. 2011;108:1071-83.
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 longlasting, 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
23
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
Gregory Crosby, M.D. (PI)
Deborah J. Culley, M.D. (PI)
COLLABORATORS
Mark G. Baxter, Ph.D. (Oxford Univ., UK, Psychology)
Carlos Blanco-Centurion, Ph.D (BWH, Neurology)
Richard C. Deth, Ph.D. (Northeastern Univ., Biochemistry)
Sharon Inouye M.D., S.M. (Beth Israel, Geriatrics)
Vesna Jevtovic-Todorovic, M.D. Ph.D (Univ Virginia, Anesthesia)
Edward Marcantonio, M.D., S.M. (Beth Israel, Geriatrics)
James Rudolph, M.D. (BWH, Geriatrics)
Priyattam Shiromani, Ph.D (BWH, Neurology)
Rudolph E. Tanzi, Ph.D. (MGH, Neurology / Genetics & Aging)
Zhongcong Xie, M.D., Ph.D. (MGH, Anesthesia)
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.
24
Xie Z, Dong Y, Maeda U, Moir R, Xia W, Culley DJ, Crosby G, Tanzi RE. Isofluraneinduced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by
memantine. J Neurosci. 2008;28(17):4551-60.
Alvaro Andres Macias M.D.
Publications:
Baron RM, Lopez-Guzman S, Riascos DF, Macias AA, Layne MD, Cheng G, Harris C,
Chung SW, Reeves R, von Andrian UH, Perrella MA. Distamycin A inhibits HMGA1binding to the P-selectin promoter and attenuates lung and liver inflammation during
murine endotoxemia. PLoS One. 2010 May 14;5(5):e10656
Lai PS, Fresco JM, Pinilla MA, Macias AA, Brown RD, Englert JA, Hofmann O, Lederer
JA, Hide W, Christiani DC, Cernadas M, Baron RM. Chronic endotoxin exposure
produces airflow obstruction and lung dendritic cell expansion. Am J Respir Cell Mol
Biol. 2012 Apr 19.
Abstracts:
Inhaled Isoflurane in Mice Ameliorates LPS-and Ventilator-Induced Lung Injury. AA
Macias, D Culley, G Crosby, MA Perrella, and RM Baron. (American Thoracic Society
Meeting – New Orleans 2010. Poster Discussion).
Airway Reactivity and Persistent Inflammation is Associated with Antigen Presenting
Cell Population Shifts in a Murine Model of Chronic Inhalational Endotoxin Exposure.
PS Lai, MD, JM Austin, MD, RD Brown, BS, AA Macias, MD, MA Pinilla, MD, JA
Englert, MD, O Hofmann, PhD, W Hide, PhD, DC Christiani, MD, MS, MPH, M
Cernadas, MD, RM Baron, MD. (American Thoracic Society Meeting-Denver
2011.Poster Presentation).
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 6 Principal Investigators, 3 Senior Research
Associates, 3 Visiting Professors (anesthesia), 5 Postdoctoral Fellows and 5 support staff,
and its work is supported by 9 NIH-funded grants.
25
Laboratory Research in Pain
Igor Kissin, M.D., Ph.D.
Dr. Kissin’s interests are centered on the pharmacology of anesthetics and analgesics.
They have led to studies on 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 A beta 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
-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 (vanilliod 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.
The other area of Dr. Kissin’s investigations is the effect of peripheral nerve blocks in
chronic pain. The working hypothesis regarding this effect is that a temporary nerve
block can restore the normal afferent processing in the CNS following block resolution.
Since 2010 Dr. Kissin has also been developing a new scientometric indicator that can
determine the probability of a drug’s success – Top Journal Selectivity Index.
Selected Publications:
26
Kissin I. A call to reassess the clinical value of preventive (preemptive) analgesia. Anesth
Analg 2011;113:977-78.
Kissin I, Szallasi A. Therapeutic targeting of TRPV1 by resiniferatoxin, from preclinical
studies to clinical trials. Curr Top Med Chem 2011;11:2159-70.
Vlassakov KV, Narang S, Kissin I. Local anesthetic blockade of peripheral nerves for
treatment of neuralgias: systematic analysis. Anesth Analg 2011;112:1487-93.
Vlassakov KV, Narang S, Kissin I. Cutaneous anesthesia in neuropathic pain: systematic
analysis. J Anesth Clin Res 2012;3:199; D01:10.4172/2155-6148. 1000199
Kissin I. Can a bibliometric indicator predict the success of an analgesic? Scientometrics
2011;86:785-95.
Kissin I, Bradley EL Jr. Top Journal Selectivity Index and ‘me-too’ drugs. Scientometrics
2012;91:131-42.
Kissin I, Gelman S. Chronic postsurgical pain: Still a neglected topic? J Pain Res
2012;5:1-17.
Gary Strichartz, Ph.D.
Mechanisms of Chronic Pain
Chronic pain is costly, emotionally and psychologically debilitating and dispiriting to
tens of thousands of people. The Strichartz laboratory is investigating three areas of
chronic pain: 1. The role of endothelin-1 (ET-1), and endogenous peptide, in abnormal
pain from tissue injury, inflammation and cancer, 2. The mechanisms by which
prolonged pain and pain sensitization is caused by nerve growth factor, another
endogenous molecule that is released when peripheral tissues are injured, and 3. The
changes in the peripheral tissues and in the central nervous system that underlie the
development and persistence of chronic post-operative pain.
1. Endothelin receptor dynamics. 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
intracellular cellular ,[Ca+2]in , and enhances nociceptor excitability, by favoring the
opening of a tetrodotoxin-resistant voltage-gated Na+ channel found exclusively in
nociceptors, as well as causing a reduction of the currents carried by delayed-rectifier
type K+ channels. All these effects are mediated by the ETA sub-type of receptors for
ET-1. In addition, acute ET-1 injection under the skin enhances the amount of both
glutamate and CGRP in the epidermis, accounting for another pathway of rapid
27
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. All these actions are conducted through ETA receptors.
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,
thereby elevating pain behavior, whereas ETB receptors on keratinocytes, in the skin's
epidermis, are anti-hyperalgesic, countering the effects of pain stimuli and pain
sensitizers. This anti-algesic action occurs by the release of the opioid peptide betaendorphin from the keratinocytes that synthesize and store it. The eventual likelihood that
a nociceptor will generate afferent impulses to signal pain is critically dependent on the
dynamic changes wrought by pro-algesic neuronal ETA and ETB receptors and the antialgesic ETB receptors on keratinocytes, a dynamic which differs among different tissues,
e.g. between hairy skin and glabrous, hairless skin, and also which changes after injury
and inflammation.
Current work is focused on the role of the ET receptors in skin, and thus in the role of
skin as a sensory transducing organ rather than just a tissue thought provides structural
support and protection. 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 in vitro cultures allow a degree of autonomy and
manipulation that is difficult to achieve 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 immuno-cytochemistry).
Findings in this system indicate that ETA receptors are expressed primarily by basal,
proliferating keratinocytes and ETB receptors by differentiated, suprabasal keratinocytes.
ET-1 stimulates these cells to effect an increase in intracellular calcium, and also to
stimulate the enzyme adenylyl cyclase and thereby elevate the signaling molecule cyclic
AMP. Western blot analysis using antibodies that selectively bind to different parts of
the ETB receptor indicate that much of this receptor is cleaved and then both remains on
the surface, where it can still bind ET-1, and resides somewhere inside the cell, where it
may or may not have some residual function.
28
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 βendorphin (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.
Lower panels. Changes in intracellular [Ca+2] in human keratinocytes in response to
endothelin-1 (ET-1). A. Resting cells show a very low Ca-related fluorescence, B.
Elevated fluorescence from [Ca+2]in in Fura-2 loaded cells, with peak responses
captured at 20-30 sec after beginning a continuous exposure to 100nM ET-1.
2. Nerve Growth Factor and pain. In collaboration with the laboratory of Professor Grant
Nicol at the University of Indiana Medical center, we have been exploring the pathways
that couple the injection of nerve growth factor (NGF) in the skin to the increased
sensitivity to tactile and thermal stimulation at the injection site. In support of Dr.
Nicol’s observations on isolated sensory neurons in vitro, we have found that much of
29
this pain sensitization from NGF in vivo occurs via the low affinity p75ntr (neurotrophin)
receptor, a finding that disputes the commonly held assumption that the high affinity trkA
(tyrosine kinase) receptor is responsible for the pain from peripheral NGF. The
activation of the p75ntr pathway involves the critical participation of an unusual enzyme
called PKMzeta, an enzyme that is controlled by its biosynthesis and degradation rather
than by a regulatory sub-unit, as are most other typical PK (protein kinase) enzymes.
PKMzeta in the brain (hippocampus) has been shown to be important for memory and so
it may have an analogous function in the development of long-lasting hypersensitivity in
pain pathways, but through its actions in the periphery, skin, and in the spinal cord.
Map of the p75ntr- linked pathway by which NGF causes hyperalgesia. Activation of the
enzyme neutral sphingomyelinase (nSMase) leads to release of ceramide from membrane
sphingo-lipids. Ceramide, in turn, is converted by several steps to sphingosine-1phosphate which then eventually increases the levels of the atypical protein kinase C
called PKMzeta (PKMζ). An inhibitor of atypical PKCs, mPPI, is able to prevent pain
that is caused by NGF injection into the paw when that inhibitor is injected into the paw
(i.pl.) or into the spinal fluid (i.th.) a day or two before NGF injection.
3. Mechanisms and Models of Chronic Post-operative Pain. Chronic post-operative pain
is an important clinical consequence following many procedures, including
thoracotomies, mastectomies, gynecological surgery, obstetrical surgery and most forms
of amputation. Our laboratory has been studying this phenbomenon by developing new
animal models that mimic surgical procedures. Using the hairy skin of the rat we have
found that skin incisions through the back, dorso-lumbar region, cause both primary (near
the wound) and secondary (far from the wound) mechanical hypersensitivity, but that
these elevated “pain” responses can be prevented by application of local anesthetics that
are released slowly from synthetic “microspheres”. Incisions through the medial thigh,
followed by an hour-long retraction of the skin and muscle that entraps the saphenous
30
nerve (skin-muscle incision and retraction, SMIR), leads to a profound and long-lasting
(4-5 week) tactile hypersensitivity of the ipsilateral plantar paw surface, a striking
example of secondary hyperalgesia since this region is not directly innervated by the
saphenous nerve. Microscopic examination documents the absence of nerve damage at
the retraction site. But investigations of spinal cord segments that process signals from
incoming nerves show that a signaling molecule called p38 MAPKinase is
phosphorylated, and thus activated, with a time-course that parallels the development of
pain after the SMIR procedure. Inhibitors of the p38 activated pathway injected into the
spinal fluid next to these segments are able to prevent the pain from developing if given
at the time of surgery, but once the pain has developed, a week or two after surgery, these
same agents are largely ineffective.
Current research on chronic pain in our laboratory uses a rat model of thoracotomy with
rib retraction. Such a procedure results in at least several months of tactile sensitivity,
that is spread over much of the back. After surgery the pre-operative “pain” responses,
local twitches and quick single withdrawal “reflexes”, are replaced by more complex
behavior that indicates a type of processing in the brain of true, perceived pain. We have
converted these complex responses to a quantifiable Qualitative Pain Index, shown that it
is responsive to the selective analgesic morphine, and that it is diminished in parallel to
the reduction in mechano-sensitive area and threshold reduction in rats that have received
spinal Resolvins at the time of surgery.
Selected Publications:
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
Khodorova A, Strichartz G. Contralateral Paw Sensitization Following Injection of
Endothelin-1: Effects of local anesthetics differentiate peripheral and central processes.
Neuroscience. 2010;165:553-60. DOI: 10.1016/j.neuroscience.2009.10.049
Khodorova A, Strichartz G. Remarkably Long-Lasting Tachyphylaxis
of Pain
Responses to ET-1: Evidence Against Central Nervous System Involvement. Can J
Physiol Pharmacol. 2010 ;88:668-75.
Gerner P, Wang CF, Lee BS, Suzuki S, Degirolami U, Gandhi A, Knaack D, Strichartz
G. The relationship between functional sciatic nerve block duration and the rate of release
of lidocaine from a controlled-release matrix. Anesth Analg. 2010;111:221-9.
Wang, C-F, Pancaro C, Gerner P, Strichartz, G. Prolonged suppression of post-incisional
pain by a slow-release formulation of lidocaine. Anesthesiology, 2011; 114:135-49.
Huang L, Wang C-F, Serhan CN, Strichartz G. Enduring prevention and transient
reduction of post-operative pain by intrathecal Resolvin D1. Pain 2011;152 : 557–565
31
Colvin A, Wang C-F, Soens MA, Mitani AA, Strichartz G, Gerner P.
Prolonged cutaneous analgesia from transdermal penetration of amitriptyline and
capsaicin. Reg Anesth Pain Med 2011; 36: 236-40.
Montmayeur JP, Barr TP, Kam SA, Packer SJ, Strichartz GR. Elevation of intracellular
calcium in clonal neuronal and embryonic kidney cells involves endogenous endothelinA receptors linked to phospholipase C through Gαq/11. Pharmacol Res 2011; 64:25867.
Huang L, Gao Y-J, Wang J, Strichartz G. Shifts in cell-type expression accompany a
diminishing role of spinal p38-MAPKinase activation over time during prolonged
postoperative pain. Anesthesiology 2011; 115:1281-90.
Ohri R, Blaskovich P, Wang J, Pham L, Nichols G, Hildebrand W, Costa D ,
Scarborough N , Herman C, Strichartz G. Prolonged nerve block by microencapsulated
bupivacaine prevents acute post-operative pain in rats. Reg Anesth Pain Med 2012;
37:607-615.
Barreveld AM, Witte J, Chahal H, Durieux ME, Strichartz G. Preventive analgesia by
local anesthetics: The reduction of post-operative pain by peripheral nerve blocks and
intravenous drugs. Anesth Analg (in press)
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 analgesics for prolonged pain relief. Local anesthetics are clinic
drugs that block action potentials in excitable membranes reversibly. The main targets of
local anesthetics are voltage-gated Na+ channels, which are responsible for the
generation and propagation of action potentials in excitable membranes. 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 α-subunit (Nav1.1-1.9) and one or two small βsubunit (β1-β4). The primary structure of the α-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
32
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. Four cell lines
have now been established in Dr. Wang’s laboratory: (1) inactivation-deficient rNav1.4WCW mutant channels, (2) inactivation-deficient hNav1.4-CW mutant channels, (3)
inactivation-deficient hNav1.7-WCW mutant channels, and (4) inactivation-deficient
hNav1.5-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.
Selected Publications:
Wang,G.K., T.Edrich, and S.Y.Wang. 2006. Time-Dependent Block and Resurgent Tail
Currents Induced by Mouse β4(154-167) 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.
Wang SY, Calderon J, G.K. Wang. Block of neuronal Na+ channels by antidepressant
duloxetine in a state-dependent manner. Anesthesiology. 2010; 113:655-65.
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
33
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:
34
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.
Edwards RR, Cahalan C, Mensing G, Smith M, Haythornthwaite JA. Pain,
catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol. 2011
Apr;7(4):216-24.
Edwards RR, Wasan AD, Michna E, Greenbaum S, Ross E, Jamison RN. Elevated pain
sensitivity in chronic pain patients at risk for opioid misuse. J Pain. 2011 Sep;12(9):95363.
Edwards RR, Mensing G, Cahalan C, Greenbaum S, Narang S, Belfer I, Schreiber KL,
Campbell C, Wasan AD, Jamison RN. Alteration in Pain Modulation in Women With
Persistent Pain After Lumpectomy: Influence of Catastrophizing. J Pain Symptom
Manage. 2012 Oct 24.
Robert N. Jamison, Ph.D.
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 Professor at Harvard Medical School with appointments in the
Departments of Anesthesiology, Perioperative and Pain Medicine, Psychiatry, and
Physical Medicine and Rehabilitation. He is a clinical psychologist with over 30 years’
experience working with chronic pain patients and 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, including a smart phone pain application, 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 in primary care, 2)
craving and neuropsychological effects of long-term opioid use in chronic pain patients,
3) the association between psychopathology and placebo analgesia in patients with back
pain, 4) use of cannabinoids for chronic pain patients and 5) motivational compliance
35
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 Edgar Ross, MD, Edward Michna, MD JD, David Janfaza, MD, Sanjeet
Narang, MD, Srdjan Nedeljkovic, MD, Elizabeth Scanlan, RNC MSN NP, Ajay Wasan,
MD, Robert Edwards, Ph.D. and Michele Matthews, Pharm.D. as well as colleagues from
other academic and private institutions. He recently also has been the principal
investigator of the Opioid Prescription Evaluation and Risk Assessment (OPERA) study
which has focused on reducing opioid misuse among chronic pain patients within
primary care. He has responsibility of serving as a primary scientific mentor on three
NIH K23 awards. He is on the Editorial Boards for Pain Medicine, Pain Practice, The
Journal of Pain, MD Net Guide, Pain Research and Practice, Clinical Journal of Pain, and
Pain: Clinical Updates. He has authored two books, a CD-ROM, and over 200 peerreviewed articles, chapters, and abstracts in the areas of behavioral medicine, chronic
pain, and opioid therapy.
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 contributions 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. 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.
Recent Publications:
Marceau LD, Link CL, Smith LD, Carolan SJ, Jamison RN. In-clinic use of electronic
pain diaries: barriers of implementation among pain physicians. J Pain Symptom Manage
2010;40:391-404.
Jamison RN, Ross EL, Michna E, Chen, LQ, Holcomb C, Wasan A. Substance abuse
treatment for high risk chronic pain patients on opioid therapy: a randomized trial. Pain
2010; 150: 390-400.
Butler SF, Budman SH, Fanciullo GJ, Jamison RN. Cross Validation of the Current
Opioid Misuse Measure (COMM) to Monitor Chronic Pain Patients on Opioid Therapy.
Clin J Pain 2010;26:770-776.
Jamison RN, Washington TA, Gulur P, Fanciullo GJ, Arscott JR, McHugo GJ, Baird JC.
Reliability of a three-dimensional pain mapping program. Pain Med 2011;12:344-351.
36
Edwards RR, Wasan A, Michna E, Greenbaum S, Ross E, Jamison RN. Elevated pain
sensitivity in chronic pain patients at risk for opioid misuse. J Pain 2011;9:953-963.
Wasan AD, Ross EL, Michna E, Chibnik L, Greenfield S, Weiss R, Jamison RN.
Characterizing craving of prescription opioids in patients with chronic pain: a
longitudinal outcomes trial. J Pain 2012; 13:146-154.
Jamison RN, Edwards RR. Risk factor assessment for problematic use of opioids for
chronic pain. Clin Neuropsychologist. August 30, 2012.
DOI:10.1080/13854046.2012.715204. http://dx.doi.org/10.1080/13854046.2012.715204.
Edwards RR, Mensing G, Cahalan C, Greenbaum S, Narang S, Belfer I, Schreiber KL,
Cambell, C, Wasan, AD, Jamison RN. Alteration in pain modulation in women with
persistent post-lumpectomy pain: influence of catastrophizing. J Pain Sym Manage 2012:
(in press).
Bruehl S, Liu, X, Burns J, Chont M, Jamison RN. Associations between daily chronic
pain intensity, daily anger expression, and trait anger expressiveness: an ecological
momentary assessment study. Pain. 2012: 153:2352-2358.
Jamison RN, Edwards RR, Liu X, Ross E, Michna E, Warnick M, Wasan AD. Effect of
negative affect on outcome of an opioid therapy trial among low back pain patients. Pain
Practice. 2012: (in press).
37
Associations between momentary chronic pain intensity and subsequent behavioral anger
expression as a function of trait anger-out levels. The greatest level of behavioral anger
expression is observed among low trait anger-out individuals experiencing high pain
intensity (Bruehl S, Liu, X, Burns J, Chont M, Jamison RN. Pain 2012).
Ajay D. Wasan, M.D., M.Sc.
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
38
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 presurgical 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
39
impact both in communicating practice and research internationally as well as improving
the quality of care in this area.
CENTER FOR PERIOPERATIVE GENOMICS
The research programs within the Center are focused on exploring the genetic inputs into
functional and structural heart disease, with a special focus on the perioperative
environment. Each program is lead by a Principal Investigator with expertise in their
area of interest. The Principal Investigators meet, collaborate and coalesce resources to
achieve their own and wider goals.
As well as being the collaborative umbrella for personnel, the Center is the over-arching
structure for three large-scale studies that are data and tissue resources for Investigators.
The CABG Genomics Program, (http://clinicaltrials.gov/show/NCT00281164) is a twoinstitution study that provides patient data and genomics resources to the investigators.
Since 2001, ~2,500 patients undergoing cardiac surgery have enrolled in the Program.
Clinical data, patient outcomes, and DNA, buffy coat mRNA, plasma, and serum, are
collected and stored for subsequent genotyping and measurement of circulating
biomarkers. Specifically, the Program seeks to identify the relationships between genetic
variation and major adverse cardiac events, bleeding and other patient outcomes after
CABG surgery. The Program has been, and will continue to be, a vital resource for our
individual research goals and has resulted in multiple studies and publications. In
addition, it has been a vehicle for collaboration with other US and International research
groups with similar resources and goals.
The International Bicuspid Aortic Valve Consortium, a 16 institution consortium
investigating the genetic etiology of bicuspid aortic valve disease, is lead by Dr. Simon
Body. The consortium was started in 2011 and encompasses investigators from Europe,
Canada and the U.S. (BAVGenetics http://clinicaltrials.gov/ct2/show/NCT01026571).
Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation,
occurring in 0.5-1.2% of the US population. The goals are to elucidate the genetic
pathways involved in BAV etiology and the subsequent progression of aortic valve
calcification; work that has been hampered by the low numbers of patients enrolled in
individual centers, the uncertain genetic model and the few animal models of BAV that
are relevant to human disease. We perform our work by identifying genetic etiologies of
BAV through exome sequencing and GWAS analyses, and re-sequencing and replication
in other BAV cohorts. To establish the role of these genes in the developmental
embryology of the aortic outflow tract, we perform high-throughput zebrafish functional
and anatomical assays and by in-situ hybridization. Finally to define BAV pathways of
calcific aortic stenosis we perform transcriptional analyses of the aging aortic valve in
GATA5-/- BAV mice, and in diseased aortic valve tissue derived from humans
undergoing AVR.
The TRANSCRIBE study (Transcriptomic Analysis of Left Ventricular Gene
Expression; http://clinicaltrials.gov/ct2/show/NCT00985049) aims to identify the genes
expressed in response to acute myocardial ischemia, and the genetic modifiers of such
40
gene expression. These genetic controllers of gene expression (expression quantitative
trait loci – eQTLs) determine an individual’s response to ischemia and allow us to
identify the pathways that respond to an ischemic insult.
The individual research report narratives of the Center's Investigators (individual PIs
listed below) indicate the research emphasis of each Principal Investigator's laboratory.
Current support includes grants from the National Institutes of Health, American Heart
Association, Society of Cardiovascular Anesthesiologists, amongst others.
Personnel in the Center for Perioperative Genomics
Dr. Simon Body, MBChB MPH, Principal Investigator
Dr. Amanda Fox, MD MPH, Principal Investigator
Dr. J. Daniel Muehlschlegel, MD MMSc, Principal Investigator
Dr. Stanton Shernan, MD, Principal Investigator
Dr. Kuang-Yu Liu, PhD, Statistician
Dr. Tim Bodinaku, MD, Research Associate
Ms. Svetlana Gorbatov, MPH, Research Associate
Mr. James Gosnell, RN, Research Nurse
Ms. Chelsea Lynes, BS, Research Assistant
Simon C, Body, MBChB MPH, Principal Investigator
Dr. Simon Body is the Principal Investigator of the CABG Genomics Program and the
International Bicuspid Aortic Valve Consortium. His primary foci are the genetic
etiology and molecular biology of atrial fibrillation occurring after cardiac surgery, and
the genetic etiology of bicuspid aortic valve disease.
1. Genetic Etiology and Molecular Biology of Atrial Fibrillation
Atrial fibrillation (AF) is a frequent cause of stroke, other morbidity, mortality and cost;
>20% of Americans will suffer from it in their lifetimes. Thus AF is an important and
costly disease with an identified heritable locus. There is strong evidence for heritability
of AF, with an off-spring risk ratio of ~2. Recently, a frequent chromosome 4q25
haplotype has been associated with AF in several Caucasian and non-Caucasian
ambulatory populations. This haplotype has a remarkably-high population-attributable
risk for AF of 23.7%. However, the biological mechanisms responsible for this
association between the 4q25 haplotype and AF have not yet been identified. AF is also a
frequent adverse outcome after cardiac surgery and is associated with significant short
and long-term patient morbidity and mortality. We have recently demonstrated that the
same genetic variants in the 4q25 locus detailed above, are also associated with newonset postoperative AF in over 1000 Caucasian patients undergoing cardiac surgery,
replicated using a separately collected cohort. We have narrowed this region to a single
haplotype encompassing 66,000 bp of chromosome 4. The concordance of variants in
two similar phenotypes strongly supports a common biological mechanism for AF in the
ambulatory and post-surgical environments, that allows examination of the genetic
mechanisms of AF using surgically-collected atrial tissue. We therefore use the
perioperative cardiac surgical environment, with its ready availability of atrial tissue and
frequent AF phenotype, as a model to determine the biological mechanisms of the
association between the AF-associated 4q25 haplotype and AF. Our overall goal is to
41
identify the genetic and molecular mechanisms whereby genetic variation in the 4q25
locus causes atrial fibrillation.
2. International Bicuspid Aortic Valve Consortium
The International Bicuspid Aortic Valve Consortium, a 16 institution consortium
investigating the genetic etiology of bicuspid aortic valve disease, is lead by Dr. Simon
Body. The consortium was started in 2011 and encompasses investigators from Europe,
Canada and the U.S. (BAVGenetics http://clinicaltrials.gov/ct2/show/NCT01026571).
Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation,
occurring in 0.5-1.2% of the US population. In young adults, it is generally a benign
abnormality; but in older adults it is associated with thoracic aortic aneurysm or
dissection in 20-30% of those with BAV. BAV is strongly associated with early
development of aortic valve calcification or incompetence in >50% of BAV patients, and
accounts for ~40% of the >30,000 aortic valve replacements (AVR) performed in the US
each year. Yet, we know little of the etiology, cellular events and modifiers of
progression of BAV to calcific aortic valve disease and we still do not understand the
genetic cause(s) of BAV despite evidence for its high heritability. In a few families,
highly-penetrant dominant mutations of NOTCH1 have been associated with BAV.
Additional susceptibility loci have also been identified but not replicated. However, a
majority of individuals with BAV do not report family members with BAV and do not
have NOTCH1 mutations. Furthermore, even though aortic disease warranting surgery
occurs much earlier with BAV than TAV, there is a wide variation in disease severity and
progression of aortic valve disease, epitomized by the range of age of presentation for
AVR, implying that this variation may be of genetic etiology, independent of the altered
blood flow patterns of BAV. Because of the previously small collected cohorts,
modifiers of disease have been difficult to identify.
Our goals are to elucidate the genetic pathways involved in BAV etiology and the
subsequent progression of aortic valve calcification; work that has been hampered by the
low numbers of patients enrolled in individual centers, the uncertain genetic model and
the few animal models of BAV that are relevant to human disease. Our Specific Aims
are to:
1. Identify genetic etiologies of BAV through exome sequencing and GWAS analyses.
2. Prioritize candidate BAV genes for re-sequencing in BAV cohorts, via highthroughput zebrafish functional and anatomical assays and by in-situ hybridization.
3. Define BAV pathways of calcific aortic stenosis through transcriptional analyses of the
aging aortic valve in GATA5-/- BAV mice, and in diseased aortic valve tissue derived
from humans undergoing AVR.
Amanda A. Fox, MD MPH, Principal Investigator
Biomarker and Genomic Associations with Heart Failure in Cardiac Surgical Patients
Dr. Amanda Fox is a Co-Investigator in the CABG Genomics Program. Her primary
research focus within this program has been to identify genetic variants and plasma
biomarkers that associate with short- and long-term heart failure and related morbidities
in primary coronary artery bypass graft (CABG) surgical patients.
42
1. Plasma B-type Natriuretic Peptide (BNP) as a Prognostic Biomarker
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 pressure and volume overload and ischemia. Using blood
and clinical perioperative and follow-up data collected from enrollees in the CABG
Genomics cohort we have demonstrated that that increased preoperative and peak
postoperative BNP concentrations associate with increased early postoperative
ventricular dysfunction, longer surgical hospital stays, increased long-term all-cause
mortality, decreased 6 month - 2 year postoperative physical functioning, decline in longterm postoperative left ventricular ejection fraction, and increased 5-year postoperative
hospitalizations and deaths related to heart failure. We have reported these findings in
multiple publications listed below.
2. Natriuretic Peptide System Genetics and Adverse Cardiovascular Events
We have assessed the relationship between variations within 7 genes related to the
natriuretic peptide system and both perioperative BNP concentrations and occurrence of
early postoperative ventricular dysfunction after primary CABG surgery. We identified
loci within the NPPA/NPPB (natriuretic peptide A and B precursor protein genes) and
NPR3 (natriuretic peptide clearance receptor gene) that independently associate with
incidence of early postoperative ventricular dysfunction. These findings were presented
at the American Society of Anesthesiologists’ Annual Meeting Best Abstracts of the
Meeting Session in 2008, and were published in Anesthesiology.
3. Natriuretic Peptide Metabolism
Corin is a serine protease that cleaves precursor A-type and B-type natriuretic peptides
into active ANP and BNP, respectively. We are assessing how variants within the Chr 4
CORIN gene associate with peak postoperative plasma BNP and corin concentrations and
longer-term (5 year) postoperative heart failure hospitalizations and mortality. We are
also exploring the role of gender in influencing perioperative BNP metabolism.
4. Genome-Wide Association Study of Early Postoperative Ventricular Dysfunction
We conducted a small whole genome association study and subsequent replication
studies to identify novel genetic loci strongly associated with early ventricular
dysfunction after primary CABG surgery. This study identified three novel genetic loci
associated with early postoperative ventricular dysfunction (PLoS ONE, 2011). We are
presently pursuing additional replication of these findings with a group who has collected
CABG cohort data at the University of British Columbia, Vancouver, Canada. We are
also assessing genetic loci that have been identified in ambulatory GWAS literature to be
associated with heart failure, cardiac conduction delay, and coronary artery disease for
association with short-term heart failure after primary CABG surgery.
5. Genome-Wide Association Study of Long-term Heart Failure
We are conducting a genome-wide association study and replication studies to identify
genetic loci associated with the development of longer-term heart failure during the 5
43
years following isolated primary CABG surgery. This work is presently supported by a
Mid-Career Grant from the Society of Cardiovascular Anesthesiologists.
Jochen Daniel Muehlschlegel, MD MMSc, Principal Investigator
Dr. J. “Danny” Muehlschlegel is a Co-investigator in the CABG Genomics Program and
the Principal Investigator of the TRANSCRIBE study (Transcriptomic Analysis of Left
Ventricular Gene Expression; http://clinicaltrials.gov/ct2/show/NCT00985049). He is
working on several projects to examine the response of the human myocardium to
ischemia.
Clinical Significance
Myocardial ischemia and infarction due to coronary artery disease impose an enormous
socioeconomic burden through their impact on a majority of Americans at some stage in
their life. Identifying genes and pathways responsible for ischemic injury and genetic
sources of variation in responses to ischemia may identify potential drug targets or other
therapeutic interventions.
With our research, we aim to identify the genes expressed in response to acute
myocardial ischemia, and the genetic modifiers of such gene expression using an in-vivo
human model. These genetic controllers of gene expression (expression quantitative trait
loci – eQTLs) determine an individual’s response to ischemia and allow us to identify the
pathways that respond to an ischemic insult.
Our novel methodology uses unbiased state-of-the-art high-coverage methods to
completely examine the human heart’s response to ischemia. Using a human model of
myocardial ischemia has tremendous value because of its direct applicability, without
errors of interpretation from species and tissue variability.
1. Genetics of Cardiovascular Disease
Coronary artery disease (CAD) and myocardial infarction (MI) are the leading causes of
death and disability worldwide. Early linkage studies identified several rare loci with
large risk of developing MI. In the last few years, genome-wide association (GWA)
studies have detected common variants for MI. The strongest and most replicated genetic
risk for MI has been found in a locus on chromosome 9p21. We recently established that
the same variants in the 9p21 locus are associated with both perioperative myocardial
injury (PMI) and mortality after isolated primary coronary artery bypass graft (CABG)
surgery with cardiopulmonary bypass (CPB), independent of CAD severity. Most
importantly, this chromosomal region and the identified SNPs are not located within
protein coding genes, but are likely markers of the causal variant. To gain full
understanding of the biology, one needs to identify the functional variant and that
variant’s mechanism. Therefore, we are examining the eQTLs associated with SNPs for
one or more nearby genes.
2. Gene expression in Cardiovascular Disease
Gene expression is an important intermediate phenotype that provides information about
environmental and genetic effects on cellular processes. Disease-associated SNPs have
44
been found in loci without nearby protein coding genes – so-called “gene deserts”, such
as 9p21. Similarly, disease-associated SNPs have been identified in promoter and
enhancer regions of genes, thus affecting gene expression levels, which have been shown
in a candidate gene-driven approach. These observations underscore the central rationale
for this proposal – that identification of nearby or distant genes that possess allelespecific expression provide direct access to the fundamental biology of cardiovascular
disease.
3. Expression Quantitative Trait Loci
Some common DNA variants alter the expression of human genes. By analyzing whole
genome RNA expression in normal and diseased tissues and treating the expression levels
of genes as quantitative traits, gene expression that is highly correlated with nearby (cis)
genetic variants can establish the direct biological mechanism of the observed association
between SNP and disease. GWA studies using eQTLs have identified widespread
regulation of gene expression by cis-acting SNPs. Similarly, several studies have found
that SNPs and other genetic variants alter the splicing of mRNA, thus creating either new
or different quantities of proteins. Public datasets of GWAS and eQTLS results are
becoming increasingly available, including the NIH Genotype-Tissue Expression (GTeX)
Project (http://nihroadmap.nih.gov/GTEx/index.asp). However, these existing datasets do
not provide the disease-specific GWAS and eQTL data in individuals with myocardial
injury.
4. Tissue Specificity of the Transcriptome
Gene expression is profoundly specific to each cell-type; even closely related cell types
such as lymphoblastoid cells and T-cells share only a small fraction of cis-eQTLs. Up to
80% of regulatory variants are cell-type specific with regulatory variant complexity
correlating with transcript complexity. Therefore, for SNPs associated with a particular
disease phenotype, eQTL associations need to be performed using the tissue involved in
the pathogenesis of the disease. We believe that only by examining left ventricular tissue
are we capable of discerning the biological mechanisms of myocardial injury.
In addition, Dr. Muehlschlegel has an active research interest in transesophageal
echocardiography (TEE) simulation and to this end, has designed a didactic TEE
curriculum for residents, during which time they get evaluated before and after their
rotation on the TEE simulator. Goals of this project are to ascertain the value of simulated
TEE teaching above and beyond conventional hands-on teaching. Furthermore, the
validity of TEE simulation as a testing tool is examined. 1-31
Publications of the Center for Perioperative Genomics
1. Opotowsky AR, Perlstein T, Landzberg MJ, Colan SD, O'Gara PT, Body SC, Ryan
LF, Aranki S, Singh MN. A shifting approach to management of the thoracic aorta in
bicuspid aortic valve. J Thorac Cardiovasc Surg 2012.
2. Lee GC, Kicza AM, Liu KY, Nyman CB, Kaufman RM, Body SC. Does rotational
thromboelastometry (ROTEM) improve prediction of bleeding after cardiac surgery?
Anesth Analg 2012;115:499-506.
45
3. Fox A, Body S, Collard C, Liu K-Y, Muehlschlegel J, Marcantonio E, Shernan S.
Increased preoperative and peak postoperative B-type natriuretic peptide (BNP) associate
with decreased left ventricular ejection fraction after primary coronary artery bypass graft
surgery American Society of Anesthesiologists Annual Meeting. Washington, DC, 2012.
4. Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Smith SA, Lichtner P, Collard CD,
Shernan SK, Hartwig JH, Body SC, Hoffmeister KM. Polymorphism in the proteaseactivated receptor-4 gene region associates with platelet activation and perioperative
myocardial injury. Am J Hematol 2011.
5. Muehlschlegel JD. If a troponin falls in a forest but no one measures it, does it really
matter? Anesthesiology 2011;114:732-3.
6. Lipman PJ, Liu KY, Muehlschlegel JD, Body S, Lange C. Inferring genetic causal
effects on survival data with associated endo-phenotypes. Genet Epidemiol 2011;35:11924.
7. Lemaire SA, McDonald ML, Guo DC, Russell L, Miller CC, 3rd, Johnson RJ,
Bekheirnia MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C,
Holmes KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M,
Coselli JS, Estrera AL, Safi HJ, Belmont JW, Leal SM, Milewicz DM. Genome-wide
association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic
dissections spanning FBN1 at 15q21.1. Nat Genet 2011;43:996-1000.
8. Fox AA, Pretorius M, Liu KY, Collard CD, Perry TE, Shernan SK, De Jager PL,
Hafler DA, Herman DS, DePalma SR, Roden DM, Muehlschlegel JD, Donahue BS,
Darbar D, Seidman JG, Body SC, Seidman CE. Genome-wide assessment for genetic
variants associated with ventricular dysfunction after primary coronary artery bypass
graft surgery. PLoS One 2011;6:e24593.
9. Fox AA, Marcantonio ER, Collard CD, Thoma M, Perry TE, Shernan SK,
Muehlschlegel JD, Body SC. Increased peak postoperative B-type natriuretic peptide
predicts decreased longer-term physical function after primary coronary artery bypass
graft surgery. Anesthesiology 2011;114:807-16.
10. Fox AA, Body SC. Assessment of preoperative B-type natriuretic peptide in adult
surgeries: is it useful? Anesth Analg 2011;112:1005-7.
11. Fox A, Body S, Collard C, Shernan S, Marcantonio E. Increased preoperative and
peak postoperative B-type natriuretic peptide (BNP) associate with heart failure related
hospitalization or mortality after primary coronary artery bypass graft surgery American
Society of Anesthesiologists Annual Meeting. Chicago, IL, 2011.
12. Perry TE, Muehlschlegel JD, Liu KY, Fox AA, Collard CD, Shernan SK, Body SC.
Plasma neutrophil gelatinase-associated lipocalin and acute postoperative kidney injury
in adult cardiac surgical patients. Anesth Analg 2010;110:1541-7.
46
13. Perry TE, Muehlschlegel JD, Liu KY, Fox AA, Collard CD, Body SC, Shernan SK.
Preoperative C-reactive protein predicts long-term mortality and hospital length of stay
after primary, nonemergent coronary artery bypass grafting. Anesthesiology
2010;112:607-13.
14. Muehlschlegel JD, Shernan SK, Body SC. From creatine kinase-MB to troponin: do
we really need to differentiate between myocardial injury and infarction? Anesthesiology
2010;113:1479-80.
15. Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Collard CD, Shernan SK, Body SC.
Heart-type fatty acid binding protein is an independent predictor of death and ventricular
dysfunction after coronary artery bypass graft surgery. Anesth Analg 2010;111:1101-9.
16. Muehlschlegel JD, Liu KY, Perry TE, Fox AA, Collard CD, Shernan SK, Body SC.
Chromosome 9p21 variant predicts mortality after coronary artery bypass graft surgery.
Circulation 2010;122:S60-5.
17. Liu KY, Muehlschlegel JD, Perry TE, Fox AA, Collard CD, Body SC, Shernan SK.
Common genetic variants on chromosome 9p21 predict perioperative myocardial injury
after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2010;139:483-8, 8
e1-2.
18. Garvin S, Muehlschlegel JD, Perry TE, Chen J, Liu KY, Fox AA, Collard CD, Aranki
SF, Shernan SK, Body SC. Postoperative activity, but not preoperative activity, of
antithrombin is associated with major adverse cardiac events after coronary artery bypass
graft surgery. Anesth Analg 2010;111:862-9.
19. Garvin S, FitzGerald DC, Despotis G, Shekar P, Body SC. Heparin concentrationbased anticoagulation for cardiac surgery fails to reliably predict heparin bolus dose
requirements. Anesth Analg 2010;111:849-55.
20. Garvin S, Fitzgerald D, Muehlschlegel JD, Perry TE, Fox AA, Shernan SK, Collard
CD, Aranki S, Body SC. Heparin dose response is independent of preoperative
antithrombin activity in patients undergoing coronary artery bypass graft surgery using
low heparin concentrations. Anesth Analg 2010;111:856-61.
21. Fox AA, Muehlschlegel JD, Body SC, Shernan SK, Liu KY, Perry TE, Aranki SF,
Cook EF, Marcantonio ER, Collard CD. Comparison of the utility of preoperative versus
postoperative B-type natriuretic peptide for predicting hospital length of stay and
mortality after primary coronary artery bypass grafting. Anesthesiology 2010;112:84251.
22. Caglayan E, Romeo GR, Kappert K, Odenthal M, Sudkamp M, Body SC, Shernan
SK, Hackbusch D, Vantler M, Kazlauskas A, Rosenkranz S. Profilin-1 is expressed in
human atherosclerotic plaques and induces atherogenic effects on vascular smooth
muscle cells. PLoS One 2010;5:e13608.
47
23. Perry TE, Muehlschlegel JD, Liu KY, Fox AA, Collard CD, Body SC, Shernan SK.
C-Reactive protein gene variants are associated with postoperative C-reactive protein
levels after coronary artery bypass surgery. BMC Med Genet 2009;10:38.
24. Muehlschlegel JD, Perry TE, Liu KY, Nascimben L, Fox AA, Collard CD, Avery
EG, Aranki SF, D'Ambra MN, Shernan SK, Body SC. Troponin is superior to
electrocardiogram and creatinine kinase MB for predicting clinically significant
myocardial injury after coronary artery bypass grafting. Eur Heart J 2009;30:1574-83.
25. Fox AA, Collard CD, Shernan SK, Seidman CE, Seidman JG, Liu KY,
Muehlschlegel JD, Perry TE, Aranki SF, Lange C, Herman DS, Meitinger T, Lichtner P,
Body SC. Natriuretic peptide system gene variants are associated with ventricular
dysfunction after coronary artery bypass grafting. Anesthesiology 2009;110:738-47.
26. Fitzgerald DJ, Patel A, Body SC, Garvin S. The relationship between heparin level
and activated clotting time in the adult cardiac surgery population. Perfusion 2009;24:936.
27. Body SC, Collard CD, Shernan SK, Fox AA, Liu KY, Ritchie MD, Perry TE,
Muehlschlegel JD, Aranki S, Donahue BS, Pretorius M, Estrada JC, Ellinor PT, NewtonCheh C, Seidman CE, Seidman JG, Herman DS, Lichtner P, Meitinger T, Pfeufer A,
Kaab S, Brown NJ, Roden DM, Darbar D. Variation in the 4q25 chromosomal locus
predicts atrial fibrillation after coronary artery bypass graft surgery. Circ Cardiovasc
Genet 2009;2:499-506.
28. Perry TE, Muehlschlegel JD, Body SC. Genomics: risk and outcomes in cardiac
surgery. Anesthesiol Clin 2008;26:399-417.
29. Muehlschlegel JD, Body SC. Impact of genetic variation on perioperative bleeding.
Am J Hematol 2008;83:732-7.
30. Fox AA, Shernan SK, Collard CD, Liu KY, Aranki SF, DeSantis SM, Jarolim P,
Body SC. Preoperative B-type natriuretic peptide is as independent predictor of
ventricular dysfunction and mortality after primary coronary artery bypass grafting. J
Thorac Cardiovasc Surg 2008;136:452-61.
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, "Sixsigma Systolic Arterial Pressure Alarms", European Society of Anesthesia Annual
Meeting, Copenhagen, Denmark, June 2008.
48
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.
Joseph M. Garfield, M.D.
Research in Professionalism, Medical Education, Clinical Decision Making &
Quality Improvement
Departmental Co-Investigators:
Daniel Dedrick, M.D.
Frances B. Garfield, Ph.D.
Pankaj Sarin, M.D.
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
49
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 intraoperative 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
50
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 studying the cardiac output changes during labor and
delivery, and coagulation profile following blood administration.
The current concept of administering 1:1 RBC/Plasma was studied in a in-vitro model.
This study showed that 1:1:1 unit RBC/Plasma/Platelets maintained better coagulation
profile as compared to blood/plasma of 3:1. This study won the Gertie Marx research
competition award to one of our fellows. The full manuscript is under preparation.
51
Cardiac output changes during labor and delivery following epidural and combined spinal
epidural analgesia were studied to determine changes in cardiac output. The study
showed significantly more decreases in cardiac output following CSE as compared to
those in the epidural group. The full manuscript is under preparation.
As a co-author, we investigated the learning profile of spring loaded syringes use for
identifying epidural space. The study is accepted for publication in Anesthesia and
Analgesia (Carabuena J, Kodali BS, Tsen L. (In press). Learning curve associated with
using spring loaded syringes for identification of epidural space. Anesth Analg; 2013).
I am continuing efforts to promote capnography use during perioperative and outside of
the operating rooms through my website www.capnography.com that has undergone
several revisions periodically. A notable publication is forthcoming in the January issue
of Anesthesiology. 2013.
Using 3 D innovation in video technology was used for teaching labor and thoracic
epidural to residents. This application won 3rd prize at ASA Annual meeting twice (2009
and 2011).
K. Annette Mizuguchi, M.D., Ph.D.
Research Focus: Perioperative acute and chronic renal injury
Under the direction of my senior mentor Gyorgy Frendl, MD, PhD, Director of STAR
(Surgical ICU Translational Research Center) and Joseph Bonventre MD, PhD, BWH
Renal Division, former Co-Director of Harvard-MIT Science Technology Program and
Susrut Waikar, MD, MPH, BWH Renal Division, we have focused our research on
understanding perioperative acute kidney injury (AKI) and predicting sustained kidney
injury in high risk surgical cohorts that will lead to future prevention and progression of
kidney injury.
Selected Publication: Mizuguchi KA et al. Clin J Am Soc Nephrol 2012; 7:1071-8. Use
of postoperative creatinine to predict sustained kidney injury in patients undergoing
mesothelioma surgery.
Beverly K. Philip, M.D.
Research in Anesthesia for Ambulatory Surgery
The goals of anesthesia for ambulatory surgery are to provide a patient-chosen level of
consciousness with control of surgical stimuli 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
52
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, James Philip,
Laura Chang, McCallum Hoyt, Naila Moghul and James Gosnell, RN.
Selected Publications:
Apfel CC, Philip BK, Cakmakkaya OS et al. Who is at risk for postdischarge nausea and
vomiting after ambulatory surgery? Anesthesiology 2012; 117:475– 86.
Pergolizzi JV, Philip BK, Leslie JB, Taylor R, Raffa RB. Perspectives on transdermal
scopolamine for the treatment of postoperative nausea and vomiting,
J Clin Anesth 2012; 24å: 334-45.
Candiotti KA et al. [Philip BK, study group co-author]. Monitored anesthesia care with
dexmedetomidine: A prospective, randomized, double-blind, multicenter trial. Anesth
Analg 2010; 110: 47-56.
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:
James H Philip ME(E), MD
Bhavani Kodali MD
Thomas Edrich PhD, MD
Dirk Varelmann, MD
Stanley Leeson, MD
Alex Kuo, MD
53
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 multidisciplinary 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.
We have applied similar modeling and analytic techniques tomonitor and change
intraoperative monitoring and control of ventilation..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. Computerdesigned 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. Adjusting
anesthetic depth and breathing with CO2 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-agentscrubbing adapter to facility emergence from anesthesia. We are exploring new ways to
use the bypassed CO2 absorber present in current anesthesia machines to increase gas
exchange.
A Calculus of Monitoring has been developed, published, and is being utilized inresearch
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
54
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:
Connor CW, Philip JH. Closed-form solutions for the optimum equivalence of first-order
compartmental models and their implications for classical models of closed-circuit
anesthesia. Physiol. Meas. 30 (2009) N11–N21 http://stacks.iop.org/0967-3334/30/N11
Philip JH, Leeson S. Hypoventilation after Inhalation Anesthesia Can Cause
Reanesthetization. New Orleans LA. ASA 2009.
Edrich T, Varelmann DJ, Philip JH. Measurement of tracheal pressure with a Codman
catheter is possible without distortion of airway pressure in an in-vitro model. Palm
Beach FL. STA 2010.
Edrich T, Varelmann DJ, Philip JH. Measurement of Tracheal Pressure during
Bronchoscopy Using a Catheter-Tip Pressure Transducer. San Diego CA. ASA 2010.
Philip JH. GAS MAN® Workbook. Chestnut Hill. Med Man Simulations, Inc., a
nonprofit charitable organization, 2011. Print and electronic. http:/www.gasmanweb.com
Philip JH, Philip BK, Leeson S. Gas Man 4.1 Teaches Inhalation Kinetics. Presented at
the 15th World Congress of Anesthesiologists, Buenos Aires, Argentina, 27 Mar 2012.
Leeson S, Strichartz GR. Kinetics of Uptake and Washout of Lidocaine in Rat Sciatic
Nerve in vitro." Anesth Analg 2013 (in press)
Christine N. Sang, M.D., M.P.H.
Translational Pain Research
55
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:
Christine N. Sang, MD, MPH, Director
Kierin O'Donnell, BA, Program Coordinator
Candinho Gomes, BS, Lead Study Coordinator
Susan Twohig, RN, Research Nurse
Jia Ke, MS, Research Associate
Michael Mohan, Medical Student
Selected Publications:
Sang CN, Sathyanarayana R, and Sweeney M. Gastroretentive gabapentin formulation
reduces intensity of pain associated with postherpetic neuralgia: A Phase III clinical trial.
Clin J Pain, 2012 Jul 13.
Benzon HT, Connis RT, De Leon-Casasola OA, Glass DD, Korevaar WC, Cynwyd B,
Mekhail NA, Merrill DG, Nickinovich DG, Rathmell JP, Sang CN, Simon DL. Practice
guidelines for chronic pain management: an updated report by the American Society of
Anesthesiologists Task Force on Chronic Pain Management and the American Society of
Regional Anesthesia and Pain Medicine. Anesthesiology. 112(4):810-33, 2010.
Chizh BA, Sang CN. Use of Sensory Methods for Detecting Target Engagement in
Clinical Trials of New Analgesics. Neurotherapeutics 6(4): 749-754, 2009.
56
Sang CN and Bennett GJ. Novel Therapies for the Control and Prevention of Neuropathic
Pain. Neurotherapeutics 6(4):607-608, 2009.
Campbell J, Basbaum A, Dubner R, Dworkin R, Sang CN, eds. Emerging Strategies for
the Treatment of Neuropathic Pain. Vancouver: IASP Press, 2005.
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 has been translational or lab-based.
For patients undergoing assisted reproductive technologies, our group has focused on
improving the quality and safety of anesthetic options on reproductive outcomes; our
current work has found a relationship between hormonal influences (primarily estrogen)
and pre- and post-operative pain. 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; another introduced the term for a new method of analgesia and
anesthesia, the dural puncture epidural (DPE) technique. Currently, we are investigating
the proteomic expression of preeclampsia in spinal fluid and mechanisms by which
epidural analgesia has an effect on maternal temperature.
My most recent area of investigation and work is related to faculty and professional
development. Working with the BWH Center for Professionalism and Peer Support (I
serve as the Associate Director of the Center) and the BWH Center for Faculty
Development and Diversity, we have created and reported a series of new programs that
should assist faculty members both internally and elsewhere.
Selected Publications:
Carabuena JM, Mitani AM, Kodali BS, Tsen LC. The Learning Curve Associated with
the Epidural Technique using the Episure™ AutoDetect™ versus Conventional Glass
Syringe: An Open-Label, Randomized, Controlled, Cross-over Trial of Experienced
Anesthesiologists in Obstetric Patients. Anesth Analg (In Press).
Bauer ME, Kountanis JA, Tsen LC, Greenfield ML, Mhyre JM. Int J Obstet Anesth.
Risk factors for failed conversion of labor epidural analgesia to cesarean delivery
anesthesia: a systematic review and meta-analysis of observational trials. 2012 Aug 20.
[Epub ahead of print]
57
Garfield JM, Garfield FB, Holzman R, Mitani AA, Tsen LC. Practice policies for older
anesthesiologists in academic departments: a national survey of academic departmental
chairpersons. J Clin Anesth. 2012 May 21 (Epub ahead of print).
Palanisamy A, Mitani AA, Tsen LC. General anesthesia for cesarean delivery at a tertiary
care hospital from 2000 to 2005: a retrospective analysis and 10-year update. Int J Obstet
Anesth. 2011 Jan;20(1):10-6.
Tsen LC, Kodali BS. Can general anesthesia for cesarean delivery be completely
avoided? An anesthetic perspective. Expert Rev Obstet Gynecol 2010;5(5):517-24
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 Nov;107(5):1646-51.
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 provide consultation, direct help and teaching in the other sectors, where the
demand for advanced peripheral nerve block techniques is steadily rising.
Orthopedic Anesthesia and Analgesia: Drs. Zinboonyahgoon, Zeballos, Jangaza and
Vlassakov are completing a pilot retrospective study on correlation between femoral
nerve block local anesthetic regimens and in-hospital postoperative functional outcomes
after total knee arthoplasty, reflecting the dynamic goals and improvement in our
practice.
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, Rickerson, 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.
Breast Surgery and Prevention of Persistent Post-Mastectomy Pain: Closer collaboration
is being established and future clinical research is planned with the BWH/DFCI breast
surgeons – Drs. Zeballos and Schreiber are the project leaders.
58
Regional Anesthesia in Trauma and Critical Care: A big part of our group, including Drs.
Zeballos, Voscopoulos, Kleiner, Gareau, Nelson, Janfaza, O’Neill, Madan and
Vlassakov, are collaborating with the Acute Pain Service, the ICU teams and the Trauma
Surgery Division to improve pain control and dependent outcomes of patients with
critical illness and trauma, focusing on multiple rib fractures. Our first pilot study
compares continuous epidural versus paravertebral analgesia, and continuous intercostal
versus patient-controlled IV analgesia.
Translational Research: 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. Our younger colleagues joining our group, Drs. Zeballos, Nelson,
Schreiber, Gavin, Macias, are poised to make strides in that direction. Several joint
projects are in early stage of realization and development. We rely on support and advice
from the research leaders in the department.
Innovation in Regional Anesthesia: The complexity of some cases and their specific
challenges has inspired innovations and modifications of existing techniques by our
anesthesiologists. In 2008, a new modified ultrasound-guided retroclavicular brachial
plexus block was introduced by Drs. Vlassakov and Janfaza and has been gaining
popularity in clinical practice locally and internationally. It offers an alternative approach
when patient anatomy and/or function are significantly altered by disease or injury and
has become our approach of choice in continuous brachial plexus anesthesia targeting the
upper extremity distal to the mid-arm. (Fig.1)
59
This Retroclavicular Block was used for bilateral continuous anesthesia and analgesia for
the first successful bilateral upper extremity transplantation at the BWH in 2011.
Our latest innovation project (Drs. Zeballos, Voscopoulos, Janfaza and Vlassakov) is the
“ultrasound-guided retrolaminar block” technique, designed to make pain control after
rib fractures, breast, thoracic and abdominal surgery simpler and safer – we are studying
our first experience and awaiting our first publications. (Fig.2)
60
Regional Anesthesia Education: Finally, our group has always been interested in
developing and 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 – this academic year, we (Drs. Zeballos,
Nelson and Vlassakov) hope to develop a research-in-education project as a part of a
Harvard Medical School/Harvard Medical Academy program.
Selected Publications:
Vlassakov KV, Narang S, Kissin I. Local Anesthetic Blockade of Peripheral Nerves for
Treatment of Neuralgias: Systematic Analysis. Anesth Analg 2011;112:1487-93
Vlassakov KV, Narang S, Kissin I. Cutaneous Anesthesia in Neuropathic Pain:
Systematic Review. J Anesthe Clinic Res 2012, 3:199.
Abstracts:
"Ultrasound-Guided Retroclavicular Approach to the Brachial Plexus Cords"
Vlassakov K, Janfaza D. ASRA Annual Meeting - May 1, 2008, Playa del
Carmen, Mexico (Abstract)
Our First Experience with the Novel Ultrasound-Guided Retroclavicular Block of the
Brachial Plexus Cords in Patients with Normal Anatomy – Vlasakov K, Brooks ML,
Islami-Manuchehry A, Janfaza D. ASRA 34th Annual Meeting Phoenix, Arizona, 2009
(Abstract)
61
Severe Ischemic Pain due to Steal Phenomenon after AV Fistula Creation under Regional
Anesthesia. Islami-Manuchehry A, Vlasakov K. NYSORA World Congress, Dubai,
OAE, 2010 (Abstract)
Bilateral Brachial Plexus Analgesia via the Novel Ultrasound-Guided Retroclavicular
Approach. Vlasakov K, Islami-Manuchehry A. NYSORA World Congress, Dubai, OAE,
2010 (Abstract)
Voscopoulos CJ, Palaniappan D, Zeballos J, Kapottos M, Ko H, Shempp I, Kleiner S, Liu
X, Frendl G, Vlassakov K. Comparative Effectiveness of Continuous Thoracic
Paravertebral Blocks versus Thoracic Epidurals in Traumatic Rib Fracture Patients.
(Late-Breaking Abstracts). ASA 2012 Annual Meeting, Washington, D.C., October 2012
2010 publications:
Educational
Vlassakov, Kamen. The forearm tourniquet Bier block. Logic and authority versus
science and experience. Minerva Anestesiologica 2010 February; 76(2): 91-92.
Maxwell Weinmann, M.D.
Principal Investigator
Research Interests:
1. The application of minimally invasive technologies in evaluating vital organ function
and injury during shock states. In particular using Near Infra Red Spectroscopy. To that
end, we have established a NIRS Study Group made up of a diverse group of clinicians
and scientists from divergent backgrounds,including transplant surgeons, pulmonologists,
cardiac surgeons, neonatologists, trauma surgeons and anesthesiologists. Residents and
fellows have also been recruited to participate in, and be mentored, in these endeavors.
2. The development of medical technology.Most recently, a non electrical
Chemiluminescent Laryngoscope has been selected to be presented to the National
Health Service of Britain to be incorporated as part of the standard of care in the UK, and
is being developed by local industry here in MA.
Example of Grants:
Covidien and Cyalume Investigator originated grants for R and D.
Example of Projects:
2010
Spatially Modulated Near Infra Red Light and Near Infra Red Spectroscopy in the
Diagnosis of Early Shock. Finalist for Harvard Catalyst Grant:
PI: Max Weinmann MD.
62
Major goal: Develop greater understanding of shock pathophysiology and ischemic
thresholds of vital organs.
2010
Application of Modulated Near Infra Red Light and Near Infra red Spectroscopy in the
Diagnosis of Organ Ischemia in a Porcine Hemorrhagic Shock Model.
Frangioni J, Weinmann M, Kelly E
NIH RO1 Grant application
Co-Investigator: Max Weinmann, MD
Major goals: Development of light technologies in assessing regional oxygenation and
perfusion during shock states.
2011
Ischemia-Reperfusion Injury in Renal Transplantation: Real-Time Optical Diagnosis
Frangioni J, Weinmann M, Kelly E
NIH RO1 Grant application
Major goals: Evaluation/Diagnosis of ischemia reperfusion injury in renal transplantation
in animal and human model
2012
Prediction of Renal Graft Function as Determined by Peri Transplant Oxygenation Status
using Near Infra Red Spectroscopy.
Co-Principal Investigator: Max Weinmann, MD and Edward Kelly, MD
Covidien Grant
Major goal: Determine the relationship between graft oxygenation status pre transplant to
post transplant function as determined by NIRS
2012
Evaluation of Organ Specific Oxygen Dynamics During Hemorrhagic Shock
Co-Principal Investigator: Max Weinmann, MD and Edward Kelly, MD
Covidien Grant
63
Major goal: Application of NIRS technology in evaluating pathophysiology of shock in
terms of organ specific events. Its early diagnosis and the development of therapeutic
strategies.
2012
The application of NIRS in the Early Diagnosis of Neonatal Necrotizing Enterocolitis
Co-PI: Max Weinmann, MD, Edward Kelly, MD and David Ringer, MD
Major goal : To explore the clinical viability of NIRS as an early warning tool for NEC in
a neonatal ICU
Example of Publications:
Gioux S, Frangioni J, Ashitate Y, Cuccia D, Durkin A, Durr N, Kelly E, Lee B, Lin S,
Mazhar A, Moffitt L, Oketokoun R, Stockdale A, Tobias A, Tromberg B, Weinmann M.
First-in-human pilot study of a spatial frequency domain oxygenation imaging system. J
Biomed Opt. 16, 086015 (2011); doi:10.1117/1.3614566
Kristin Schreiber, MD.PhD
Dr. Schreiber is a clinical Anesthesiologist who joined BWH in July 2012 as a part time
staff anesthesiologist, part time regional anesthesia and research fellow. Her clinical
interests are in the further expansion of use of Regional Anesthesia, and the improvement
of management and prevention of acute and persistent pain after surgery. She has a PhD
in Neuroscience, which work focused on the role of spinal neural-immune intereactions
involved in the development of persistent hyperalgesia in animal models, as well as
neural-immune interactions in the enteric nervous system regulating pathogen invasion
during stress. She has more recently begun clinical studies in postmastectomy patients to
discern risk factors that may be used in a multifactorial preoperative screen for
individuals at risk for persistent pain after mastectomy and other types of surgery. These
studies suggest that psychosocial questionnaires, which measure psychological processes
such as catastrophizing and somatization, may reveal individual differences in the
psychological processing of pain. Similarly quantitative sensory testing, which assays the
individual’s threshold and response to standardized pain stimuli, may measure
differences in individual pain processing. These two groups of factors appear to correlate
more closely with the expression of persistent post mastectomy pain than surgical and
medical factors. She is also working in conjunction with Rob Edwards to investigate the
relationship between catastrophizing and pain processing, through psychophysical studies
employing quantitative sensory testing in chronic pain patients. She has also planned and
implemented an ongoing clinical trial comparing regional techniques (epidural vs
paravertebral nerve block) in open liver resection patients at the University of Pittsburgh,
where she completed her residency. Her research goals are to implement interventional
studies employing regional anesthestic and pharmacologic blockade in the perioperative
period to prevent persistent pain in those at highest risk.
64
Publications:
Alteration in Pain Modulation in Women with Persistent Postoperative Pain: Influence of
Catastrophizing. Robert R. Edwards, Ph.D., George Mensing, BA, Christine Cahalan,
BA, Seth Greenbaum, BA, Sanjeet Narang, MD., Robert N. Jamison, Ph.D., Inna
Belfer,MD, Ph.D., Kristin L. Schreiber, MD, Ph.D., Ajay D. Wasan, MD, (2012)Journal
of Pain and Symptom management, in press
Editorial: Perioperative Analgesia for Patients Undergoing Open Liver Resection:
Epidural or Paravertebral? Kristin L. Schreiber, MD, PhD, Tetsuro Sakai, MD, PhD,
(2012) Journal of Pain Relief 1:e112
Activation of spinal microglia in a model of peripheral inflammation-induced, longlasting contralateral hyperalgesia in mice. Kristin L. Schreiber, Alvin J. Beitz, and
George L. Wilcox (2008) Neuroscience Letters, 440(1):63-7
Evidence for neuromodulation of Salmonella internalization in porcine ileal mucosa.
Kristin L. Schreiber and David R. Brown (2007) Journal of Neuroimmune Pharmacology,
2(4):329-37
Adrenocorticotrophic hormone modulates Escherichia coli O157:H7 adherence to porcine
colonic mucosa Kristin L.Schreiber and David R. Brown (2005) Stress, 8(3): 185–190.
Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury.
Fairbanks CA., Schreiber KL., Brewer KL., Yu CG., Stone LS. Kitto KF., Nguyen HO,
Grocholski BM., Shoeman DW., Kehl LJ., Regunathan S., Reis DJ.,Yezierski RP.,
Wilcox GL (2000) Proceedings of the National Academy of Sciences of the United States
of America 97(19):10584-9
NEUROANESTHESIA/CLINICAL NEUROPHYSIOLOGY
Linda S. Aglio, MD, MS
Neuroanesthesia is devoted to multidisciplinary research efforts with a cluster of highly
talented faculty members that have unique scientific expertise and perspectives.
The perioperative arena provides a wide, unmet clinical challenge and need for
development of novel therapeutics that, if achieved, can shorten the duration of
perioperative times and hospital stays. In many respects, the mechanisms that are
involved or observed in the surgical arena, can provide us with a wealth of new
information. This information could have wide-ranging implications for many medical
specialties beyond our own.
Scope of Research in 2012 and Beyond
65
The research studies within the neuroanesthesia division take a multidisciplinary team
approach to solve unexplained terrain relevant to the central nervous system.
The current tools focus on elucidating key components. This provides a unique
opportunity for discovery and program development with a balanced training
environment.
Mission Statement
“Team Neuro” is a multidisciplinary team of faculty members that are dedicated to
clinical research.
To accomplish our objective, we have a platform that brings together a group of
clinicians who have expertise in different areas.
Summary of Ongoing Projects
(1) Compare the Effectiveness of Pain Control Between Different Epidural Medication in
Patients Undergoing Thoraclumbar Spine Surgery
We are proposing that a single shot epidural injection of local anesthetic and oral opioids
given prior to major bony work will result in decreased post-operative pain, better patient
satisfaction and less overall oral opioid consumption.
Hence, we would like to investigate which combination of medications will result in the
best patient satisfaction, quickest increase in post-operive physical therapy participation,
earlier return to activities of daily living, and the largest decrease in post-operative oral
opioid consumption and concomitant decrease in side effects from oral opioid
consumption.
(2) Recording and Analysis of Human Intracranial Neurophysiology During Induction
and Emergence.
Patients with intractable epilepsy are routinely implanted with intracranial electrodes to
localize seizure activity for later treatment. Implantation and explanation (removal) of
these electrodes require surgery under general anesthesia. The anesthetic portion of these
procedures presents a remarkable opportunity to study the neural mechanisms of general
anesthesia by recording from these electrodes during anesthetic induction and emergence.
In this protocol, we describe an experiment that does this using a gradual 10 minute
anesthetic induction that will permit a detailed characterization of the full range of brain
states under anesthesia linked to auditory processing and behavior. These experiments
will provide data of unprecedented novelty and importance, while making efficient use of
clinical resources, and presenting minimal additional risk to study subjects who were
already scheduled to have surgery under anesthesia.
66
(3) Comparison of Cardiac Output, Stroke Volume and Stroke Volume Variation
Measurements Using Pulse Contour versus Bioreactance Based Monitors in
Neurosurgical Operations (current.
Perioperative hemodynamic and fluid optimization is crucial in neuroanesthesia. Stroke
volume variation analysis (SVV) has emerged to be an important parameter for fluid
optimization and management.
Conventional volume stroke monitoring uses central venous pressure or arterial pressure.
The Vigleo™ requires invasive arterial or venous catheter placement. This is a
retrospective study which seeks to analyze the accuracy of this monitor and will attempt
to access postoperative brain edema and length of hospital stay.
(4) Fluid Restriction in Neurosurgical Patients: Does it Make a Difference?
Hemodynamic stability and maintenance of cerebral perfusion pressure are crucial for
managing patients with intracranial pathology. While decreased intravascular volume is
easily corrected, excessive and even normal fluid replacement may result in brain
swelling and longer hospital stays.
Neurosurgical patients undergoing tumor resection are evaluated according to the
following parameters: a metabolic profile and preoperative and postoperative radiologic
study to assess the impact of intraoperative fluid management on cerebral edema. Long
term outcome includes time to discharge and length of hospital stay.
Recent Publications/Presentations/Abstracts
2011 “Intraoperative Neurophysiological Workshop,” Society for Neuroscience,
Anesthesia and Critical Care, Chicago, IL
2011 “Intraoperative Monitoring,” Moderator/Discussant, Society for Neuroscience,
Anesthesia and Critical Care, Chicago, IL
2012 “Intraoperative Neurophysiology Workshop – Advanced Level,”
Society for Neuroscience, Anesthesia and Critical Care, Washington, DC
2012 “Intraoperative Neurophysiology Workshop,”
American Society of Anesthesiologists, Washington, DC
Zhou J, Aglio LS. Abstract: 108 - Comparison of Cardiac Output, Stroke Volume and
Stroke Volume Variation Measurements Using Pulse Contour versus Bioreactance Based
Monitors in Neurosurgical Operations. SNACC 39th Annual Meeting, Chicago Marriott;
Oct 2011.
Zhou J, Aglio LS. Abstract: 15 - Comparison of Cardiac Output, Stroke Volume and
Stroke Volume Variation Measurements Using Pulse Contour versus Bioreactance Based
67
Monitors in Neurosurgical Operations. Harvard Ansthesia Research Consortium, Harvard
Medical School, Boston, MA; Oct 2011.
Zhou J, Branam S, Aglio LS. Retrospective Review of Stroke Volume Variation Guided
Intraoperative Fluid Individualization and Optimization for Skull Based Operations.
American Society of Anesthesiolgoists; October 2012.
Zhou J, Lin X, Aglio LS. Cardiac Hemodynamic Measurements Using Arterial PressureBased Versus Cardiometry-Based Monitors in Neurosurgical Operations. American
Society of Anesthesiolgoists; October 2012.
Zhou J, Lin X,, de Luna W, Aglio LS. Comparison of Cardiac Hemodynamic
Measurements Using Arterial Based Monitors in Neurosurgical Operations. American
Society of Anesthesiolgoists; October 2012.
Zhou J, Aglio LS. Comparison of Cardiac Output, Stroke Volume and Stroke Volume
Variation Measurements Using Arterial Pressure-Based Versus Biorectance Based
Monitors in Neurosurgical Operations. Society for Neuroscience and Critical Care,
October 2012.
de Luna W, Jiang S, Zhou J, Huang R, Mukundan SW, Aglio LS. Fluid Restriction in
Neurosurgery Patients: Does it Make a Difference? American Society of
Anesthesiologists, Foundation of Anesthesia, Education and Safety for Medical Research
Scholars: October 2012.
Zhou J, Branam S, de Luna W, Aglio LS. Retrospective Review of Stroke Volume
Variation Guided Intraoperative Fluid Individualization and Optimization for Skull Based
Surgery. Brigham and Women’s Hospital Women’s Research Day, September 2012.
Clinical Faculty Involved in Perioperative Research
Linda S. Aglio, MD, MS – Director
Lisa J. Crossley, MD
Laverne D. Gugino, MD, PhD
Grace Y. Kim, MD
Jie Zhou, MD, MS, MBA
RESEARCH PUBLICATIONS OF THE DEPARTMENT OF
ANESTHESIOLOGY, PERIOPERATIVE AND PAIN MEDICINE:
2010-2011
2010 Publications:
CLINICAL RESEARCH
68
[1] Almazrooa SA, Chen K, Nascimben L, Woo SB, Treister N. Osteonecrosis of the
mandible after laryngoscopy and endotracheal tube placement. Anesthesia and analgesia
111:437-41.
[2] Ashikhmina E, Sundt TM, 3rd, Dearani JA, Connolly HM, Li Z, Schaff HV. Repair of
the bicuspid aortic valve: a viable alternative to replacement with a bioprosthesis. The
Journal of thoracic and cardiovascular surgery 139:1395-401.
[3] Ashikhmina EA, Schaff HV, Ommen SR, Dearani JA, Nishimura RA, Abel MD.
Intraoperative direct measurement of left ventricular outflow tract gradients to guide
surgical myectomy for hypertrophic cardiomyopathy. The Journal of thoracic and
cardiovascular surgery.
[4] Ashikhmina EA, Schaff HV, Sinak LJ, Li Z, Dearani JA, Suri RM, et al. Pericardial
effusion after cardiac surgery: risk factors, patient profiles, and contemporary
management. The Annals of thoracic surgery 89:112-8.
[5] Ashikhmina EA, Schaff HV, Suri RM, Enriquez-Sarano M, Abel MD. Left
ventricular remodeling early after correction of mitral regurgitation: maintenance of
stroke volume with decreased systolic indexes. The Journal of thoracic and
cardiovascular surgery 140:1300-5.
[6] Benzo RP, Chang CC, Farrell MH, Kaplan R, Ries A, Martinez FJ, et al. Physical
activity, health status and risk of hospitalization in patients with severe chronic
obstructive pulmonary disease. Respiration; international review of thoracic diseases
80:10-8.
[7] Berna C, Leknes S, Holmes EA, Edwards RR, Goodwin GM, Tracey I. Induction of
depressed mood disrupts emotion regulation neurocircuitry and enhances pain
unpleasantness. Biological psychiatry 67:1083-90.
[8] Butler SF, Budman SH, Fanciullo GJ, Jamison RN. Cross validation of the current
opioid misuse measure to monitor chronic pain patients on opioid therapy. The Clinical
journal of pain 26:770-6.
[9] Caglayan E, Romeo GR, Kappert K, Odenthal M, Sudkamp M, Body SC, et al.
Profilin-1 is expressed in human atherosclerotic plaques and induces atherogenic effects
on vascular smooth muscle cells. PloS one 5:e13608.
[10] Campbell CM, Kronfli T, Buenaver LF, Smith MT, Berna C, Haythornthwaite JA, et
al. Situational versus dispositional measurement of catastrophizing: associations with
pain responses in multiple samples. J Pain 11:443-53 e2.
[11] Campbell CM, Quartana PJ, Buenaver LF, Haythornthwaite JA, Edwards RR.
Changes in situation-specific pain catastrophizing precede changes in pain report during
69
capsaicin pain: a cross-lagged panel analysis among healthy, pain-free participants. J Pain
11:876-84.
[12] Campbell CM, Witmer K, Simango M, Carteret A, Loggia ML, Campbell JN, et al.
Catastrophizing delays the analgesic effect of distraction. Pain 149:202-7.
[13] Chandra D, Lipson DA, Hoffman EA, Hansen-Flaschen J, Sciurba FC, Decamp
MM, et al. Perfusion scintigraphy and patient selection for lung volume reduction
surgery. American journal of respiratory and critical care medicine 182:937-46.
[14] Connor CW, Segal S. Accurate classification of difficult intubation by computerized
facial analysis. Anesthesia and analgesia 112:84-93.
[15] Coughlin JW, Edwards RR, Redgrave GW, Guarda AS. Pain severity in eating
disorders predicts longer inpatient hospitalization. The International journal of eating
disorders 43:737-42.
[16] Curley MD, Ferrigno M, Lovrincevic MM, Wylegala J, Lundgren CE. Extending
submarine crew survival by reducing CO2 production with quickly reversible sedation.
Aviation, space, and environmental medicine 81:537-44.
[17] Darveau M, Lachance P. Reticulocyte hemoglobin content in critically ill patients.
Anesthesiology 113:1479.
[18] Davidyuk G, Soriano SG, Goumnerova L, Mizrahi-Arnaud A. Acute intraoperative
neurogenic pulmonary edema during endoscopic ventriculoperitoneal shunt revision.
Anesthesia and analgesia 110:594-5.
[19] Edrich T, Sadovnikoff N. Anesthesia for patients with severe chronic obstructive
pulmonary disease. Current opinion in anaesthesiology 23:18-24.
[20] Edwards RR, Giles J, Bingham CO, 3rd, Campbell C, Haythornthwaite JA, Bathon
J. Moderators of the negative effects of catastrophizing in arthritis. Pain medicine
(Malden, Mass 11:591-9.
[21] Farber MK, Angelo TE, Castells M, Tsen LC. Anesthetic management of a patient
with an allergy to propylene glycol and parabens. Anesthesia and analgesia 110:839-42.
[22] Fox AA, Muehlschlegel JD, Body SC, Shernan SK, Liu KY, Perry TE, et al.
Comparison of the utility of preoperative versus postoperative B-type natriuretic peptide
for predicting hospital length of stay and mortality after primary coronary artery bypass
grafting. Anesthesiology 112:842-51.
[23] Garvin S, Fitzgerald D, Muehlschlegel JD, Perry TE, Fox AA, Shernan SK, et al.
Heparin dose response is independent of preoperative antithrombin activity in patients
70
undergoing coronary artery bypass graft surgery using low heparin concentrations.
Anesthesia and analgesia 111:856-61.
[24] Garvin S, FitzGerald DC, Despotis G, Shekar P, Body SC. Heparin concentrationbased anticoagulation for cardiac surgery fails to reliably predict heparin bolus dose
requirements. Anesthesia and analgesia 111:849-55.
[25] Garvin S, Muehlschlegel JD, Perry TE, Chen J, Liu KY, Fox AA, et al.
Postoperative activity, but not preoperative activity, of antithrombin is associated with
major adverse cardiac events after coronary artery bypass graft surgery. Anesthesia and
analgesia 111:862-9.
[26] Gianni D, Li A, Tesco G, McKay KM, Moore J, Raygor K, et al. Protein aggregates
and novel presenilin gene variants in idiopathic dilated cardiomyopathy. Circulation
121:1216-26.
[27] Giardino ND, Curtis JL, Andrei AC, Fan VS, Benditt JO, Lyubkin M, et al. Anxiety
is associated with diminished exercise performance and quality of life in severe
emphysema: a cross-sectional study. Respiratory research 11:29.
[28] Han MK, Wise R, Mumford J, Sciurba F, Criner GJ, Curtis JL, et al. Prevalence and
clinical correlates of bronchoreversibility in severe emphysema. Eur Respir J 35:1048-56.
[29] Hilberath JN, Oakes DA, Shernan SK, Bulwer BE, D'Ambra MN, Eltzschig HK.
Safety of transesophageal echocardiography. J Am Soc Echocardiogr 23:1115-27; quiz
220-1.
[30] Jamison RN, Butler SF, Budman SH, Edwards RR, Wasan AD. Gender differences
in risk factors for aberrant prescription opioid use. J Pain 11:312-20.
[31] Jamison RN, Ross EL, Michna E, Chen LQ, Holcomb C, Wasan AD. Substance
misuse treatment for high-risk chronic pain patients on opioid therapy: a randomized
trial. Pain 150:390-400.
[32] Kajstura J, Gurusamy N, Ogorek B, Goichberg P, Clavo-Rondon C, Hosoda T, et al.
Myocyte turnover in the aging human heart. Circulation research 107:1374-86.
[33] Kajstura J, Urbanek K, Perl S, Hosoda T, Zheng H, Ogorek B, et al.
Cardiomyogenesis in the adult human heart. Circulation research 107:305-15.
[34] Karamanlidis G, Nascimben L, Couper GS, Shekar PS, del Monte F, Tian R.
Defective DNA replication impairs mitochondrial biogenesis in human failing hearts.
Circulation research 106:1541-8.
[35] Lee YC, Lu B, Bathon JM, Haythornthwaite JA, Smith MT, Page GG, et al. Pain
sensitivity and pain reactivity in osteoarthritis. Arthritis care & research.
71
[36] Likosky DS, FitzGerald DC, Groom RC, Jones DK, Baker RA, Shann KG, et al.
Effect of the perioperative blood transfusion and blood conservation in cardiac surgery
clinical practice guidelines of the Society of Thoracic Surgeons and the Society of
Cardiovascular Anesthesiologists upon clinical practices. Anesthesia and analgesia
111:316-23.
[37] Lipman PJ, Liu KY, Muehlschlegel JD, Body S, Lange C. Inferring genetic causal
effects on survival data with associated endo-phenotypes. Genetic epidemiology.
[38] Liu KY, Muehlschlegel JD, Perry TE, Fox AA, Collard CD, Body SC, et al.
Common genetic variants on chromosome 9p21 predict perioperative myocardial injury
after coronary artery bypass graft surgery. The Journal of thoracic and cardiovascular
surgery 139:483-8, 8 e1-2.
[39] Marceau LD, Link CL, Smith LD, Carolan SJ, Jamison RN. In-clinic use of
electronic pain diaries: barriers of implementation among pain physicians. Journal of pain
and symptom management 40:391-404.
[40] Muehlschlegel JD, Liu KY, Perry TE, Fox AA, Collard CD, Shernan SK, et al.
Chromosome 9p21 variant predicts mortality after coronary artery bypass graft surgery.
Circulation 122:S60-5.
[41] Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Collard CD, Shernan SK, et al.
Heart-type fatty acid binding protein is an independent predictor of death and ventricular
dysfunction after coronary artery bypass graft surgery. Anesthesia and analgesia
111:1101-9.
[42] Nurok M, Czeisler CA, Lehmann LS. Sleep deprivation, elective surgical
procedures, and informed consent. The New England journal of medicine 363:2577-9.
[43] Nurok M, Eslick I, Carvalho CR, Costabel U, D'Armiento J, Glanville AR, et al. The
International LAM Registry: a component of an innovative web-based clinician,
researcher, and patient-driven rare disease research platform. Lymphatic research and
biology 8:81-7.
[44] Nurok M, Lipsitz S, Satwicz P, Kelly A, Frankel A. A novel method for
reproducibly measuring the effects of interventions to improve emotional climate, indices
of team skills and communication, and threat to patient outcome in a high-volume
thoracic surgery center. Arch Surg 145:489-95.
[45] Perry TE, Muehlschlegel JD, Liu KY, Fox AA, Collard CD, Body SC, et al.
Preoperative C-reactive protein predicts long-term mortality and hospital length of stay
after primary, nonemergent coronary artery bypass grafting. Anesthesiology 112:607-13.
72
[46] Perry TE, Muehlschlegel JD, Liu KY, Fox AA, Collard CD, Shernan SK, et al.
Plasma neutrophil gelatinase-associated lipocalin and acute postoperative kidney injury
in adult cardiac surgical patients. Anesthesia and analgesia 110:1541-7.
[47] Pizov R, Eden A, Bystritski D, Kalina E, Tamir A, Gelman S. Arterial and
plethysmographic waveform analysis in anesthetized patients with hypovolemia.
Anesthesiology 113:83-91.
[48] Quartana PJ, Buenaver LF, Edwards RR, Klick B, Haythornthwaite JA, Smith MT.
Pain catastrophizing and salivary cortisol responses to laboratory pain testing in
temporomandibular disorder and healthy participants. J Pain 11:186-94.
[49] Roberts DJ, Ball CG, Kirkpatrick AW. Expansion of postoperative pneumothorax
and pneumomediastinum: determining when it is safe to fly. Aviation, space, and
environmental medicine 81:891; author reply
[50] Salgado DM, Eltit JM, Mansfield K, Panqueba C, Castro D, Vega MR, et al. Heart
and skeletal muscle are targets of dengue virus infection. The Pediatric infectious disease
journal 29:238-42.
[51] Schneider JP, Matthews M, Jamison RN. Abuse-deterrent and tamper-resistant
opioid formulations: what is their role in addressing prescription opioid abuse? CNS
drugs 24:805-10.
[52] Segal S. Labor epidural analgesia and maternal fever. Anesthesia and analgesia
111:1467-75.
[53] Tsen LC, Balki M. Oxytocin protocols during cesarean delivery: time to
acknowledge the risk/benefit ratio? International journal of obstetric anesthesia 19:243-5.
[54] Varelmann D, Pancaro C, Cappiello EC, Camann WR. Nocebo-induced hyperalgesia
during local anesthetic injection. Anesthesia and analgesia 110:868-70.
[55] Wasan AD, Kong J, Pham LD, Kaptchuk TJ, Edwards R, Gollub RL. The impact of
placebo, psychopathology, and expectations on the response to acupuncture needling in
patients with chronic low back pain. J Pain 11:555-63.
[56] Washko GR, Martinez FJ, Hoffman EA, Loring SH, Estepar RS, Diaz AA, et al.
Physiological and computed tomographic predictors of outcome from lung volume
reduction surgery. American journal of respiratory and critical care medicine 181:494500.
[57] Williams M, Hevelone N, Alban RF, Hardy JP, Oxman DA, Garcia E, et al.
Measuring communication in the surgical ICU: better communication equals better care.
Journal of the American College of Surgeons 210:17-22.
LABORATORY RESEARCH
73
[1] Banda NK, Levitt B, Wood AK, Takahashi K, Stahl GL, Holers VM, et al.
Complement activation pathways in murine immune complex-induced arthritis and in
C3a and C5a generation in vitro. Clinical and experimental immunology 159:100-8.
[2] Burgess P, Hutt PB, Farokhzad OC, Langer R, Minick S, Zale S. On firm ground: IP
protection of therapeutic nanoparticles. Nature biotechnology 28:1267-70.
[3] Cao JJ, Sun L, Gao H. Diet-induced obesity alters bone remodeling leading to
decreased femoral trabecular bone mass in mice. Annals of the New York Academy of
Sciences 1192:292-7.
[4] Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion
independence and HMGA2 activation after gene therapy of human beta-thalassaemia.
Nature 467:318-22.
[5] Chan JM, Zhang L, Tong R, Ghosh D, Gao W, Liao G, et al. Spatiotemporal
controlled delivery of nanoparticles to injured vasculature. Proceedings of the National
Academy of Sciences of the United States of America 107:2213-8.
[6] De Angelis A, Piegari E, Cappetta D, Marino L, Filippelli A, Berrino L, et al.
Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and
is rescued by restoration of progenitor cell function. Circulation 121:276-92.
[7] Dhar S, Kolishetti N, Lippard SJ, Farokhzad OC. Targeted delivery of a cisplatin
prodrug for safer and more effective prostate cancer therapy in vivo. Proceedings of the
National Academy of Sciences of the United States of America 108:1850-5.
[8] Eickmeier O, Hilberath JN, Zielen S, Haworth O. [Pro-Resolving Lipid Mediators in
Inflammatory Lung Diseases.]. Pneumologie (Stuttgart, Germany) 65:149-58.
[9] Eltit JM, Feng W, Lopez JR, Padilla IT, Pessah IN, Molinski TF, et al. Ablation of
skeletal muscle triadin impairs FKBP12/RyR1 channel interactions essential for
maintaining resting cytoplasmic Ca2+. The Journal of biological chemistry 285:3845362.
[10] Eltit JM, Yang T, Li H, Molinski TF, Pessah IN, Allen PD, et al. RyR1-mediated
Ca2+ leak and Ca2+ entry determine resting intracellular Ca2+ in skeletal myotubes. The
Journal of biological chemistry 285:13781-7.
[20] Feng W, Barrientos GC, Cherednichenko G, Yang T, Padilla IT, Truong K, et al.
Functional and biochemical properties of ryanodine receptor type 1 channels from
heterozygous R163C malignant hyperthermia-susceptible mice. Molecular pharmacology
79:420-31.
[21] Feng W, Cherednichenko G, Ward CW, Padilla IT, Cabrales E, Lopez JR, et al.
Green tea catechins are potent sensitizers of ryanodine receptor type 1 (RyR1).
Biochemical pharmacology 80:512-21.
74
[22] Fredman G, Van Dyke TE, Serhan CN. Resolvin E1 regulates adenosine
diphosphate activation of human platelets. Arteriosclerosis, thrombosis, and vascular
biology 30:2005-13.
[23] Gao W, Chan JM, Farokhzad OC. pH-Responsive nanoparticles for drug delivery.
Molecular pharmaceutics 7:1913-20.
[24] Gao W, Langer R, Farokhzad OC. Poly(ethylene glycol) with observable shedding.
Angewandte Chemie (International ed 49:6567-71.
[25] Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of
neuropathic pain. Pharmacology & therapeutics 126:56-68.
[26] Gao YJ, Ji RR. Targeting astrocyte signaling for chronic pain. Neurotherapeutics
7:482-93.
[27] Gao YJ, Ji RR. Light touch induces ERK activation in superficial dorsal horn
neurons after inflammation: involvement of spinal astrocytes and JNK signaling in touchevoked central sensitization and mechanical allodynia. Journal of neurochemistry
115:505-14.
[28] Gao YJ, Xu ZZ, Liu YC, Wen YR, Decosterd I, Ji RR. The c-Jun N-terminal kinase
1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical
allodynia under a persistent inflammatory pain condition. Pain 148:309-19.
[29] Gao YJ, Zhang L, Ji RR. Spinal injection of TNF-alpha-activated astrocytes
produces persistent pain symptom mechanical allodynia by releasing monocyte
chemoattractant protein-1. Glia 58:1871-80.
[30] Gerner P, Wang CF, Lee BS, Suzuki S, Degirolami U, Gandhi A, et al. The
relationship between functional sciatic nerve block duration and the rate of release of
lidocaine from a controlled-release matrix. Anesthesia and analgesia 111:221-9.
[31] Giulivi C, Ross-Inta C, Omanska-Klusek A, Napoli E, Sakaguchi D, Barrientos G, et
al. Basal bioenergetic abnormalities in skeletal muscle from ryanodine receptor malignant
hyperthermia-susceptible R163C knock-in mice. The Journal of biological chemistry
286:99-113.
[32] Gleissman H, Yang R, Martinod K, Lindskog M, Serhan CN, Johnsen JI, et al.
Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic
intermediates. Faseb J 24:906-15.
[33] Gosselin RD, Suter MR, Ji RR, Decosterd I. Glial cells and chronic pain.
Neuroscientist 16:519-31.
75
[34] Hampson CL, Body S, den Boon FS, Cheung TH, Bezzina G, Langley RW, et al.
Comparison of the effects of 2,5-dimethoxy-4-iodoamphetamine and D-amphetamine on
the ability of rats to discriminate the durations and intensities of light stimuli.
Behavioural pharmacology 21:11-20.
[35] Hattori H, Subramanian KK, Sakai J, Jia Y, Li Y, Porter TF, et al. Small-molecule
screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis.
Proceedings of the National Academy of Sciences of the United States of America
107:3546-51.
[36] Ho KJ, Spite M, Owens CD, Lancero H, Kroemer AH, Pande R, et al. Aspirintriggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and
correlate with peripheral atherosclerosis. The American journal of pathology 177:211623.
[37] Hosoda T, Kajstura J, Leri A, Anversa P. Mechanisms of myocardial regeneration.
Circ J 74:13-7.
[38] Hung YC, Suzuki S, Huang CJ, Chen CC, Pan YY, Wang CF, et al. Resiniferatoxin
combined with antidepressants preferentially prolongs sensory/nociceptive block in rat
sciatic nerve. Anesthesia and analgesia 111:207-13.
[39] Ji RR. Targeting microglial purinergic signaling to improve morphine analgesia.
Pain 150:377-8.
[40] Kashiyama T, Murayama T, Suzuki E, Allen PD, Ogawa Y. Frog alpha- and betaryanodine receptors provide distinct intracellular Ca2+ signals in a myogenic cell line.
PloS one 5:e11526.
[41] Keely S, Glover LE, Weissmueller T, MacManus CF, Fillon S, Fennimore B, et al.
Hypoxia-inducible factor-dependent regulation of platelet-activating factor receptor as a
route for gram-positive bacterial translocation across epithelia. Molecular biology of the
cell 21:538-46.
[42] Khodorova A, Strichartz GR. Contralateral paw sensitization following injection of
endothelin-1: effects of local anesthetics differentiate peripheral and central processes.
Neuroscience 165:553-60.
[43] Khodorova A, Strichartz GR. Remarkably long-lasting tachyphylaxis of pain
responses to ET-1: evidence against central nervous system involvement. Canadian
journal of physiology and pharmacology 88:668-75.
[44] Kolishetti N, Dhar S, Valencia PM, Lin LQ, Karnik R, Lippard SJ, et al. Engineering
of self-assembled nanoparticle platform for precisely controlled combination drug
therapy. Proceedings of the National Academy of Sciences of the United States of
America 107:17939-44.
76
[45] Kolliputi N, Shaik RS, Waxman AB. The inflammasome mediates hyperoxiainduced alveolar cell permeability. J Immunol 184:5819-26.
[46] Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH, Yang R, et al.
Resolvin D1 binds human phagocytes with evidence for proresolving receptors.
Proceedings of the National Academy of Sciences of the United States of America
107:1660-5.
[47] Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus.
Nature neuroscience 13:1460-2.
[48] Liu Y, Abdel Samad O, Zhang L, Duan B, Tong Q, Lopes C, et al. VGLUT2dependent glutamate release from nociceptors is required to sense pain and suppress itch.
Neuron 68:543-56.
[49] Marcheselli VL, Mukherjee PK, Arita M, Hong S, Antony R, Sheets K, et al.
Neuroprotectin D1/protectin D1 stereoselective and specific binding with human retinal
pigment epithelial cells and neutrophils. Prostaglandins, leukotrienes, and essential fatty
acids 82:27-34.
[50] Mathews JC, Chin MS, Fernandez-Esparrach G, Shaikh SN, Pietramaggiori G,
Scherer SS, et al. Early healing of transcolonic and transgastric natural orifice
transluminal endoscopic surgery access sites. Journal of the American College of
Surgeons 210:480-90.
[51] Obokata H, Kojima K, Westerman K, Yamato M, Okano T, Tsuneda S, et al. The
potential of stem cells in adult tissues representative of the three germ layers. Tissue
engineering 17:607-15.
[52] Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN. Resolvin E1
receptor activation signals phosphorylation and phagocytosis. The Journal of biological
chemistry 285:3451-61.
[53] Planaguma A, Pfeffer MA, Rubin G, Croze R, Uddin M, Serhan CN, et al.
Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal
immunology 3:270-9.
[54] Royer L, Sztretye M, Manno C, Pouvreau S, Zhou J, Knollmann BC, et al.
Paradoxical buffering of calcium by calsequestrin demonstrated for the calcium store of
skeletal muscle. The Journal of general physiology 136:325-38.
[55] Shi J, Votruba AR, Farokhzad OC, Langer R. Nanotechnology in drug delivery and
tissue engineering: from discovery to applications. Nano letters 10:3223-30.
77
[56] Shin JW, Pancaro C, Wang CF, Gerner P. The effects of resiniferatoxin in an
experimental rat thoracotomy model. Anesthesia and analgesia 110:228-32.
[57] Thibault HB, Kurtz B, Raher MJ, Shaik RS, Waxman A, Derumeaux G, et al.
Noninvasive assessment of murine pulmonary arterial pressure: validation and
application to models of pulmonary hypertension. Circ Cardiovasc Imaging 3:157-63.
[58] Tong HH, Li YX, Stahl GL, Thurman JM. Enhanced susceptibility to acute
pneumococcal otitis media in mice deficient in complement C1qa, factor B, and factor
B/C2. Infection and immunity 78:976-83.
[59] Urbanek K, Cabral-da-Silva MC, Ide-Iwata N, Maestroni S, Delucchi F, Zheng H, et
al. Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the
neonatal heart. Circulation research 107:429-41.
[60] Valencia PM, Basto PA, Zhang L, Rhee M, Langer R, Farokhzad OC, et al. Singlestep assembly of homogenous lipid-polymeric and lipid-quantum dot nanoparticles
enabled by microfluidic rapid mixing. ACS nano 4:1671-9.
[61] Vassalle M, Nett MP, Catanzaro JN, Rota M. Novel oscillatory mechanisms in the
cholinergic control of Guinea pig sino-atrial node discharge. Journal of cardiovascular
electrophysiology 22:71-80.
[62] Wang AZ, Yuet K, Zhang L, Gu FX, Huynh-Le M, Radovic-Moreno AF, et al.
ChemoRad nanoparticles: a novel multifunctional nanoparticle platform for targeted
delivery of concurrent chemoradiation. Nanomedicine (London, England) 5:361-8.
[63] Wang SY, Calderon J, Kuo Wang G. Block of neuronal Na+ channels by
antidepressant duloxetine in a state-dependent manner. Anesthesiology 113:655-65.
[64] Wang X, Bao X, Pal R, Agbas A, Michaelis EK. Transcriptomic responses in mouse
brain exposed to chronic excess of the neurotransmitter glutamate. BMC genomics
11:360.
[65] Westerman KA, Penvose A, Yang Z, Allen PD, Vacanti CA. Adult muscle 'stem'
cells can be sustained in culture as free-floating myospheres. Experimental cell research
316:1966-76.
[66] Xu X, Yang Z, Liu Q, Wang Y. In vivo fluorescence imaging of muscle cell
regeneration by transplanted EGFP-labeled myoblasts. Mol Ther 18:835-42.
[67] Xu ZZ, Zhang L, Liu T, Park JY, Berta T, Yang R, et al. Resolvins RvE1 and RvD1
attenuate inflammatory pain via central and peripheral actions. Nature medicine 16:5927, 1p following 7.
[68] Yan C, Cao J, Wu M, Zhang W, Jiang T, Yoshimura A, et al. Suppressor of cytokine
signaling 3 inhibits LPS-induced IL-6 expression in osteoblasts by suppressing
78
CCAAT/enhancer-binding protein {beta} activity. The Journal of biological chemistry
285:37227-39.
[69] Zeng Q, Yang Z, Gao YJ, Yuan H, Cui K, Shi Y, et al. Treating triple-negative
breast cancer by a combination of rapamycin and cyclophosphamide: an in vivo
bioluminescence imaging study. Eur J Cancer 46:1132-43.
EDUCATIONAL PUBLICATION
[1] Alexis F, Pridgen EM, Langer R, Farokhzad OC. Nanoparticle technologies for
cancer therapy. Handbook of experimental pharmacology:55-86.
[2] Bannenberg G, Serhan CN. Specialized pro-resolving lipid mediators in the
inflammatory response: An update. Biochimica et biophysica acta 1801:1260-73.
[3] Bazan NG, Calandria JM, Serhan CN. Rescue and repair during photoreceptor cell
renewal mediated by docosahexaenoic acid-derived neuroprotectin D1. Journal of lipid
research 51:2018-31.
[4] Chan JM, Valencia PM, Zhang L, Langer R, Farokhzad OC. Polymeric nanoparticles
for drug delivery. Methods in molecular biology (Clifton, NJ 624:163-75.
[5] Desai, Sukumar. Eponyms in the Operating Room: Careers of Six European
Physicians* Anesthesia History. Volume 28:Number2. July 2010
[6] Hoyt, MR. Anesthetic Options for Labor and Delivery: Diseases of the Fetus and
Infant. Fanaroff and Martin’s Neonatal-Perinatal Medicine. Chapter 25. 2010.
[7] Jamison RN, Clark JD. Opioid medication management: clinician beware!
Anesthesiology 112:777-8.
[8] Jamison RN. The doctor-patient relationship in pain management: dealing with
difficult clinician-patient interactions. Bonica’s Management of Pain, Chapter 33. 2010.
[9] Jamison, RN. Bridging the gap between pain and chemical dependency. Journal of
Pain and System Management Vol. 39. No.1 January, 2010.
[10] Kissin I. The development of new analgesics over the past 50 years: a lack of real
breakthrough drugs. Anesthesia and analgesia 110:780-9.
[11] Kissin I. Preemptive analgesia: problems with assessment of clinical significance.
Methods in molecular biology (Clifton, NJ 617:475-82.
[12] Kissin, Igor. Can a bibliometric indicator predict the success of an analgesic?
Scientometrics, p1-11. November, 2010.
79
[13] Kodali BS. Bloodless trilogy? Anesthesia, obstetrics and interventional radiology for
cesarean delivery. International journal of obstetric anesthesia 19:131-2.
[14] Mamo T, Moseman EA, Kolishetti N, Salvador-Morales C, Shi J, Kuritzkes DR, et
al. Emerging nanotechnology approaches for HIV/AIDS treatment and prevention.
Nanomedicine (London, England) 5:269-85.
[15] Max BA, Gelfand B, Brooks MR, Beckerly R, Segal S. Have personal statements
become impersonal? An evaluation of personal statements in anesthesiology residency
applications. Journal of clinical anesthesia 22:346-51.
[16] Muehlschlegel JD, Shernan SK, Body SC. From creatine kinase-MB to troponin: do
we really need to differentiate between myocardial injury and infarction? Anesthesiology
113:1479-80.
[17] Norling LV, Serhan CN. Profiling in resolving inflammatory exudates identifies
novel anti-inflammatory and pro-resolving mediators and signals for termination. Journal
of internal medicine 268:15-24.
[18] Papadakis MA, Wofsy D. Plagiarism on personal statements: a disturbing symptom
of a broader trend. Annals of internal medicine 153:128-9.
[19] Reuter DA, Huang C, Edrich T, Shernan SK, Eltzschig HK. Cardiac output
monitoring using indicator-dilution techniques: basics, limits, and perspectives.
Anesthesia and analgesia 110:799-811.
[20] Ross E, Jamison R, Edwards R. The Opioid Debate-Missing the Point. J Pain.
[21] Segal S, Gelfand BJ, Hurwitz S, Berkowitz L, Ashley SW, Nadel ES, et al.
Plagiarism in residency application essays. Annals of internal medicine 153:112-20.
[22] Serhan CN. Novel lipid mediators and resolution mechanisms in acute inflammation:
to resolve or not? The American journal of pathology 177:1576-91.
[23] Serhan, CN, Ward, PA, Gilroy, DW, Haeggstrom, JZ, et al. Fundamentals of
Inflammation. Cambridge University Press, 2010. Chapter 12: Lipid Mediators in Acute
Inflammation and Resolution: Eicosanoids, PAF, Resolvins, and Protectins.153-174.
[24] Serhan, CN and Bannenberg, G. The Brain and Host Defense. Elsevier, 2010.
Chapter 4: A Novel Genus of Specialized Anti-Inflammatory and Preo-Resolution Lipid
Mediators. 37-57.
[25] Spite M, Serhan CN. Novel lipid mediators promote resolution of acute
inflammation: impact of aspirin and statins. Circulation research 107:1170-84.
[26] Strichartz, GR, Lilly, LS, et al. Pathophysiology of Heart Disease: A Collaborative
Project of Medical Students and Faculty. Chapter 1: Basic Cardiac Structure and
Function. Edition 5. 2010. 1-27
80
[27] Strichartz, GR, Lilly, LS, et al. Pathophysiology of Heart Disease: A Collaborative
Project of Medical Students and Faculty. Chapter 11: Mechanisms of Cardiac
Arrhythmias. Edition 5. 2010. 261-278.
[28] Strichartz, GR, Lilly, LS, et al. Pathophysiology of Heart Disease: A Collaborative
Project of Medical Students and Faculty. Chapter 17: Cardiovascular Drugs. Edition 5.
2010. 386-436.
[29] Tsen, Lawrence. Can general anesthesia for cesarean delivery be completely
avoided? An anesthetic perspective. Expert Rev. Obstet. Gynecol. 5(5), 517-524 (2010).
[30] Vlassakov, Kamen. The forearm tourniquet Bier block. Logic and authority versus
science and experience. Anestesiologica 2010 February; 76(2): 91-92.
[31] Xiao, Zeyu, Gao, Weiwei, Farokhzad, Omid C., et al. Progress in sIRNA delivery
using multifunctional nanoparticles. RNA Therapeutics, Methods in Molecular Biology
629. 2010.
2011 Anesthesiology Department Publications.
Clinical Research Publications
1. Herman SC, Zhou J. Isoproterenol infusion for treatment of refractory symptomatic
bradycardia in parturients with congenital complete heart block. Int J Obstet
Anesth;20:361-3; author reply 363.
2. Zhou J. Detection of neurosurgical intraoperative brisk blood loss with stroke volume
variation. J Neurosurg Anesthesiol;23:272-3.
3. Fox AA, Marcantonio ER, Collard CD, Thoma M, Perry TE, Shernan SK,
Muehlschlegel JD, Body SC. Increased peak postoperative B-type natriuretic peptide
predicts decreased longer-term physical function after primary coronary artery bypass
graft surgery. Anesthesiology;114:807-16..
4. Lipman PJ, Liu KY, Muehlschlegel JD, Body S, Lange C. Inferring genetic causal
effects on survival data with associated endo-phenotypes. Genet Epidemiol;35:119-24.
Inferring genetic causal effects on survival data with associated endo-phenotypes.
5. Fox AA, Pretorius M, Liu KY, Collard CD, Perry TE, Shernan SK, De Jager PL,
Hafler DA, Herman DS, DePalma SR, Roden DM, Muehlschlegel JD, Donahue BS,
Darbar D, Seidman JG, Body SC, Seidman CE. Genome-wide assessment for genetic
variants associated with ventricular dysfunction after primary coronary artery bypass
graft surgery. PLoS One;6:e24593.
81
6. Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Smith SA, Lichtner P, Collard CD,
Shernan SK, Hartwig JH, Body SC, Hoffmeister KM. Polymorphism in the proteaseactivated receptor-4 gene region associates with platelet activation and perioperative
myocardial injury. Am J Hematol. Epub 2011; Nov 2
7. Edwards RR, Wasan AD, Michna E, Greenbaum S, Ross E, Jamison RN. Elevated
pain sensitivity in chronic pain patients at risk for opioid misuse. J Pain;12:953-63.
8. Edwards RR, Cahalan C, Mensing G, Smith M, Haythornthwaite JA. Pain,
catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol;7:216-24.
9. Edwards RR, Quartana PJ, Allen RP, Greenbaum S, Earley CJ, Smith MT. Alterations
in pain responses in treated and untreated patients with restless legs syndrome:
associations with sleep disruption. Sleep Med;12:603-9.
10. Fabian LA, McGuire L, Goodin BR, Edwards RR. Ethnicity, catastrophizing, and
qualities of the pain experience. Pain Med;12:314-21.
11. McCann UD, Edwards RR, Smith MT, Kelley K, Wilson M, Sgambati F, Ricaurte G.
Altered pain responses in abstinent (+/-)3,4-methylenedioxymethamphetamine (MDMA,
"ecstasy") users. Psychopharmacology (Berl);217:475-84.
12. Mogil JS, Sorge RE, LaCroix-Fralish ML, Smith SB, Fortin A, Sotocinal SG, Ritchie
J, Austin JS, Schorscher-Petcu A, Melmed K, Czerminski J, Bittong RA, Mokris JB,
Neubert JK, Campbell CM, Edwards RR, Campbell JN, Crawley JN, Lariviere WR,
Wallace MR, Sternberg WF, Balaban CD, Belfer I, Fillingim RB. Pain sensitivity and
vasopressin analgesia are mediated by a gene-sex-environment interaction. Nat
Neurosci;14:1569-73.
13. Ashikhmina EA, Schaff HV, Dearani JA, Sundt TM, 3rd, Suri RM, Park SJ, Burkhart
HM, Li Z, Daly RC. Aortic valve replacement in the elderly: determinants of late
outcome. Circulation;124:1070-8.
14. Ashikhmina EA, Schaff HV, Ommen SR, Dearani JA, Nishimura RA, Abel MD.
Intraoperative direct measurement of left ventricular outflow tract gradients to guide
surgical myectomy for hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg;142:539.
15. Said SM, Ashikhmina E, Greason KL, Suri RM, Park SJ, Daly RC, Burkhart HM,
Dearani JA, Sundt TM 3rd, Schaff HV. Do Pericardial Bioprosthesis Improve Outcome
of Elderly Patients Undergoing Aortic Valve Replacement? Ann Thorac
Surg;93(6):1868-75
16. Cesselli D, Beltrami AP, D'Aurizio F, Marcon P, Bergamin N, Toffoletto B, Pandolfi
M, Puppato E, Marino L, Signore S, Livi U, Verardo R, Piazza S, Marchionni L, Fiorini
82
C, Schneider C, Hosoda T, Rota M, Kajstura J, Anversa P, Beltrami CA, Leri A. Effects
of age and heart failure on human cardiac stem cell function. Am J Pathol;179:349-66.
17. D'Amario D, Fiorini C, Campbell PM, Goichberg P, Sanada F, Zheng H, Hosoda T,
Rota M, Connell JM, Gallegos RP, Welt FG, Givertz MM, Mitchell RN, Leri A, Kajstura
J, Pfeffer MA, Anversa P. Functionally competent cardiac stem cells can be isolated from
endomyocardial biopsies of patients with advanced cardiomyopathies. Circ Res;108:85761.
18. D'Amario D, Cabral-Da-Silva MC, Zheng H, Fiorini C, Goichberg P, Steadman E,
Ferreira-Martins J, Sanada F, Piccoli M, Cappetta D, D'Alessandro DA, Michler RE,
Hosoda T, Anastasia L, Rota M, Leri A, Anversa P, Kajstura J. Insulin-like growth
factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic
potential for myocardial regeneration. Circ Res;108:1467-81.
19. Hosoda T, Zheng H, Cabral-da-Silva M, Sanada F, Ide-Iwata N, Ogorek B, FerreiraMartins J, Arranto C, D'Amario D, del Monte F, Urbanek K, D'Alessandro DA, Michler
RE, Anversa P, Rota M, Kajstura J, Leri A. Human cardiac stem cell differentiation is
regulated by a mircrine mechanism. Circulation;123:1287-96.
20. Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D, Sanada F, Zheng H, Ogorek B,
Rondon-Clavo C, Ferreira-Martins J, Matsuda A, Arranto C, Goichberg P, Giordano G,
Haley KJ, Bardelli S, Rayatzadeh H, Liu X, Quaini F, Liao R, Leri A, Perrella MA,
Loscalzo J, Anversa P. Evidence for human lung stem cells. N Engl J Med;364:1795-806.
21. Leri A, Hosoda T, Kajstura J, Anversa P, Rota M. Identification of a coronary stem
cell in the human heart. J Mol Med (Berl);89:947-59.
22. Jamison RN, Washington TA, Gulur P, Fanciullo GJ, Arscott JR, McHugo GJ, Baird
JC. Reliability of a three-dimensional pain mapping program. Pain Med 2011;12:344351.
23. Marceau LD, Smith LD, Jamison RN. Electronic pain assessment in clinical practice.
Pain Manage 2011; 1(4):325-336.
24. Suri P, Rainville J, Fitzmaurice GM, Katz JN, Jamison RN, Martha J, Hartigan C,
Limke J, Jouve C, Hunter DJ. Acute low back pain is marked by variability: an internetbased pilot study. BMC Musculo Disorders 2011; 12:220.
25. Jamison RN. Nonspecific treatment effects in pain medicine. Pain: Clin Updates.
IASP Press, 2011:19, issue 2.
26. Chow L, Farber MK, Camann WR. Anesthesia in the pregnant patient with
hematologic disorders. Hematol Oncol Clin North Am;25:425-43, ix-x.
83
27. Chang LY, Carabuena JM, Camann W. Neurologic issues and obstetric anesthesia.
Semin Neurol;31:374-84.
28. Vlassakov KV, Narang S, Kissin I. Local anesthetic blockade of peripheral nerves for
treatment of neuralgias: systematic analysis. Anesth Analg;112:1487-93.
29. Kissin I. Can a bibliometric indicator predict the success of an analgesic?
Scientometrics 2011; 86(3):785-795.
30. Kissin I. Top Journals Selectivity Index: is it acceptable for drugs beyond the field of
analgesia? Scientometric 2011:88(2):589.
31. Kissin I, Bradley E. Top Journal Selectivity Index and “me-too” drugs.
Scientometrics 2011:1-12
32. Bolli R, Chugh AR, D'Amario D, Loughran JH, Stoddard MF, Ikram S, Beache GM,
Wagner SG, Leri A, Hosoda T, Sanada F, Elmore JB, Goichberg P, Cappetta D, Solankhi
NK, Fahsah I, Rokosh DG, Slaughter MS, Kajstura J, Anversa P. Cardiac stem cells in
patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1
trial. Lancet;378:1847-57.
2011 Educational Publications
1. Hartigan PM. Practical Handbook for Thoracic Anesthesia. Springer Science +
Business Media, LLC 2012. Book chapters 4, 5, 6, 16, 18, 19, 20, 21, 30, 37
Chapter 4: Respiratory Effects of General Anesthesia
Chapter 5: Physiology of One-Lung Ventilation
Chapter 6: Idiopathic Acute Lung Injury Following Thoracic Surgery
Chapter 16: Principles of Anesthetic Management for Pulmonary Resection
Chapter 18: Flexible Bronchoscopy
Chapter 19: Mediastinoscopy
Chapter 20: Anterior Mediastinal Mass
Chapter 21: Lung-Sparing Pulmonary Resections: Bronchoplastic/Sleeve Resection
Chapter 30: Tracheal Resection and Reconstruction
Chapter 37: Acute Postoperative Pain Control Following Thoracic Surgery
2. Brattain LJ, Floryan C, Hauser OP, Nguyen M, Yong RJ, Kesner SB, Corn SB, Walsh
CJ. Simple and effective ultrasound needle guidance system. Conf Proc IEEE Eng Med
Biol Soc;2011:8090-3.
3. Vacanti CA, Sikka PK, Urman RD, Dershwitz M, Segal BS. Essential Clinical
Anesthesia . Cambridge University Press, 2011.
Book Chapter 32: Pharmacokinetics of inhalational agents (Philip, James)
Pre-Print Chapter: 11 Pharmacokinetics of inhalational agents (Philip, James)
84
5. Desai SP, Buterbaugh J, Desai MS. The making of an anesthesia historian: lessons
from a worldwide biographical survey. Anesth Analg;113:383-6.
6. LeVasseur R, Desai SP. Experiencing Anesthesia History In Massachusetts. Mass Soc
of Anesth, Inc. 2011; 39:1.
7. Barr TP, Kam S, Khodorova A, Montmayeur JP, Strichartz GR. New perspectives on
the endothelin axis in pain. Pharmacol Res;63:532-40.
8. Hosoda T, Rota M, Kajstura J, Leri A, Anversa P. Role of stem cells in cardiovascular
biology. J Thromb Haemost;9 Suppl 1:151-61.
9. Chow L, Farber MK, Camann WR. Anesthesia in the pregnant patient with
hematologic disorders. Hematol Oncol Clin North Am;25:425-43, ix-x.
10. Lemaire SA, McDonald ML, Guo DC, Russell L, Miller CC, 3rd, Johnson RJ,
Bekheirnia MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C,
Holmes KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M,
Coselli JS, Estrera AL, Safi HJ, Belmont JW, Leal SM, Milewicz DM. Genome-wide
association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic
dissections spanning FBN1 at 15q21.1. Nat Genet;43:996-1000.
11. Jamison RN, Serraillier J, Michna E. Assessment and treatment of abuse risk in
opioid prescribing for chronic pain. Pain Res Treat 2011 Article ID 941808 (review
article)
12. Manit Arya, Hashim Uddin Ahmed, Peter Scardino, Mark Emberton. Interventional
Techniques in Uro-Oncology. Wiley-Blackwell. 2011.
Book Chapter 7: Perspectives on nanotechnology. (Farokhzad, OC)
13. Shi J, Xiao Z, Kamaly N, Farokhzad OC. Self-assembled targeted nanoparticles:
evolution of technologies and bench to bedside translation. Acc Chem Res;44:1123-34.
14. Gao W, Farokhzad OC. Self-propelled microrockets to capture and isolate circulating
tumor cells. Angew Chem Int Ed Engl;50:7220-1.
15. Kissin I, Szallasi A. Therapeutic targeting of TRPV1 by resiniferatoxin, from
preclinical studies to clinical trials. Curr Top Med Chem;11:2159-70.
16. Kissin I. A call to reassess the clinical value of preventive (preemptive) analgesia.
Anesth Analg;113:977-8.
17. Serhan CN, Krishnamoorthy S, Recchiuti A, Chiang N. Novel anti-inflammatory-pro-resolving mediators and their receptors. Curr Top Med Chem;11:629-47.
85
18. Serhan CN. The resolution of inflammation: the devil in the flask and in the details.
Faseb J;25:1441-8.
19. Oh SF, Vickery TW, Serhan CN. Chiral lipidomics of E-series resolvins: aspirin and
the biosynthesis of novel mediators. Biochim Biophys Acta;1811:737-47.
20. Fredman G, Serhan CN. Specialized proresolving mediator targets for RvE1 and
RvD1 in peripheral blood and mechanisms of resolution. Biochem J;437:185-97.
21. Back M, Dahlen SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T,
Rovati GE. International Union of Basic and Clinical Pharmacology. LXXXIV:
leukotriene receptor nomenclature, distribution, and pathophysiological functions.
Pharmacol Rev;63:539-84.
22. Serhan CN, Petasis NA. Resolvins and protectins in inflammation resolution. Chem
Rev;111:5922-43.
23. Campbell EL, Serhan CN, Colgan SP. Antimicrobial aspects of inflammatory
resolution in the mucosa: a role for proresolving mediators. J Immunol;187:3475-81.
24. Greene ER, Huang S, Serhan CN, Panigrahy D. Regulation of inflammation in cancer
by eicosanoids. Prostaglandins Other Lipid Mediat;96:27-36.
25. Yang R, Chiang N, Oh SF, Serhan CN. Metabolomics-lipidomics of eicosanoids and
docosanoids generated by phagocytes. Curr Protoc Immunol;Chapter 14:Unit 14 26.
26. John Erdman, Maria Oria, Laura Pillsbury. Nutrition and Traumatic Brain Injury:
Improving Acute and Subacute Health Outcomes in Military Personnel.
Appendix C, Page 50: Specialized Pro-Resolving Mediators and Nutrition: Not just N-6
VS. N-3 In The Control Of Inflammation- A temporal Progression to Catabasis. (Serhan,
CN)
27. Goligorsky, Michael. Regenerative Nephrology, 1st Ed. Elsevier, 2011.
Book chapter 4: Endogenous Anti-inflammatory and Proresolving Lipid Mediators in
Renal Disease. (Serhan CN, Godson C)
2011 Laboratory Research Publications
1. Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR. TNF-alpha contributes to spinal cord
synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2.
Pain;152:419-27.
2. Xu ZZ, Ji RR. Resolvins are potent analgesics for arthritic pain. Br J
Pharmacol;164:274-7.
86
3. Wen YR, Tan PH, Cheng JK, Liu YC, Ji RR. Microglia: a promising target for treating
neuropathic and postoperative pain, and morphine tolerance. J Formos Med
Assoc;110:487-94.
4. Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H, Koyanagi S,
Ohdo S, Ji RR, Salter MW, Inoue K. JAK-STAT3 pathway regulates spinal astrocyte
proliferation and neuropathic pain maintenance in rats. Brain;134:1127-39.
5. Suter MR, Siegenthaler A, Decosterd I, Ji RR. Perioperative nerve blockade: clues
from the bench. Anesthesiol Res Pract;2011:124898.
6. Park CK, Xu ZZ, Liu T, Lu N, Serhan CN, Ji RR. Resolvin D2 is a potent endogenous
inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal
cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1. J
Neurosci;31:18433-8.
7. Park CK, Lu N, Xu ZZ, Liu T, Serhan CN, Ji RR. Resolving TRPV1- and TNF-alphamediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J
Neurosci;31:15072-85.
8. Ji RR, Xu ZZ, Strichartz G, Serhan CN. Emerging roles of resolvins in the resolution
of inflammation and pain. Trends Neurosci;34:599-609.
9. Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, Liu N, Xiong W,
Ripsch MS, Wang Y, Fehrenbacher JC, Fitz SD, Khanna M, Park CK, Schmutzler BS,
Cheon BM, Due MR, Brustovetsky T, Ashpole NM, Hudmon A, Meroueh SO, Hingtgen
CM, Brustovetsky N, Ji RR, Hurley JH, Jin X, Shekhar A, Xu XM, Oxford GS, Vasko
MR, White FA, Khanna R. Suppression of inflammatory and neuropathic pain by
uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex. Nat Med;17:822-9.
10. Kohler D, Straub A, Weissmuller T, Faigle M, Bender S, Lehmann R, Wendel HP,
Kurz J, Walter U, Zacharowski K, Rosenberger P. Phosphorylation of vasodilatorstimulated phosphoprotein prevents platelet-neutrophil complex formation and dampens
myocardial ischemia-reperfusion injury. Circulation;123:2579-90.
11. Ferrigno M, Tahir N, Connor CW. The feasibility of pharmacological mitigation of
nitrogen narcosis during submarine escapes from depths down to 1,000 fsw. Undersea
Hyperb Med;38:549-55.
12. Fahlman A, Loring SH, Ferrigno M, Moore C, Early G, Niemeyer M, Lentell B,
Wenzel F, Joy R, Moore MJ. Static inflation and deflation pressure-volume curves from
excised lungs of marine mammals. J Exp Biol;214:3822-8.
13. Goichberg P, Bai Y, D'Amario D, Ferreira-Martins J, Fiorini C, Zheng H, Signore S,
del Monte F, Ottolenghi S, D'Alessandro DA, Michler RE, Hosoda T, Anversa P,
87
Kajstura J, Rota M, Leri A. The ephrin A1-EphA2 system promotes cardiac stem cell
migration after infarction. Circ Res;108:1071-83.
14. Philip J. Inhalation anesthesia insights learned through computer simulation. Assoc of
Anesth. 2011; 9:13-15.
15. Colvin AC, Wang CF, Soens MA, Mitani AA, Strichartz G, Gerner P. Prolonged
cutaneous analgesia with transdermal application of amitriptyline and capsaicin. Reg
Anesth Pain Med;36:236-40.
16. Huang L, Wang CF, Serhan CN, Strichartz G. Enduring prevention and transient
reduction of postoperative pain by intrathecal resolvin D1. Pain;152:557-65.
17. Wang CF, Pancaro C, Gerner P, Strichartz G. Prolonged suppression of postincisional
pain by a slow-release formulation of lidocaine. Anesthesiology;114:135-49.
18. Montmayeur JP, Barr TP, Kam SA, Packer SJ, Strichartz GR. ET-1 induced
Elevation of intracellular calcium in clonal neuronal and embryonic kidney cells involves
endogenous endothelin-A receptors linked to phospholipase C through Galpha(q/11).
Pharmacol Res;64:258-67.
19. Perez CF. On the footsteps of Triadin and its role in skeletal muscle. World J Biol
Chem;2:177-83.
20. Eltit JM, Szpyt J, Li H, Allen PD, Perez CF. Reduced gain of excitation-contraction
coupling in triadin-null myotubes is mediated by the disruption of FKBP12/RyR1
interaction. Cell Calcium;49:128-35.
21. Wu M, Huang H, Zhang W, Kannan S, Weaver A, McKibben M, Herington D, Zeng
H, Gao H. Host DNA repair proteins in response to Pseudomonas aeruginosa in lung
epithelial cells and in mice. Infect Immun;79:75-87.
22. Eickmeier O, Hilberath JN, Zielen S, Haworth O. Pro-resolving lipid mediators in
inflammatory lung diseases. Pneumologie;65:149-58.
23. Hilberath JN, Carlo T, Pfeffer MA, Croze RH, Hastrup F, Levy BD. Resolution of
Toll-like receptor 4-mediated acute lung injury is linked to eicosanoids and suppressor of
cytokine signaling 3. Faseb J;25:1827-35.
24. Takahashi K, Chang WC, Takahashi M, Pavlov V, Ishida Y, La Bonte L, Shi L,
Fujita T, Stahl GL, Van Cott EM. Mannose-binding lectin and its associated proteases
(MASPs) mediate coagulation and its deficiency is a risk factor in developing
complications from infection, including disseminated intravascular coagulation.
Immunobiology;216:96-102.
88
25. Morrison H, Frye J, Davis-Gorman G, Funk J, McDonagh P, Stahl G, Ritter L. The
contribution of mannose binding lectin to reperfusion injury after ischemic stroke. Curr
Neurovasc Res;8:52-63.
26. Dahlke K, Wrann CD, Sommerfeld O, Sossdorf M, Recknagel P, Sachse S, Winter
SW, Klos A, Stahl GL, Ma YX, Claus RA, Reinhart K, Bauer M, Riedemann NC.
Distinct different contributions of the alternative and classical complement activation
pathway for the innate host response during sepsis. J Immunol;186:3066-75.
27. Li Q, Li YX, Stahl GL, Thurman JM, He Y, Tong HH. Essential role of factor B of
the alternative complement pathway in complement activation and opsonophagocytosis
during acute pneumococcal otitis media in mice. Infect Immun;79:2578-85.
28. Shishova EY, Stoll JM, Ersoy BA, Shrestha S, Scapa EF, Li Y, Niepel MW, Su Y,
Jelicks LA, Stahl GL, Glicksman MA, Gutierrez-Juarez R, Cuny GD, Cohen DE. Genetic
ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates dietinduced hepatic glucose production. Hepatology;54:664-74.
29. Banda NK, Takahashi M, Takahashi K, Stahl GL, Hyatt S, Glogowska M, Wiles TA,
Endo Y, Fujita T, Holers VM, Arend WP. Mechanisms of mannose-binding lectinassociated serine proteases-1/3 activation of the alternative pathway of complement. Mol
Immunol;49:281-9.
30. Sebastian BM, Roychowdhury S, Tang H, Hillian AD, Feldstein AE, Stahl GL,
Takahashi K, Nagy LE. Identification of a cytochrome P4502E1/Bid/C1q-dependent axis
mediating inflammation in adipose tissue after chronic ethanol feeding to mice. J Biol
Chem;286:35989-97.
31. Takahashi K, Saha D, Shattino I, Pavlov VI, Stahl GL, Finnegan P, Melo MF.
Complement 3 is involved with ventilator-induced lung injury. Int
Immunopharmacol;11:2138-43.
32. Obokata H, Kojima K, Westerman K, Yamato M, Okano T, Tsuneda S, Vacanti CA.
The potential of stem cells in adult tissues representative of the three germ layers. Tissue
Eng Part A;17:607-15.
33. Oikonomopoulos A, Sereti KI, Conyers F, Bauer M, Liao A, Guan J, Crapps D, Han
JK, Dong H, Bayomy AF, Fine GC, Westerman K, Biechele TL, Moon RT, Force T,
Liao R. Wnt signaling exerts an antiproliferative effect on adult cardiac progenitor cells
through IGFBP3. Circ Res;109:1363-74.
34. Dhar S, Kolishetti N, Lippard SJ, Farokhzad OC. Targeted delivery of a cisplatin
prodrug for safer and more effective prostate cancer therapy in vivo. Proc Natl Acad Sci
U S A;108:1850-5.
89
35. Rhee M, Valencia PM, Rodriguez MI, Langer R, Farokhzad OC, Karnik R. Synthesis
of size-tunable polymeric nanoparticles enabled by 3D hydrodynamic flow focusing in
single-layer microchannels. Adv Mater;23:H79-83.
36. Shi J, Xiao Z, Votruba AR, Vilos C, Farokhzad OC. Differentially charged hollow
core/shell lipid-polymer-lipid hybrid nanoparticles for small interfering RNA delivery.
Angew Chem Int Ed Engl;50:7027-31.
37. Valencia PM, Hanewich-Hollatz MH, Gao W, Karim F, Langer R, Karnik R,
Farokhzad OC. Effects of ligands with different water solubilities on self-assembly and
properties of targeted nanoparticles. Biomaterials;32:6226-33.
38. Wang GK, Strichartz GR. State-Dependent Inhibition of Sodium Channels by Local
Anesthetics: A 40-Year Evolution. Biochemistry 2011: 6:120-127.
39. Leri A, Kajstura J, Anversa P. Role of cardiac stem cells in cardiac pathophysiology:
a paradigm shift in human myocardial biology. Circ Res;109:941-61.
40. Recchiuti A, Krishnamoorthy S, Fredman G, Chiang N, Serhan CN. MicroRNAs in
resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.
Faseb J;25:544-60.
41. Schif-Zuck S, Gross N, Assi S, Rostoker R, Serhan CN, Ariel A. Saturatedefferocytosis generates pro-resolving CD11b low macrophages: modulation by resolvins
and glucocorticoids. Eur J Immunol;41:366-79.
42. Oh SF, Pillai PS, Recchiuti A, Yang R, Serhan CN. Pro-resolving actions and
stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine
inflammation. J Clin Invest;121:569-81.
43. Dartt DA, Hodges RR, Li D, Shatos MA, Lashkari K, Serhan CN. Conjunctival
goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to
promote resolution of inflammation. J Immunol;186:4455-66.
44. Merched AJ, Serhan CN, Chan L. Nutrigenetic disruption of inflammation-resolution
homeostasis and atherogenesis. J Nutrigenet Nutrigenomics;4:12-24.
45. Norling LV, Spite M, Yang R, Flower RJ, Perretti M, Serhan CN. Cutting edge:
Humanized nano-proresolving medicines mimic inflammation-resolution and enhance
wound healing. J Immunol;186:5543-7.
46. Palmer CD, Mancuso CJ, Weiss JP, Serhan CN, Guinan EC, Levy O. 17(R)-Resolvin
D1 differentially regulates TLR4-mediated responses of primary human macrophages to
purified LPS and live E. coli. J Leukoc Biol;90:459-70.
90
47. Serhan CN, Fredman G, Yang R, Karamnov S, Belayev LS, Bazan NG, Zhu M,
Winkler JW, Petasis NA. Novel proresolving aspirin-triggered DHA pathway. Chem
Biol;18:976-87.
48. Yang R, Fredman G, Krishnamoorthy S, Agrawal N, Irimia D, Piomelli D, Serhan
CN. Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA)
identifies novel bioactive signals. J Biol Chem;286:31532-41.
49. Fredman G, Oh SF, Ayilavarapu S, Hasturk H, Serhan CN, Van Dyke TE. Impaired
phagocytosis in localized aggressive periodontitis: rescue by Resolvin E1. PLoS
One;6:e24422.
50. Huang L, Gao YJ, Wang J, Strichartz G. Shifts in cell-type expression accompany a
diminishing role of spinal p38-mapkinase activation over time during prolonged
postoperative pain. Anesthesiology 2011;115:1281-90.
2011 Editorials, Reviews, Case Reports, Letters to the Editor and Monographs
1. Dix SK, Rosner GF, Nayar M, Harris JJ, Guglin ME, Winterfield JR, Xiong Z, Mudge
GH, Jr. Intractable cardiac arrest due to lidocaine toxicity successfully resuscitated with
lipid emulsion. Crit Care Med;39:872-4.
2. Leeson S. The highlight technique: airway exchange catheters with a colored marking
may improve safety of airway management. Anesth Analg;112:481.
3. Fox AA, Body SC. Assessment of preoperative B-type natriuretic peptide in adult
surgeries: is it useful? Anesth Analg;112:1005-7.
4. Camann W, Tuomala R. Antibiotic prophylaxis for cesarean delivery: always before
skin incision! Int J Obstet Anesth;20:1-2.
5. Anversa P, Kajstura J, Leri A, Loscalzo J. Tissue-specific adult stem cells in the
human lung. Nat Med;17:1038-9.
6. Spite M, Serhan CN. Lipid signatures of unstable atheromas: fossils or a step toward
personalized lipidomics-metabolomics? Circ Cardiovasc Genet;4:215-7.
7. Ross E, Jamison R, Edwards R. The opioid debate-missing the point. J Pain;12:508.
8. Ferrigno, M. Is swimming in cold water okay for my heart? Harvard Heart Letter to the
Editor. August 2011.
9. Voscopoulos C, Kirk FL, Lovrincevic M, Lema M. The use of “High Dose”
Dexmedetomidine in a Patient with Critical Tracheal Stenosis and Anterior Mediastinal
Mass. The Open Anesthesiology Journal. 2011; 5:42-49
91
10. Voscopoulos C, Jalota L, Kirk FL, Saxena A, Lema M, Apfel C, Antoine J.
Extubation of the Difficult Airway: An Algorithmic Approach. The Open Anesthesiology
Journal. 2011; 6:1-8.
11. Voscopoulos C, Barker T, Pozner C, Listwa T, Antoine J. A Comparison of Rescue
Airway Devices Placed by EMS Providers in a Human Patient Simulation Model.
American Society of Anesthesiologists. Oct 2011: Abstract.