Publications by authors named "John A Mannick"

32 Publications

Eagle scouting.

Authors:
John A Mannick

J Vasc Surg 2012 Nov 10;56(5):1468-9. Epub 2012 Sep 10.

Brigham and Women's Hospital, Harvard Medical School, Weston, Mass, USA.

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http://dx.doi.org/10.1016/j.jvs.2012.07.010DOI Listing
November 2012

Injury-induced GR-1+ macrophage expansion and activation occurs independently of CD4 T-cell influence.

Shock 2011 Aug;36(2):162-9

Department of Surgery (Immunology), Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

Burn injury initiates an enhanced inflammatory condition referred to as the systemic inflammatory response syndrome or the two-hit response phenotype. Prior reports indicated that macrophages respond to injury and demonstrate a heightened reactivity to Toll-like receptor stimulation. Since we and others observed a significant increase in splenic GR-1 F4/80 CD11b macrophages in burn-injured mice, we wished to test if these macrophages might be the primary macrophage subset that shows heightened LPS reactivity. We report here that burn injury promoted higher level TNF-α expression in GR-1, but not GR-1 macrophages, after LPS activation both in vivo and ex vivo. We next tested whether CD4 T cells, which are known to suppress injury-induced inflammatory responses, might control the activation and expansion of GR-1 macrophages. Interestingly, we found that GR-1 macrophage expansion and LPS-induced TNF-α expression were not significantly different between wild-type and CD4 T cell-deficient CD4(-/-) mice. However, further investigations showed that LPS-induced TNF-α production was significantly influenced by CD4 T cells. Taken together, these data indicate that GR-1 F4/80 CD11b macrophages represent the primary macrophage subset that expands in response to burn injury and that CD4 T cells do not influence the GR-1 macrophage expansion process, but do suppress LPS-induced TNF-α production. These data suggest that modulating GR-1 macrophage activation as well as CD4 T cell responses after severe injury may help control the development of systemic inflammatory response syndrome and the two-hit response phenotype.
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http://dx.doi.org/10.1097/SHK.0b013e31821af669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139815PMC
August 2011

Regulatory T cells suppress antigen-driven CD4 T cell reactivity following injury.

J Leukoc Biol 2011 Jan 30;89(1):137-47. Epub 2010 Sep 30.

Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Injury initiates local and systemic host responses and is known to increase CD4 Treg activity in mice and humans. This study uses a TCR transgenic T cell adoptive transfer approach and in vivo Treg depletion to determine specifically the in vivo influence of Tregs on antigen-driven CD4 T cell reactivity following burn injury in mice. We report here that injury in the absence of recipient and donor Tregs promotes high antigen-driven CD4 T cell expansion and increases the level of CD4 T cell reactivity. In contrast, CD4 T cell expansion and reactivity were suppressed significantly in injured Treg-replete mice. In additional experiments, we found that APCs prepared from burn- or sham-injured, Treg-depleted mice displayed significantly higher antigen-presenting activity than APCs prepared from normal mice, suggesting that Tregs may suppress injury responses by controlling the intensity of APC activity. Taken together, these findings demonstrate that Tregs can actively control the in vivo expansion and reactivity of antigen-stimulated, naïve CD4 T cells following severe injury.
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http://dx.doi.org/10.1189/jlb.0210082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004517PMC
January 2011

Analysis of factorial time-course microarrays with application to a clinical study of burn injury.

Proc Natl Acad Sci U S A 2010 Jun 17;107(22):9923-8. Epub 2010 May 17.

Department of Statistics, Stanford University, Stanford, CA 94305, USA.

Time-course microarray experiments are capable of capturing dynamic gene expression profiles. It is important to study how these dynamic profiles depend on the multiple factors that characterize the experimental condition under which the time course is observed. Analytic methods are needed to simultaneously handle the time course and factorial structure in the data. We developed a method to evaluate factor effects by pooling information across the time course while accounting for multiple testing and nonnormality of the microarray data. The method effectively extracts gene-specific response features and models their dependency on the experimental factors. Both longitudinal and cross-sectional time-course data can be handled by our approach. The method was used to analyze the impact of age on the temporal gene response to burn injury in a large-scale clinical study. Our analysis reveals that 21% of the genes responsive to burn are age-specific, among which expressions of mitochondria and immunoglobulin genes are differentially perturbed in pediatric and adult patients by burn injury. These new findings in the body's response to burn injury between children and adults support further investigations of therapeutic options targeting specific age groups. The methodology proposed here has been implemented in R package "TANOVA" and submitted to the Comprehensive R Archive Network at http://www.r-project.org/. It is also available for download at http://gluegrant1.stanford.edu/TANOVA/.
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http://dx.doi.org/10.1073/pnas.1002757107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890487PMC
June 2010

Murine dendritic cell antigen-presenting cell function is not altered by burn injury.

J Leukoc Biol 2009 May 19;85(5):862-70. Epub 2009 Feb 19.

Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Severe injury disrupts normal immune regulation causing a transient hyperinflammatory reaction and suppressed adaptive immune function. This report addresses the potential contribution of dendritic cells (DC) to changes in adaptive immune function after injury by specifically measuring injury-induced changes in splenic DC numbers and subsets, cell-surface markers, TLR responses, and APC function. Using a mouse burn injury model, we found that injury did not markedly alter the relative percentage of lymphoid, myeloid, or plasmacytoid DC in the spleens of burn-injured mice. Moreover, we did not observe a significant reduction in cell-surface expression of several major costimulatory molecules, CD40, CD80, CD86, programmed death 1 ligand, ICOS ligand, and B7-H3, on DC. Instead, we observed increased cell-surface expression of CD86 at 1 day after injury with no significant changes in costimulatory molecule expression at 7 days after injury, suggesting that burn injury causes an early activation of DC. In addition, injury did not suppress DC reactivity to TLR2, TLR4, or TLR9 agonists. Most important, DC prepared from injured mice were able to present peptide antigen to naive OTII TCR transgenic CD4+ T cells as efficiently and effectively as DC from sham-injured mice. We also found that CD4 T cells stimulated with antigen presented by DC from sham or burn mice showed similar levels of IL-2, IFN-gamma, IL-10, and IL-13 production. Taken together, these findings support the conclusion that DC do not acquire a suppressive phenotype following severe injury in mice.
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http://dx.doi.org/10.1189/jlb.0408257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669406PMC
May 2009

Twentieth anniversary of American Vascular Association/Lifeline Foundation: a celebration.

J Vasc Surg 2008 Jun 28;47(6):1351-5. Epub 2008 Apr 28.

Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

The American Vascular Association/Lifeline Foundation is celebrating its 20th anniversary this year. This remarkable two-decade journey represents a cumulative effort by the leaders and members of the Society for Vascular Surgery (SVS). For the historical record, we would like to chart the sequence of events leading to various programs. In 1986, the Executive Council of SVS approved the formation of an Education/Research Foundation, from which the Lifeline Foundation evolved, with the mission to support the career development of young research-oriented vascular surgeons. Since that time, Lifeline has awarded 141 Student Fellowships, 21 Wylie Traveling Fellowships, 17 Mentored Clinical Scientist Development (K08) Awards, and three Mentored Patient-Oriented Research Career Development (K23) Awards. In 2001, the American Vascular Association (AVA) was established under the aegis of American Association for Vascular Surgery (formerly International Society for Cardiovascular Surgery-North American Chapter). In 2004, with the merger of the SVS and the American Association of Vascular Surgery into a single entity (SVS), Lifeline and the AVA merged into a single foundation, the AVA. As AVA/Lifeline is poised to launch a campaign for an endowment fund, we hope this report will let the members of the SVS know what has been accomplished, what we plan to do, and, most importantly, what we need to do in the future.
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http://dx.doi.org/10.1016/j.jvs.2008.03.026DOI Listing
June 2008

Injury enhances resistance to Escherichia coli infection by boosting innate immune system function.

J Immunol 2008 Feb;180(4):2450-8

Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Major injury is widely thought to predispose the injured host to opportunistic infections. This idea is supported by animal studies showing that major injury causes reduced resistance to polymicrobial sepsis induced by cecal ligation and puncture. Although cecal ligation and puncture represents a clinically relevant sepsis model, we wanted to test whether injury might also lead to greater susceptibility to peritoneal infection caused by a single common pathogen, Escherichia coli. Contrary to our expectation, we show herein that the LD(50) for sham-injured mice was 10(3) CFU of E. coli, whereas the LD(50) for burn-injured mice was 50 x 10(3) CFU at 7 days postinjury. This injury-associated enhanced resistance was apparent as early as 1 day after injury, and maximal resistance was observed at days 7 and 14. We found that burn-injured mice had higher numbers of circulating neutrophils and monocytes than did sham mice before infection and that injured mice were able to recruit greater numbers of neutrophils to the site of infection. Moreover, the peritoneal neutrophils in burn-injured mice were more highly activated than neutrophils from sham mice as determined by Mac-1 expression, superoxide generation, and bactericidal activity. Our findings suggest that the enhanced innate immune response that develops following injury, although it is commonly accepted as the mediator of the detrimental systemic inflammatory response syndrome, may also, in some cases, benefit the injured host by boosting innate immune antimicrobial defenses.
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http://dx.doi.org/10.4049/jimmunol.180.4.2450DOI Listing
February 2008

Comparison of longitudinal leukocyte gene expression after burn injury or trauma-hemorrhage in mice.

Physiol Genomics 2008 Feb 6;32(3):299-310. Epub 2007 Nov 6.

Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts 02115, USA.

A primary objective of the large collaborative project entitled "Inflammation and the Host Response to Injury" was to identify leukocyte genes that are differentially expressed after two different types of injury in mouse models and to test the hypothesis that both forms of injury would induce similar changes in gene expression. We report here the genes that are expressed in white blood cells (WBCs) and in splenocytes at 2 h, 1 day, 3 days, and 7 days after burn and sham injury or trauma-hemorrhage (T-H) and sham T-H. Affymetrix Mouse Genome 430 2.0 GeneChips were used to profile gene expression, and the results were analyzed by dCHIP, BRB Array Tools, and Ingenuity Pathway Analysis (IPA) software. We found that the highest number of genes differentially expressed following burn injury were at day 1 for both WBCs (4,989) and for splenocytes (4,715) and at day 1 for WBCs (1,167) and at day 3 for splenocytes (1,117) following T-H. The maximum overlap of genes that were expressed after both forms of injury were at day 1 in WBCs (136 genes) and at day 7 in splenocytes (433 genes). IPA revealed that the cell-to-cell signaling, cell death, immune response, antiapoptosis, and cell cycle control pathways were affected most significantly. In summary, this report provides a database of genes that are modulated in WBCs and splenocytes at sequential time points after burn or T-H in mice and reveals that relatively few leukocyte genes are expressed in common after these two forms of injury.
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http://dx.doi.org/10.1152/physiolgenomics.00086.2007DOI Listing
February 2008

Reviving the vascular surgeon-scientist: an interim assessment of the jointly sponsored Lifeline Foundation/National Heart, Lung, and Blood Institute William J. von Liebig Mentored Clinical Scientist Development (K08) Program.

J Vasc Surg 2007 Jun;45 Suppl A:A2-7

Department of Surgery (Section of Vascular Surgery), Washington University School of Medicine, St. Louis, MO 63110, USA.

The Lifeline Foundation/National Heart, Lung, and Blood Institute William J. von Liebig Mentored Clinical Scientist Development (K08) Award program was established as a unique partnership to support vascular surgeon-scientists. Between 1999 and 2005, 39 applications were submitted, and the overall funding rate was 49% (14 von Liebig K08s and 5 additional NHLBI K08s). Vascular surgeon K08 recipients (median age, 38 years) had held faculty appointments for 2.5 +/- 0.4 years, with 2.6 +/- 0.2 years of previous research experience and 28.4 +/- 6.2 publications. These individuals subsequently authored 5.1 +/- 0.8 peer-reviewed publications per recipient per year, of which 35% were research and 65% were clinical. Six of seven holding the K08 over 3 years had received academic promotion, and all five completing the 5-year award had achieved independent investigator status with National Institutes of Health support. The von Liebig K08 program has therefore been an effective vehicle to stimulate research career development in the field of vascular surgery.
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http://dx.doi.org/10.1016/j.jvs.2007.02.045DOI Listing
June 2007

Increased CD4+ CD25+ T regulatory cell activity in trauma patients depresses protective Th1 immunity.

Ann Surg 2006 Oct;244(4):514-23

Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Objectives: We recently reported increased CD4 CD25 T regulatory (Treg) activity after burn injury in mice. This study sought to determine if Tregs mediate the reduction in TH1-type immunity after serious injury in man and if Treg function is altered by injury.

Methods: Peripheral blood was withdrawn from 19 consenting adult patients (35.1 +/- 16.3 years of age) with Injury Severity Scores (ISS) 36.6 +/- 13.9 on days 1 and 7 after trauma and from 5 healthy individuals. CD4 T cells were purified and sorted into Treg (CD25(high)) and Treg-depleted populations. After activation of cells with anti-CD3/CD28 antibody, production of the TH1-type cytokine IFNgamma, TH2-type cytokines (IL-4 and IL-5), and the inhibitory cytokine IL-10 was measured using cytometric bead arrays. Treg activity was measured by in vitro suppression of autologous CD4 T cell proliferation.

Results: All patients survived, 9 (47%) developed infection postinjury. IFNgamma production by patient CD4 T cells was decreased on day 1 and day 7, when compared with healthy controls. However, when Tregs were depleted from the CD4 T cells, the IFNgamma production increased to control levels. Tregs were the chief source of IL-4 and IL-5 as well as IL-10. Treg suppression of T cell proliferation increased significantly from day 1 to day 7 after injury.

Conclusions: We demonstrate for the first time that human Tregs are increased in potency after severe injury. Most significantly, Tregs are important mediators of the suppression of T cell activation and the reduction in TH1 cytokine production found after injury.
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http://dx.doi.org/10.1097/01.sla.0000239031.06906.1fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856576PMC
October 2006

Burn injury induces an early activation response by lymph node CD4+ T cells.

Shock 2006 Feb;25(2):135-40

Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Several reports have shown that burn injury primes the immune system for an early and vigorous proinflammatory CD4 T cell response, suggesting that injury might signal CD4 T cell activation. We addressed this possibility by investigating changes in CD4 T cell activation marker expression, proliferation, and T cell receptor (TCR) usage at several early time points after burn injury. Using a sensitive flow cytometry approach to measure changes in the expression of Ki-67 antigen, a nuclear protein detected only in proliferating cells, we observed an early burst of proliferation by lymph node, but not spleen, CD4 T cells 12 h after burn injury. In contrast, mice that were treated with the bacterial superantigen staphylococcal enterotoxin B (SEB) as a positive control for in vivo T cell activation did not show this early proliferation. Instead, we observed a significant increase in proliferating lymph node and spleen CD4 and CD8 T cells by 3 days after SEB treatment. Burn injury induced higher cell surface CD25 and CD152 expression on lymph node CD4 T cells, whereas SEB treatment increased CD25 and CD69 expression on CD4 and CD8 T cells. Finally, we found that burn injury induced a proliferative response at 12 h by an oligoclonal subset of TCR Vbeta-chain-expressing CD4 T cells (Vbeta4, Vbeta6, Vbeta11, and Vbeta14). Interestingly, CD4 T cells expressing the Vbeta11-TCR remained significantly increased in the lymph nodes 3 days after burn injury. Taken together, these findings indicate that burn injury induces an early proliferation and activation of CD4 T cells in the regional lymph nodes and that these proliferating cells show restricted TCR Vbeta-chain usage consistent with the idea that injury triggers an early T cell activation signal.
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http://dx.doi.org/10.1097/01.shk.0000190824.51653.32DOI Listing
February 2006

Commonality and differences in leukocyte gene expression patterns among three models of inflammation and injury.

Physiol Genomics 2006 Feb 20;24(3):298-309. Epub 2005 Dec 20.

Department of Genetics, Washington University, St. Louis, Missouri, USA.

The aim of this study was to compare gene expression profiles of leukocytes from blood (white blood cells; WBCs) and spleen harvested at an early time point after injury or sham injury in mice subjected to trauma/hemorrhage, burn injury, or lipopolysaccharide (LPS) infusion at three experimental sites. Groups of injured or LPS-infused animals and sham controls were killed at 2 h after injury and resuscitation, blood and spleen were harvested, and leukocyte populations were recovered after erythrocyte lysis. RNA was extracted from postlysis leukocyte populations. Complementary RNA was synthesized from each RNA sample and hybridized to microarrays. A large number (500-1,400) of genes were differentially expressed at the 2-h time point in injured or LPS-infused vs. sham animals. Thirteen of the differentially expressed genes in blood, and 46 in the spleen, were upregulated or downregulated in common among all three animal models and may represent a common, early transcriptional response to systemic inflammation from a variety of causes. The majority of these genes could be assigned to pathways involved in the immune response and cell death. The up- or downregulation of a cohort of 23 of these genes was validated by RT-PCR. This large-scale microarray analysis shows that, at the 2-h time point, there is marked alteration in leukocyte gene expression in three animal models of injury and inflammation. Although there is some commonality among the models, the majority of the differentially expressed genes appear to be uniquely associated with the type of injury and/or the inflammatory stimulus.
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http://dx.doi.org/10.1152/physiolgenomics.00213.2005DOI Listing
February 2006

Platelet depletion in mice increases mortality after thermal injury.

Blood 2006 Jun 7;107(11):4399-406. Epub 2006 Feb 7.

Julian and Eunice Cohen Laboratory for Surgical Research, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.

Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in innate and adaptive immunity. However, the role of platelets in the immune response to injury remains undefined. We tested the importance of platelets in the host response to serious injury in a newly developed platelet-deficient mouse model. Wild-type and platelet-depleted C57BL/6J mice underwent a 25% full-thickness total body surface area thermal or sham injury. Platelet-deficient mice showed survival of 51% at 48 hours after injury compared with 94% to 100% survival in experimental control mice (P < .001). Necropsy and histology ruled out hemorrhage and hypovolemia as causes of death. Percentages of peripheral blood monocytes (P < .01) and neutrophils (P < .05) were increased between 36 and 48 hours after thermal injury in platelet-deficient mice compared with control mice. Plasma levels of TNFalpha (P < .001), IL-6 (P < .001), and MCP-1 (P < .05) were also elevated by 24 hours whereas levels of TGFbeta(1) were reduced between 24 and 36 hours following injury in platelet-depleted mice (P < .001) compared with control mice. Our findings demonstrate for the first time that platelets play a critical protective role during the host response to injury. Moreover, our findings suggest that platelets and, more importantly, platelet-derived TGFbeta(1) modulate the systemic inflammatory response occurring after injury.
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http://dx.doi.org/10.1182/blood-2005-09-3776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895793PMC
June 2006

Enhanced regulatory T cell activity is an element of the host response to injury.

J Immunol 2006 Jan;176(1):225-36

Department of Surgery (Immunology), Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

CD4+CD25+ regulatory T cells (Tregs) play a critical role in suppressing the development of autoimmune disease, in controlling potentially harmful inflammatory responses, and in maintaining immune homeostasis. Because severe injury triggers both excessive inflammation and suppressed adaptive immunity, we wished to test whether injury could influence Treg activity. Using a mouse burn injury model, we demonstrate that injury significantly enhances Treg function. This increase in Treg activity is apparent at 7 days after injury and is restricted to lymph node CD4+CD25+ T cells draining the injury site. Moreover, we show that this injury-induced increase in Treg activity is cell-contact dependent and is mediated in part by increased cell surface TGF-beta1 expression. To test the in vivo significance of these findings, mice were depleted of CD4+CD25+ T cells before sham or burn injury and then were immunized to follow the development of T cell-dependent Ag-specific immune reactivity. We observed that injured mice, which normally demonstrate suppressed Th1-type immunity, showed normal Th1 responses when depleted of CD4+CD25+ T cells. Taken together, these observations suggest that injury can induce or amplify CD4+CD25+ Treg function and that CD4+CD25+ T cells contribute to the development of postinjury immune suppression.
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http://dx.doi.org/10.4049/jimmunol.176.1.225DOI Listing
January 2006

Enhanced TLR4 reactivity following injury is mediated by increased p38 activation.

J Leukoc Biol 2005 Aug 27;78(2):565-73. Epub 2005 Apr 27.

Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Severe injury primes the innate-immune system for increased Toll-like receptor 4 (TLR4)-induced proinflammatory cytokine production by macrophages. In this study, we examined changes in TLR4 signaling pathways in splenic macrophages from burn-injured or sham mice to determine the molecular mechanism(s) responsible for the increased TLR4 responsiveness. Using flow cytometry and specific antibodies, we first looked for injury-induced changes in the expression levels of several TLR-associated signaling molecules. We found similar levels of myeloid differentiation primary-response protein 88 (MyD88) and interleukin-1 receptor-associated kinase-M (IRAK-M) and somewhat lower levels of total p38, extracellular signal-regulated kinase (ERK), and stress-activated protein kinase (SAPK)/c-jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) in burn compared with sham macrophages. However, with the use of antibodies specific for the phosphorylated (activated) forms of the three MAPKs, we found that macrophages from burn mice showed a twofold increase in purified lipopolysaccharide (LPS)-stimulated p38 activation as compared with cells from sham mice on days 1 and 7 post-injury, whereas ERK and SAPK/JNK activation was increased by burn injury only on day 1. Using the specific p38 inhibitor (SB203580), we confirmed that the increase in tumor necrosis factor alpha production by LPS-stimulated burn macrophages requires p38 activation. Although we demonstrated that injury increases macrophage TLR4 mRNA expression and intracellular expression of TLR4-myeloid differentiation protein-2 (MD-2) protein, macrophage cell-surface expression of TLR4-MD-2 was not changed by burn injury. Our results suggest that the injury-induced increase in TLR4 reactivity is mediated, at least in part, by enhanced activation of the p38 signaling pathway.
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http://dx.doi.org/10.1189/jlb.1204698DOI Listing
August 2005

CD4+CD25+ regulatory T cells control innate immune reactivity after injury.

J Immunol 2005 Mar;174(5):2957-63

Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Major injury initiates a systemic inflammatory response that can be detrimental to the host. We have recently reported that burn injury primes innate immune cells for a progressive increase in TLR4 and TLR2 agonist-induced proinflammatory cytokine production and that this inflammatory phenotype is exaggerated in adaptive immune system-deficient (Rag1(-/-)) mice. The present study uses a series of adoptive transfer experiments to determine which adaptive immune cell type(s) has the capacity to control innate inflammatory responses after injury. We first compared the relative changes in TLR4- and TLR2-induced TNF-alpha, IL-1beta, and IL-6 production by spleen cell populations prepared from wild-type (WT), Rag1(-/-), CD4(-/-), or CD8(-/-) mice 7 days after sham or burn injury. Our findings indicated that splenocytes prepared from burn-injured CD8(-/-) mice displayed TLR-induced cytokine production levels similar to those in WT mice. In contrast, spleen cells from burn-injured CD4(-/-) mice produced cytokines at significantly higher levels, equivalent to those in Rag1(-/-) mice. Moreover, reconstitution of Rag1(-/-) or CD4(-/-) mice with WT CD4(+) T cells reduced postinjury cytokine production to WT levels. Additional separation of CD4(+) T cells into CD4(+)CD25(+) and CD4(+)CD25(-) subpopulations before their adoptive transfer into Rag1(-/-) mice showed that CD4(+)CD25(+) T cells were capable of reducing TLR-stimulated cytokine production levels to WT levels, whereas CD4(+)CD25(-) T cells had no regulatory effect. These findings suggest a previously unsuspected role for CD4(+)CD25(+) T regulatory cells in controlling host inflammatory responses after injury.
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http://dx.doi.org/10.4049/jimmunol.174.5.2957DOI Listing
March 2005

Linking the "two-hit" response following injury to enhanced TLR4 reactivity.

J Leukoc Biol 2005 Jan 20;77(1):16-23. Epub 2004 Oct 20.

Department of Surgery (Immunology), Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115,USA.

Severe injury can initiate an exaggerated systemic inflammatory response and multiple organ failure (MOF) if a subsequent immune stimulus, "second hit", occurs. Using a mouse thermal injury model, we tested whether changes in innate immune cell reactivity following injury can contribute to the development of heightened inflammation and MOF. Using high-purity Escherichia coli lipopolysaccharide (LPS) to selectively stimulate Toll-like receptor 4 (TLR4), we demonstrate augmented interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 production by 1 day but particularly, at 7 days after injury. The in vivo significance of enhanced TLR4 responsiveness was explored by challenging sham or burn mice with LPS at 1 or 7 days after injury and determining mortality along with in vivo cytokine and chemokine levels. Mortality was high (75%) in LPS-challenged burn but not sham mice at 7 days, although not at 1 day, after injury. Death was associated with leukocyte sequestration in the lungs and livers along with increased proinflammatory cytokine and chemokine levels in these organs. Blocking TNF-alpha activity prevented this mortality, suggesting that excessive TNF-alpha production contributes to this lethal response. These findings demonstrate the potential lethality of excessive TLR4 reactivity after injury and provide an explanation for the exaggerated inflammatory response to a second hit, which can occur following severe injury.
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http://dx.doi.org/10.1189/jlb.0704382DOI Listing
January 2005

Thoracovisceral segment aneurysm repair after previous infrarenal abdominal aortic aneurysm surgery.

J Vasc Surg 2004 Jun;39(6):1163-70

Division of Vascular and Endovascular Surgery, Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Objective: Repair of thoracovisceral aortic aneurysms (TVAA) after previous open repair of an infrarenal abdominal aortic aneurysm (AAA) poses significant challenges. We sought to better characterize such recurrent aneurysms and to evaluate their operative outcome.

Methods: We reviewed the records and radiographs of 49 patients who underwent repair of TVAAs between 1988 and 2002 after previous repair of an AAA. Visceral artery reconstructions were completed with combinations of beveled anastomoses, inclusion patches, and side arm grafts. In 14 patients visceral endarterectomy was required to treat associated occlusive disease. Sixteen patients had cerebrospinal fluid drainage, and 10 patients had distal perfusion during cross-clamping.

Results: Patient mean age was 72 years, and 80% were men. Fifty-one percent of patients had symptomatic disease, and average TVAA diameter was 6.2 cm. Mean time between AAA and TVAA repair was 77 months. Twenty-six percent of aneurysms were restricted to the lower visceral aortic segment, 35% extended to the diaphragm, another 35% extended to the distal or middle thoracic aorta, and 4% involved the entire remaining visceral and thoracic aorta. The 30-day operative mortality rate was 4.1% in patients with nonruptured aneurysms and 50% in patients with ruptured aneurysms, for an overall mortality rate of 8.2%. Fifteen patients (30.6%) had major morbidity, including paresis in two patients and dialysis-dependent renal failure in five patients. At late follow-up, three patients required further aortic operations to treat additional aneurysms, and four patients had fatal aortic ruptures. Two-year and 5-year cumulative survival rates were 61% (+/-7.5%) and 37% (+/-7.8%), respectively. At univariate analysis, operative blood loss was the sole significant predictor of major morbidity (P <.023), and rupture (P <.030, P <.0001) and aneurysm extent (P <.0007, P <.0001) correlated with both operative death and long-term survival. Only aneurysm extent (P <.010, relative risk 37.3) remained a significant predictor of long-term survival at multivariate analysis.

Conclusion: Elective repair of TVAAs after previous AAA repair can be performed with an acceptable level of operative mortality, though with considerable operative morbidity. Limited long-term survival mandates careful patient selection, and the high mortality associated with ruptured TVAA underscores the need for post-AAA surveillance.
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http://dx.doi.org/10.1016/j.jvs.2003.12.019DOI Listing
June 2004

Burn injury initiates a shift in superantigen-induced T cell responses and host survival.

J Immunol 2004 Apr;172(8):4883-92

Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Severe injury induces a temporal shift in immune reactivity that can cause serious complications or even death. We previously reported that mice exposed to bacterial superantigen (SAg) early after injury undergo a strong SAg response with lethal consequences. This study compares the early and late effects of burn injury on SAg reactivity in vivo to establish how injury influences adaptive immune responses. We found that mice challenged with ordinarily sublethal doses of staphylococcal enterotoxin A or staphylococcal enterotoxin B at 1 day after burn injury exhibited high mortality, whereas no mortality occurred at 7 days after injury. This shift in mortality correlated with higher Th2-type cytokines (IL-4 and IL-10) being expressed by CD4(+) and CD8(+) T cells from burn as opposed to sham mice at 7 days after injury. Lymph node cells from burn-injured mice also produced higher levels of Th2-type cytokines at 7 days after injury. The results of cell-mixing studies using CD4(+) and CD8(+) T cells mixed with APCs from sham or burn mice suggested that changes in both T cells and APCs are involved in the altered SAg response. Finally, the biological significance of altered SAg reactivity following injury was shown by demonstrating that blocking IL-10 activity in vivo caused higher SAg-induced mortality at 7 days after injury. These findings support the idea that injury promotes a Th2-type shift in adaptive immune reactivity. Although prior studies link this counterinflammatory-type response to lowered resistance to infection, the present results suggest it may sometimes benefit the injured host.
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http://dx.doi.org/10.4049/jimmunol.172.8.4883DOI Listing
April 2004

Injury, sepsis, and the regulation of Toll-like receptor responses.

J Leukoc Biol 2004 Mar 13;75(3):400-7. Epub 2003 Oct 13.

Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.

Although we tend to think that the immune system has evolved to protect the host from invading pathogens and to discriminate between self and nonself, there must also be an element of the immune system that has evolved to control the response to tissue injury. Moreover, these potential immune-regulatory pathways controlling the injury response have likely coevolved in concert with self and nonself discriminatory immune-regulatory networks with a similar level of complexity. From a clinical perspective, severe injury upsets normal immune function and can predispose the injured patient to developing life-threatening infectious complications. This remains a significant health care problem that has driven decades of basic and clinical research aimed at defining the functional effects of injury on the immune system. This review and update on our ongoing research efforts addressing the immunological response to injury will highlight some of the most recent advances in our understanding of the impact that severe injury has on the innate and adaptive immune system focusing on phenotypic changes in innate immune cell responses to Toll-like receptor stimulation.
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http://dx.doi.org/10.1189/jlb.0503233DOI Listing
March 2004

Burn injury promotes antigen-driven Th2-type responses in vivo.

J Immunol 2003 Oct;171(8):3983-90

Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

Severe injury induces detrimental changes in immune function, often leaving the host highly susceptible to developing life-threatening opportunistic infections. Advances in our understanding of how injury influences host immune responses suggest that injury causes a phenotypic imbalance in the regulation of Th1- and Th2-type immune responses. We report in this study, using a TCR transgenic CD4(+) T cell adoptive transfer approach, that injury skews T cell responses toward increased Th2-type reactivity in vivo without substantially limiting Ag-driven CD4(+) T cell expansion. The increased Th2-type response did not occur unless injured mice were immunized with specific Ag, suggesting that the phenotypic switch is Ag dependent. These findings establish that severe injury induces fundamental changes in the induction of Ag-specific CD4(+) Th cell responses favoring the development of Th2-type immune reactivity in vivo.
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http://dx.doi.org/10.4049/jimmunol.171.8.3983DOI Listing
October 2003

Use of intracellular cytokine staining and bacterial superantigen to document suppression of the adaptive immune system in injured patients.

Ann Surg 2003 Sep;238(3):401-10; discussion 410-1

Department of Surgery, Julian and Eunice Cohen Laboratory, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Objective: To determine the percentages of major T lymphocyte subsets in the circulating peripheral blood mononuclear cell population in patients with major traumatic injury at early and late time points and to determine the expression of coreceptors and cytokine production by these T cell subsets.

Summary Background Data: Prior studies suggest that serious injury in humans suppresses the adaptive immune system as revealed by diminished proliferation and altered cytokine production in response to polyclonal T cell activation. However, the contribution of individual cell types to this immune dysfunction has not been well characterized.

Methods: The percentage of circulating CD4+ and CD8+ T cells and the relative density of CD4 and CD8 coreceptor expression was determined by flow cytometry in 17 consecutive trauma patients (injury severity score > 20) within 24 hours of injury and at day 7. Intracellular expression of the cytokines interleukin 2 (IL-2), interferon gamma (IFNgamma), IL-4, and IL-10 were also studied after stimulation with bacterial superantigen (SEB). Patients were compared with age- and sex-matched controls and to themselves for differences between early and late cytokine expression.

Results: The percentage of circulating CD4+ and CD8+ T cells was decreased versus controls at day 1 and further decreased by day 7 following injury. CD4 and CD8 cell surface expression was also decreased at days 1 and 7. CD4+ T cells in injured patients responded to SEB activation with decreased expression of IFNgamma and IL-2 on day 1 versus controls (P < 0.05) and of all 4 cytokines by day 7 (P < 0.05), while CD8+ T cells showed diminished expression of IFNgamma and IL-2 only at both time points. When day 1 and day 7 cytokine expression results were compared in the same patients, CD4+ T cells showed diminished expression of IFNgamma, IL-2, and IL-4 by day 7 (P < 0.05), but maintained expression of IL-10. CD8 T cells showed diminished expression of IFNgamma only.

Conclusions: Severe injury induces a loss of circulating CD4+ and CD8+ T lymphocytes and diminished coreceptor expression by these cells. Both T cell subsets show progressive loss of immunostimulatory cytokine production with maintenance of potentially suppressive IL-10 production. These events may have negative consequences for host defense.
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http://dx.doi.org/10.1097/01.sla.0000086661.45300.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422703PMC
September 2003

Injury primes the innate immune system for enhanced Toll-like receptor reactivity.

J Immunol 2003 Aug;171(3):1473-83

Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

Severe injury causes a dramatic host response that disrupts immune homeostasis and predisposes the injured host to opportunistic infections. Because Toll-like receptors (TLRs) recognize conserved microbial Ags and endogenous danger signals that may be triggered by injury, we wanted to determine how injury influences TLR responses. Using an in vivo injury model, we demonstrate that injury significantly increased TLR2- and TLR4-induced IL-1beta, IL-6, and TNF-alpha production by spleen cells. This influence of injury on TLR reactivity was observed as early as 1 day after injury and persisted for at least 7 days. The outcome of similar studies performed using TLR4-mutant C57BL/10ScN/Cr mice revealed that TLR2 responses remained primed, thus suggesting that injury-induced priming can occur independently of endogenous TLR4 signaling. Increased TLR4 reactivity was also observed in vivo, because LPS-challenged injured mice demonstrated significantly higher cytokine expression levels in the lung, liver, spleen, and plasma. Macrophages and dendritic cells were the major source of these cytokines as judged by intracellular cytokine staining. Moreover, ex vivo studies using enriched macrophage and dendritic cell populations confirmed that T cells did not contribute to the enhanced TLR2 and TLR4 responses. The results of flow cytometry studies using TLR2- and TLR4-MD-2-specific Abs indicated that injury did not markedly alter cell surface TLR2 or TLR4-MD-2 expression. Taken together, these findings establish that injury primes the innate immune system for enhanced TLR2- and TLR4-mediated responses and provides evidence to suggest that augmented TLR reactivity might contribute to the development of heightened systemic inflammation following severe injury.
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http://dx.doi.org/10.4049/jimmunol.171.3.1473DOI Listing
August 2003

Interaction between the innate and adaptive immune systems is required to survive sepsis and control inflammation after injury.

Shock 2003 Aug;20(2):123-9

Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.

Substantial clinical and laboratory research has revealed that major injury causes abnormalities in both the innate and adaptive immune systems. However, the relative importance of each of these systems in the immune dysfunction after injury is poorly understood and difficult to establish by clinical studies alone. Rag1 (-/-) C57BL/6 mice (Rag1), which lack an adoptive immune system, and immune-sufficient wild-type (WT) C57BL/6 mice underwent 25% total body surface area burn injury or sham injury under anesthesia and were subjected to cecal ligation and puncture (CLP) at day 10 postinjury, a time of high CLP mortality in this model. To test the effect of adaptive immune deficiency on inflammatory cytokine production after injury, adaptive cell-depleted splenocytes from sham and burn WT and Rag1 mice were stimulated with LPS, and TNF-alpha and IL-6 production were assayed at days 1 and 7 postinjury. Intracellular expression of TNFalpha and IL-6 by F4/80 macrophages was also assessed on day 7 by intracellular cytokine staining. Finally, Rag1 animals were reconstituted with WT splenocytes, and the effect of such reconstitution on CLP survival and cytokine production was determined. Survival of sham WT animals after CLP was significantly higher (P < 0.01) than survival of burn WT and Rag1 sham and burn animals, all of which had equivalently low survival. Reconstitution of Rag1 animals with WT splenocytes restored CLP survival to WT sham levels. Splenocytes from Rag1 burn mice showed significantly augmented cytokine production when compared with WT burn mice on day 7 (P < 0.05). Reconstitution of Rag1 mice with WT splenocytes at the time of injury returned cytokine production to WT levels. Intracellular cytokine expression in F4/80 macrophages was increased to a similar degree after burn, but not sham burn injury in Rag1, reconstituted Rag1 and WT animals. These studies demonstrate that the adaptive immune system is necessary for protection from polymicrobial sepsis and plays a significant role in regulating the inflammatory response to injury.
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http://dx.doi.org/10.1097/01.shk.0000079426.52617.00DOI Listing
August 2003

Mast cells and resistance to peritoneal sepsis after burn injury.

Shock 2003 Jun;19(6):513-8

Department of Surgery, Julian and Eunice Cohen Laboratory, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

A mouse model of burn injury demonstrates increasing mortality to an infectious challenge in the form of cecal ligation and puncture (CLP) reaching a peak at 10 days after injury. Because it is widely believed that peritoneal mast cells play an important role in the defense against peritoneal sepsis, we wished to explore the possibility that peritoneal mast cell dysfunction contributed to increased CLP mortality after burn injury. Kit(W-v) C57BL/6 mice, which were shown to lack peritoneal mast cells by cytospin and flow cytometry, and normal littermate control animals were subjected to 25% burn or sham burn injury and 10 days later underwent CLP. Burn injured Kit(W-v) and normal littermates had a high CLP mortality when compared with sham-injured Kit(W-v) and normal littermates (P < 0.003), but the sham- and burn-injured Kit(W-v) and normal littermate animals did not differ from one another with respect to CLP mortality. This result prompted a comparison of CLP mortality in untreated WBB6F1 Kit(W/W-v) mice, known to be mast cell deficient, and normal littermate controls, as well as untreated C57BL/6 Kit(W-v) and normal littermates. The WBB6F1 Kit(W/W-v) mice showed significantly increased mortality after CLP as compared with the littermate controls (P = 0.03), whereas both C57BL/6 Kit(W-v) and littermate controls had very low mortality after CLP. A study of peritoneal cell populations 24 h after CLP failed to reveal an obvious cause for the difference in CLP survival between the two mast cell-deficient strains. Tumor necrosis factor-alpha (TNF-alpha) measurements in peritoneal fluid showed appreciable amounts of TNF-alpha in the littermate controls of both strains and little in the fluid obtained from the mast cell-deficient animals of both strains. We conclude that peritoneal mast cell dysfunction is unlikely to be a major cause of decreased resistance to peritoneal sepsis in burn-injured animals and that the importance of peritoneal mast cells in combating peritoneal sepsis in the mouse appears to be strain dependent.
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http://dx.doi.org/10.1097/.01.shk0000055239.25446.2dDOI Listing
June 2003

The impact of patient age and aortic size on the results of aortobifemoral bypass grafting.

J Vasc Surg 2003 Jun;37(6):1219-25

Division of Vascular Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA.

Objectives: On the basis of the widespread belief that aortobifemoral bypass (ABF) represents the optimal mode of revascularization for patients with diffuse aortoiliac disease, vascular surgeons are often aggressive about its application in young adults. We undertook this retrospective evaluation of ABFs performed from 1980 to 1999 to determine whether the results justify this approach. Patients of less than 50 years of age (n = 45) were compared with those aged 50 to 59 years (n = 93) and those aged more than 60 years (n = 146).

Results: Younger patients were more likely to undergo operation for claudication than were older patients (72% versus 59% and 55%; P <.04). Younger patients were significantly more likely to be smokers (87%) but less likely to have diabetes, hypertension, or cerebrovascular disease. Bypasses were constructed in an end-to-end fashion in 71.1% of patients of less than 50 years versus 68.8% and 71.2% of older patients (P = not significant). The mean diameter of aortic grafts was significantly smaller in younger patients (14.6 mm) than in older patients (15.6 mm and 15.5 mm; P <.01). The need for a subsequent infrainguinal reconstruction was highest in the youngest patients (24% versus 17% and 7%; P <.01). Surgical mortality rates were low in all groups (0%, 1%, and 2.0% for increasing age groups; P = not significant). Five-year primary and secondary patency rates increased significantly with each increase in age interval: 5-year primary patency rate: less than 50 years, 66% +/- 8%; 50 to 59 years, 87% +/- 5%; more than 60 years, 96% +/-2% (P <.05 for all comparisons). Five-year secondary patency rates were: less than 50 years, 79% +/- 7%; 50 to 59 years, 91% +/- 4%; more than 60 years, 98% +/- 2% (P <.05 for all comparisons). Five-year survival rate was comparable in all three groups: less than 50 years, 93% +/- 5%; 50 to 59 years, 92% +/- 4%; more than 60 years, 87% +/- 4% (P = not significant).

Conclusion: Increased virulence of aortic disease, smaller aortic size, and more progressive infrainguinal disease may all negatively impact the results of ABF in younger patients. Although 5-year results are acceptable, increased caution is warranted in the routine application of ABF in young patients without limb-threatening ischemia.
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http://dx.doi.org/10.1016/s0741-5214(02)75179-3DOI Listing
June 2003

Preoperative risk factors for carotid endarterectomy: defining the patient at high risk.

J Vasc Surg 2003 Jun;37(6):1191-9

Division of Vascular Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.

Purpose: The efficacy of carotid endarterectomy (CEA) for prevention of stroke has been demonstrated in randomized trials; however, the optimal approach in patients excluded from these trials or who have other significant comorbid conditions remains controversial, particularly with the advent of percutaneous interventions. We examined the influence of putative risk factors on outcome of CEA in a single-center experience.

Methods: A retrospective analysis of 1370 consecutive CEA performed from 1990 to 1999 was undertaken. Preoperative risk factors examined included age older than 80 years, congestive heart failure, chronic obstructive pulmonary disease, renal failure (serum creatinine concentration > 2.0 mg/dL), contralateral carotid artery occlusion, recurrent ipsilateral carotid artery stenosis, ipsilateral hemispheric symptoms within 6 weeks, and recent coronary bypass grafting (CABG). The Fisher exact test was used to identify baseline variables associated with perioperative (30 days) risk for stroke or death. Multivariate analysis with Poisson regression was used to study the effect of all univariate criteria in combination.

Results: In the overall cohort, there were 32 adverse events (2.3%), including 11 deaths (0.8%), 6 disabling strokes (0.4%), and 10 nondisabling strokes (0.7%). There was no significant difference in incidence of perioperative stroke or death between patients with one or more risk factors (n = 689) and those with no risk factors (low risk, n = 681). Thirty-day mortality was significantly greater in patients with two or more risk factors compared with patients with no risk factors (2.8% vs 0.3%; P =.04), but no significant difference was noted in perioperative stroke rate (2.3% vs 1.0%). Univariate analysis demonstrated that contralateral carotid occlusion (n = 75) was the only significant predictor of adverse outcome (5 events, 6.7%) among the variables tested; this was confirmed with multivariate analysis (relative risk, 4.3; 95% confidence interval, 1.2-12.3; P =.01). Five-year survival for patients with two or more risk factors was notably diminished compared with that for patients with no risk factors (38.7% +/- 5.9% vs 75.0% +/- 2.6%; P <.001). Contralateral occlusion was also associated with reduced 5-year survival (38 +/- 11% vs 67 +/- 2%; P <.004).

Conclusion: CEA can be safely performed in patients deemed at high risk, including those aged 80 years or older and others with significant comorbid conditions, with combined stroke and mortality rates comparable to those found in randomized trials, ie, the Asymptomatic Carotid Atherosclerosis Study and the North American Symptomatic Carotid Endarterectomy Trial. Contralateral occlusion may be a predictor for moderately increased perioperative risk and for reduced long-term survival. Caution may be warranted in asymptomatic patients with multiple risk factors, in whom presumed long-term benefit of CEA may be compromised by markedly reduced 5-year survival.
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http://dx.doi.org/10.1016/s0741-5214(03)00336-7DOI Listing
June 2003

15th Annual Semmelweis Lecture Surgical Infection Society-Europe. Injury-induced immune dysfunction: is the lymphocyte irrelevant?

Authors:
John A Mannick

Surg Infect (Larchmt) 2002 ;3(4):297-302

Brigham and Women's Hospital, Boston, MA 02115, USA.

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http://dx.doi.org/10.1089/109629602762539526DOI Listing
May 2003

Outcome in patients at high risk after open surgical repair of abdominal aortic aneurysm.

J Vasc Surg 2003 Feb;37(2):285-92

Division of Vascular Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.

Objective: Outcomes after surgical repair of abdominal aortic aneurysm (AAA) in patients at high risk remain poorly defined. We investigated the short-term and long-term results of open repair of infrarenal AAA in a high-risk and comparison low-risk patient population.

Methods: Conventional open surgical repair of nonruptured infrarenal AAA was performed in 572 consecutive patients from 1990 to 2000. Patients were considered at high risk if they had one or more of the following criteria: age 80 years or more, creatinine level 3.0 mg/dL or higher, severe pulmonary insufficiency, severe cardiac dysfunction, or hepatic failure. A retrospective review was carried out to determine relative risks, perioperative morbidity and mortality, and long-term survival. A P value of less than.05 was considered statistically significant.

Results: One hundred twenty-eight of the study patients (22%) were at high risk and 444 were at low risk. Patients at high risk were older (77 versus 69 years; P <.001), were more likely female (26% versus 16%; P <.009), and had larger (mean, 5.9 versus 5.6 cm; P <.024), more symptomatic (20% versus 13%; P <.001) aneurysms. The 30-day operative mortality rate for the high-risk group was 4.7%, compared with 0.0% (P <.001) in the low-risk group. Overall and major morbidity rates were 29% and 14% in the high-risk cohort versus 17% (P <.003) and 5% in the low-risk cohort, respectively. The 5-year survival rate was 46% (standard deviation, 5.2%) in the high-risk group versus 74% (standard deviation, 2.6%) in the low-risk group (P <.001). On multivariate analysis, age 80 years or more (P <.046), creatinine level 3.0 mg/dL or higher (P <.022), prior stroke (P <.012), and pulmonary dysfunction were significant predictors of poor operative outcome (30-day mortality and major morbidity), and female gender (P <.035), cardiac dysfunction (P <.004), creatinine level 3.0 mg/dL or higher (P <.0001), prior stroke (P <.005), and pulmonary dysfunction (P <.0001) negatively impacted long-term survival rates.

Conclusion: This study shows that open repair of infrarenal AAA in patients at high risk can be performed with relative safety and with results that offer a benchmark with which endovascular repair can be compared. Poor long-term survival in this population, however, highlights the importance of patient selection and raises the question of whether repair of many patients at high risk is warranted.
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http://dx.doi.org/10.1067/mva.2003.121DOI Listing
February 2003

Circadian rhythm of cytokine secretion following thermal injury in mice: implications for burn and trauma research.

Shock 2002 Jun;17(6):527-9

Eunice and Julian Cohen Laboratory of Surgical Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Although there are many reports of circadian variation in hormone secretion, there are only a few reports on the relationship between circadian rhythm and cytokine production. The aim of the present studies was to investigate whether there is a circadian effect on cytokine production of splenic lymphocytes and adherent splenocytes in mice after burn or sham injury. We selected day 7 after injury for our determinations because we have previously shown day 7 is the time of maximal suppression of T cell IL-2 and IFNgamma production and maximal increase in adherent cell proinflammatory cytokine secretion in this model. IL-2 and TNFalpha were chosen as reference cytokines since the former is known to be produced by T cells and the latter by adherent cells of the innate immune system. The results showed that seven days after sham or thermal injury both T cell IL-2 and adherent cell TNFalpha production were altered by time of injury or time of cell harvest. IL-2 secretion was significantly decreased in burn compared to sham animals when splenocytes were harvested in the morning; the decrease was non-significant when splenocytes were harvested in the afternoon. TNFalpha secretion was significantly increased in burn vs. sham adherent cells only when injury took place in the morning. The observed circadian variations in cytokine production could have a significant effect on cytokine levels measured in clinical and animal studies of injury and may explain some of the reported discrepancies among these studies.
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http://dx.doi.org/10.1097/00024382-200206000-00015DOI Listing
June 2002