Leora B. Balsam, M.D.

Mitral-valve surgery in the elderly: Comparative results of mitral repair and replacement
Balsam L.B.; Grossi E.A.; Galloway A.C.
2011 ;7(2):265-270, Aging Health
Evaluation of: Chikwe J, Goldstone AB, Passage J et al.: A propensity score-adjusted retrospective comparison of early- and mid-term results of mitral-valve repair versus replacement in octogenarians. Eur. Heart J. 32(5), 618-626 (2011). Mitral regurgitation (MR) is common in the elderly, increasing in prevalence with age. Common causes of MR include: degenerative disease of the valve and subvalvular apparatus; ischemic MR due to annular dilatation, papillary muscle displacement and left ventricular remodeling; rheumatic mitral valve disease and infectious endocarditis. The optimal treatment of severe mitral insufficiency in the elderly remains unknown. Mitral-valve repair or replacement have historically been considered high risk in older patients and, for this reason, many elderly patients are not offered surgery. Yet with recent advances in surgical techniques and outcomes, mitral-valve surgery is being increasingly utilized in elderly patients. A recent study by Chikwe et al. in the European Heart Journal examines overall and comparative outcomes of mitral-valve repair and mitral-valve replacement in an elderly cohort. This study finds that mitral-valve repair confers a survival benefit relative to mitral-valve replacement in octogenarians, particularly in patients undergoing surgery for degenerative disease. 2011 Future Medicine Ltd
— id: 132598, year: 2011, vol: 7, page: 265, stat: Journal Article,

Historical perspectives of The American Association for Thoracic Surgery: Frank B. Berry (1892-1976)
Balsam, Leora B; Deanda, Abe Jr
2011 Aug;142(2):253-256, Journal of thoracic & cardiovascular surgery
— id: 135549, year: 2011, vol: 142, page: 253, stat: Journal Article,

Historical perspectives of The American Association for Thoracic Surgery: Adrian V. S. Lambert (1872-1952)
Deanda, Abe Jr; Balsam, Leora B
2011 Jun;141(6):1344-1345, Journal of thoracic & cardiovascular surgery
— id: 132883, year: 2011, vol: 141, page: 1344, stat: Journal Article,

Giant Coronary Artery Aneurysm in a Patient with Behcet's Disease
Greenhouse, David G; Hackett, Katherine; Kahn, Philip; Balsam, Leora B; Galloway, Aubrey C
2011 May;26(3):268-270, Journal of cardiac surgery
Abstract Behcet's disease is a rare autoimmune vasculitis that may cause coronary artery aneurysms. We discuss the evaluation and management decisions for a 19-year-old female with a giant rapidly expanding aneurysm of the proximal left anterior descending coronary artery and Behcet's disease. (J Card Surg 2011;26:268-270)
— id: 132574, year: 2011, vol: 26, page: 268, stat: Journal Article,

Simulating video-assisted thoracoscopic lobectomy: A virtual reality cognitive task simulation
Solomon, Brian; Bizekis, Costas; Dellis, Sophia L; Donington, Jessica S; Oliker, Aaron; Balsam, Leora B; Zervos, Michael; Galloway, Aubrey C; Pass, Harvey; Grossi, Eugene A
2011 Jan;141(1):249-255, Journal of thoracic & cardiovascular surgery
OBJECTIVE: Current video-assisted thoracoscopic surgery training models rely on animals or mannequins to teach procedural skills. These approaches lack inherent teaching/testing capability and are limited by cost, anatomic variations, and single use. In response, we hypothesized that video-assisted thoracoscopic surgery right upper lobe resection could be simulated in a virtual reality environment with commercial software. METHODS: An anatomy explorer (Maya [Autodesk Inc, San Rafael, Calif] models of the chest and hilar structures) and simulation engine were adapted. Design goals included freedom of port placement, incorporation of well-known anatomic variants, teaching and testing modes, haptic feedback for the dissection, ability to perform the anatomic divisions, and a portable platform. RESULTS: Preexisting commercial models did not provide sufficient surgical detail, and extensive modeling modifications were required. Video-assisted thoracoscopic surgery right upper lobe resection simulation is initiated with a random vein and artery variation. The trainee proceeds in a teaching or testing mode. A knowledge database currently includes 13 anatomic identifications and 20 high-yield lung cancer learning points. The 'patient' is presented in the left lateral decubitus position. After initial camera port placement, the endoscopic view is displayed and the thoracoscope is manipulated via the haptic device. The thoracoscope port can be relocated; additional ports are placed using an external 'operating room' view. Unrestricted endoscopic exploration of the thorax is allowed. An endo-dissector tool allows for hilar dissection, and a virtual stapling device divides structures. The trainee's performance is reported. CONCLUSIONS: A virtual reality cognitive task simulation can overcome the deficiencies of existing training models. Performance scoring is being validated as we assess this simulator for cognitive and technical surgical education
— id: 116215, year: 2011, vol: 141, page: 249, stat: Journal Article,

Ectopic liver: an unexpected finding in a right atrial mass
Trocciola, Susan M; Balsam, Leora B; Yee, Herman; Gianos, Eugenia; Srichai, Monvadi B; Deanda, Abe Jr
2011 Aug;92(2):715-718, Annals of thoracic surgery
Ectopic liver is a rare finding, particularly in intrathoracic locations. We report the case of a 42-year-old woman with a mobile right atrial mass that was subsequently identified as ectopic liver by histology. Its point of origin was in a hepatic vein with extension into the right atrium. Although accurate diagnosis of ectopic liver may be possible with advanced imaging techniques, limited familiarity with the clinical entity is a barrier to early diagnosis
— id: 135564, year: 2011, vol: 92, page: 715, stat: Journal Article,

Cardiac varix presenting as a right atrial mass
Trocciola, Susan M; Yee, Herman; Balsam, Leora B; Gianos, Eugenia; Deanda, Abe Jr
2011 Mar;26(2):164-165, Journal of cardiac surgery
Abstract A cardiac varix is an unusual tumor of vascular origin that is rarely discovered antemortem. Here, we report the incidental finding of this lesion in the right atrium of a patient with concomitant prostate cancer. (J Card Surg 2011;26:164-165)
— id: 127229, year: 2011, vol: 26, page: 164, stat: Journal Article,

Calcified noncoronary sinus of valsalva aneurysm
Balsam, Leora B; DeAnda, Abe
2010 Nov;25(6):700-701, Journal of cardiac surgery
— id: 138246, year: 2010, vol: 25, page: 700, stat: Journal Article,

Reoperative valve surgery in the elderly: predictors of risk and long-term survival
Balsam, Leora B; Grossi, Eugene A; Greenhouse, David G; Ursomanno, Patricia; Deanda, Abelardo; Ribakove, Greg H; Culliford, Alfred T; Galloway, Aubrey C
2010 Oct;90(4):1195-1200, Annals of thoracic surgery
BACKGROUND: Elderly patients requiring reoperative cardiac surgery for valve disease are considered high risk for immediate outcomes, but little is known about their long-term survival. It is often conjectured that medical therapy provides equivalent late survival in this population, which may dissuade both patient and surgeon from considering reoperation. We analyzed a cohort of such patients undergoing reoperative valve surgery to determine their long-term survival. METHODS: From 1992 through 2007, 363 patients aged 75 years or more underwent reoperative isolated valve surgery; 211 (58%) had aortic valve replacement and 152 (42%) had mitral valve surgery. Mean age was 80.5 years. Hospital outcomes were prospectively recorded. Survival from all-cause death was determined from the Social Security Death Index. RESULTS: Hospital mortality was 13.8% (12.8% for aortic and 15.1% for mitral valve operations; p = 0.52). Multivariable predictors of hospital death were New York Heart Association functional class III or IV heart failure (odds ratio = 3.19, p = 0.012), dialysis (odds ratio = 15.63, p = 0.003), and more than one reoperation (odds ratio = 2.59, p = 0.058). At 5 years, overall survival was 62% +/- 3% for all patients (66% +/- 4% for aortic and 56% +/- 4% for mitral valve patients). For aortic valve patients aged 80 years or more, 5-year survival was 60% +/- 0.6%. Life expectancy table analysis predicted a 5-year survival of 57% for an age-matched and sex-matched comparison group. CONCLUSIONS: Reoperative surgery for elderly patients with isolated aortic or mitral valve pathology is associated with excellent long-term survival, particularly when treating aortic valve disease. While in-hospital mortality is higher among the elderly than among younger patients, specific predictors of poor outcome can be identified preoperatively to risk stratify these patients
— id: 113664, year: 2010, vol: 90, page: 1195, stat: Journal Article,

Factor eight inhibitor bypassing activity (FEIBA) for refractory bleeding in cardiac surgery: review of clinical outcomes
Balsam, Leora B; Timek, Tomasz A; Pelletier, Marc P
2008 Nov-Dec;23(6):614-621, Journal of cardiac surgery
BACKGROUND: Refractory postoperative bleeding complicates a significant number of cardiac surgical procedures and results in both morbidity and mortality. Conventional strategies to effect hemostasis include surgical reexploration and administration of blood products. In some cases, bleeding remains intractable despite these methods, and alternatives are needed. Herein, we report our experience with the use of factor eight inhibitor bypassing activity (FEIBA), a coagulation factor concentrate, for refractory postoperative bleeding. METHODS: A retrospective review of the experience with FEIBA at a university-affiliated cardiac surgery program between February 2004 and January 2007 was performed. RESULTS: Sixteen patients received FEIBA for refractory postoperative bleeding. The majority (69%) received a single dose, either intraoperatively or postoperatively. The recipients of multiple doses were more likely to undergo operative reexploration. Blood product utilization and hourly chest tube output were decreased significantly following administration of FEIBA. Three deaths occurred (19%), two from multisystem organ failure and one from respiratory failure. Thrombotic events included the development of a clotted hemothorax in one patient and distal extremity ischemia in another. CONCLUSIONS: FEIBA administration is associated with decreased blood product utilization and chest tube output in patients with refractory postoperative bleeding
— id: 95071, year: 2008, vol: 23, page: 614, stat: Journal Article,

Progressive Dyspnea After CABG: Complication of Retained Epicardial Pacing Wires
Horng, George S; Ashley, Euan; Balsam, Leora; Reitz, Bruce; Zamanian, Roham T
2008 Oct;86(4):1352-1354, Annals of thoracic surgery
We report a case of progressive dyspnea and recurrent pneumonia after uneventful coronary artery bypass graft surgery caused by migration of retained epicardial pacing wires into the right upper lobe of the lung. Removal of the wires by open thoracotomy resulted in significant improvement in dyspnea and near complete resolution of the bronchiectasis and consolidation
— id: 104360, year: 2008, vol: 86, page: 1352, stat: Journal Article,

Current trends in heart transplantation
Balsam, L B; Robbins, R C
2007 ;96(2):125-130, Scandinavian journal of surgery : SJS
— id: 81147, year: 2007, vol: 96, page: 125, stat: Journal Article,

Caspase-3 inhibition preserves myocardial geometry and long-term function after infarction
Balsam, Leora B; Kofidis, Theo; Robbins, Robert C
2005 Apr;124(2):194-200, Journal of surgical research
BACKGROUND: Cardiac remodeling after infarction is characterized by progressive ventricular dilation and functional impairment. Although surgical and percutaneous revascularization strategies may prevent remodeling, not all patients are candidates for these procedures. Apoptosis in the border-zone myocardium is thought to be critical to the remodeling process, and caspase-3 is a downstream effector of apoptosis. We hypothesized that inhibition of caspase-3 activity might limit dysfunction and remodeling after permanent coronary artery ligation. METHODS: FVB male mice underwent permanent ligation of the left anterior descending coronary artery. Immediately before surgery and for 7 subsequent days, animals were treated daily with 3 mg/kg DEVD-CHO, a cell-permeable inhibitor of caspase-3 (n = 16), or vehicle (n = 28). At 2 weeks and 6 weeks, echocardiography was performed and ventricular dimensions and function were assessed. At 8 weeks, invasive hemodynamic measurements were made and the animals were sacrificed. RESULTS: There was a trend toward improved survival in the inhibitor-treated group compared to the vehicle-treated group (56.3% versus 21.4%, P = 0.07). Infarct size at the time of sacrifice was comparable in both groups. At both 2 and 6 weeks, left ventricular dimensions, including end-diastolic and end-systolic diameters, were less in inhibitor-treated animals. Fractional shortening was higher at 6 weeks in the inhibitor-treated animals (22.1 +/- 6.0% versus 15.0 +/- 6.0%, P = 0.02). Invasive hemodynamic parameters at 8 weeks were comparable, with the exception of diastolic blood pressure, which was less in the inhibitor group. CONCLUSION: Treatment with a caspase-3 inhibitor improved survival and prevented ventricular dilation and dysfunction after permanent coronary artery occlusion
— id: 81135, year: 2005, vol: 124, page: 194, stat: Journal Article,

Early inhibition of caspase-3 activity lessens the development of graft coronary artery disease
Balsam, Leora B; Mokhtari, G Kimia; Jones, Sophie; Peterson, Shannon; Hoyt, E Grant; Kofidis, Theo; Tanaka, Masashi; Cooke, David T; Robbins, Robert C
2005 Jul;24(7):827-832, Journal of heart & lung transplantation
BACKGROUND: The role of apoptosis in the development of graft coronary artery disease (GCAD) is poorly understood. We have previously shown that early overexpression of the anti-apoptotic protein Bcl-2 lessens the development of GCAD. We hypothesized that early inhibition of apoptosis with a caspase-3 inhibitor would also lessen the development of GCAD. METHODS: Heterotopic heart transplantation was performed in 4 groups of rats. Donor hearts were pretreated with 50 microg DEVD-CHO, a cell-permeable caspase-3 inhibitor, or vehicle. Recipient animals were pretreated with 1.7 mg/kg intraperitoneal DEVD-CHO or vehicle. Animals were treated with 7.5 mg/kg/d cyclosporine for 10 days to prevent acute rejection. On post-operative day 90, the animals were sacrificed and the transplanted hearts were assessed morphometrically for evidence of GCAD. RESULTS: At 90 days, intimal proliferation was significantly higher in vehicle treated animals than in inhibitor treated animals. Moreover, the percentage of vessels with high-grade occlusion (>50%) was also lower in inhibitor treated animals. CONCLUSIONS: Early inhibition of caspase-3 activity with cell-permeable DEVD-CHO lessens the development of GCAD. Caspase-3 inhibition may be a useful strategy for prevention of GCAD in clinical transplantation
— id: 81137, year: 2005, vol: 24, page: 827, stat: Journal Article,

Haematopoietic stem cells and repair of the ischaemic heart
Balsam, Leora B; Robbins, Robert C
2005 Dec;109(6):483-492, Clinical science (London, 1979)
HSCs (haematopoietic stem cells) are multipotent stem cells that give rise to all cells of the blood cell lineage. In recent years, it has been proposed that bone marrow serves as a reservoir for cardiomyogenic precursors and that, following cardiac injury, these stem cells circulate to the site of injury where they contribute to myocardial repair and regeneration. This concept of stem cell plasticity has been controversial and, in fact, several key studies on the cardiomyogenic potential of HSCs have not been reproducible in the hands of independent investigators. Despite this controversy, the clinical community has pushed forward with clinical trials of bone marrow transplantation for the treatment of ischaemic heart disease. The following review summarizes the mechanistic underpinnings of bone marrow transplantation into ischaemic myocardium, focusing on the basic science that forms the foundation of this field, and highlights the controversies and new avenues for research that have emerged. It also describes the current state of the art in clinical trials of bone marrow transplantation for heart failure
— id: 81138, year: 2005, vol: 109, page: 483, stat: Journal Article,

Cyclosporine mitigates graft coronary artery disease in murine cardiac allografts: description and validation of a novel fully allogeneic model
Tanaka, Masashi; Mokhtari, Golnaz K; Balsam, Leora B; Cooke, David T; Kofidis, Theo; Zwierzchonievska, Monika; Robbins, Robert C
2005 Apr;24(4):446-453, Journal of heart & lung transplantation
BACKGROUND: The effect of cyclosporine (CsA) on the development of graft coronary artery disease (GCAD) is controversial. We developed a novel allogeneic mouse model of heart transplantation and investigated the effect of CsA on acute rejection and GCAD. METHODS: Hearts of FVB mice (H-2(q)) were heterotopically transplanted into 60 C57BL/6 mice (H-2(b)). CsA was administered to recipients at 10, 20 or 30 mg/kg/day for 10 or 30 days after transplantation. Untreated recipients as well as isograft recipients served as controls. Viability of the grafts was assessed daily by palpation. Parenchymal rejection was scored in grafts surviving 30 days in the 30-day treatment groups. GCAD was evaluated by the percentage of luminal narrowing, intima/media ratio and percentage of diseased vessels. Blood CsA and creatinine levels were also evaluated. Results were evaluated statistically. RESULTS: All groups except the untreated control group and the allograft groups treated with 10 or 20 mg for 10 days showed significant graft survival (>/=33% survival for 30 days). An inverse correlation was observed between CsA treatment dose, parenchymal rejection score and degree of GCAD in the 30-day treatment groups. However, graft survival in the 20-mg/kg/day group was significantly better than that in the 30-mg/kg/day group. Serum creatine levels showed no nephrotoxicity. CONCLUSIONS: Relatively high-dose CsA mitigated parenchymal rejection and GCAD of the mouse cardiac allografts. In addition, a valuable mouse model mimicking the clinical course of GCAD was achieved with CsA treatment of 20 mg/kg/day for 30 days
— id: 81134, year: 2005, vol: 24, page: 446, stat: Journal Article,

Prolonged cold ischemia in rat cardiac allografts promotes ischemia-reperfusion injury and the development of graft coronary artery disease in a linear fashion
Tanaka, Masashi; Mokhtari, Golnaz K; Terry, Raya D; Gunawan, Feny; Balsam, Leora B; Hoyt, Grant; Lee, Keun-Ho; Tsao, Philip S; Robbins, Robert C
2005 Nov;24(11):1906-1914, Journal of heart & lung transplantation
BACKGROUND: Prolonged cold ischemia is thought to exacerbate ischemia-reperfusion injury and graft coronary artery disease (GCAD). We investigated the effect of varying lengths of cold ischemia on inflammation and apoptosis during ischemia-reperfusion injury and correlated this with the degree of GCAD in rat cardiac allografts. METHODS: PVG rat (RT1c) hearts subjected to 30, 60, 90, 120, or 150 minutes of cold ischemia were heterotopically transplanted into ACI rats (RT1a). Grafts were procured after 4 hours of reperfusion and analyzed for superoxide generation, myeloperoxidase activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) production, cardiomyocyte apoptosis, and caspase-2, -3, -8, -9 activities. Additional transplanted animals received cyclosporine A (7.5 mg/kg/day) for 10 days as chronic rejection models. Indices of GCAD were determined at 90 days. RESULTS: A direct linear correlation was found between cold ischemic time, ischemia-reperfusion injury, and GCAD. Superoxide generation, myeloperoxidase activity, TNF-alpha, IL-1beta, MCP-1/CCL2 production, cardiomyocyte apoptosis, and caspase-2, -3, -8, and -9 activities increased with ischemic time, peaking at 120 minutes and plateauing at 150 minutes. GCAD, assessed by the percentage of luminal narrowing, the intima/media ratio, and the percentage of diseased vessels, worsened with increased ischemic time, peaking at 120 minutes and plateauing at 150 minutes. All tested variables in both the acute and chronic phases were significantly increased with 120-minute ischemia compared with 30-minute ischemia. CONCLUSIONS: These data indicate that the degree of cardiomyocyte apoptosis and inflammatory response in cardiac allografts during ischemia-reperfusion injury depends on the duration of cold ischemia. More important, that prolonged cold ischemia correlates with increased GCAD
— id: 81140, year: 2005, vol: 24, page: 1906, stat: Journal Article,

Progression of alloresponse and tissue-specific immunity during graft coronary artery disease
Tanaka, Masashi; Zwierzchoniewska, Monika; Mokhtari, Golnaz K; Terry, Raya D; Balsam, Leora B; Robbins, Robert C; Fedoseyeva, Eugenia V
2005 Jun;5(6):1286-1296, American journal of transplantation
Chronic rejection remains the major obstacle for long-term transplant survival. Both indirect alloresponse and tissue-specific autoimmunity have been implicated in its pathogenesis. The interrelationship between these two types of host anti-graft response remains poorly understood. We have developed an immunosuppression-free mouse model of graft coronary artery disease (GCAD), in which all FVB (H-2(q)) cardiac allografts placed into minor Ag (mHC)-mismatched DBA/1 (H-2(q)) hosts survived more than 112 days, and developed GCAD. We then examined the kinetics of both anti-mHC alloresponse and host autoimmunity against heart-specific antigen, cardiac myosin (CM). At 8 days post-transplantation, recipient mice showed minimal intragraft inflammation and apoptosis, and limited expansion of allo-specific T cells. In addition, we observed early production of anti-myosin IgG1 autoantibodies, which occurred in the absence of activated CM-specific T lymphocytes. By day 56, GCAD indices, the numbers of mHC- and CM-reactive T cells, and the levels of circulating allo- and CM-specific antibodies were all significantly increased. While host alloresponse was exhausted at 112 days post-transplant, T-cell reactivity against CM persisted. Our data suggest that both allo- and tissue-specific immunity might contribute to the induction of GCAD. They indicate that continual autoimmune response against graft tissue antigens may provide for GCAD sustenance
— id: 81136, year: 2005, vol: 5, page: 1286, stat: Journal Article,

Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium
Balsam, Leora B; Wagers, Amy J; Christensen, Julie L; Kofidis, Theo; Weissman, Irving L; Robbins, Robert C
2004 Apr 8;428(6983):668-673, Nature
Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates
— id: 81121, year: 2004, vol: 428, page: 668, stat: Journal Article,

Microvascular resistance is not influenced by epicardial coronary artery stenosis severity: experimental validation
Fearon, William F; Aarnoudse, Wilbert; Pijls, Nico H J; De Bruyne, Bernard; Balsam, Leora B; Cooke, David T; Robbins, Robert C; Fitzgerald, Peter J; Yeung, Alan C; Yock, Paul G
2004 May 18;109(19):2269-2272, Circulation
BACKGROUND: The effect of epicardial artery stenosis on myocardial microvascular resistance remains controversial. Recruitable collateral flow, which may affect resistance, was not incorporated into previous measurements. METHODS AND RESULTS: In an open-chest pig model, distal coronary pressure was measured with a pressure wire, and the apparent minimal microvascular resistance was calculated during peak hyperemia as pressure divided by flow, measured either with a flow probe around the coronary artery (R(micro app)) or with a novel thermodilution technique (apparent index of microcirculatory resistance [IMR(app)]). These apparent resistances were compared with the actual R(micro) and IMR after the coronary wedge pressure and collateral flow were incorporated into the calculation. Measurements were made at baseline (no stenosis) and after creation of moderate and severe epicardial artery stenoses. In 6 pigs, 189 measurements of R(micro) and IMR were made under the various epicardial artery conditions. Without consideration of collateral flow, R(micro app) (0.43+/-0.12 to 0.46+/-0.10 to 0.51+/-0.11 mm Hg/mL per minute) and IMR(app) (14+/-4 to 17+/-7 to 20+/-10 U) increased progressively and significantly with increasing epicardial artery stenosis (P<0.001 for both). With the incorporation of collateral flow, neither R(micro) nor IMR increased as a result of increasing epicardial artery stenosis. CONCLUSIONS: After collateral flow is taken into account, the minimum achievable microvascular resistance is not affected by increasing epicardial artery stenosis
— id: 81123, year: 2004, vol: 109, page: 2269, stat: Journal Article,

Distinct cell-to-fiber junctions are critical for the establishment of cardiotypical phenotype in a 3D bioartificial environment
Kofidis, Theo; Balsam, Leora; de Bruin, Jorg; Robbins, Robert C
2004 Mar;26(2):157-163, Medical engineering & physics
The first step toward improving the cell-matrix interactions that occur in bioartificial myocardial tissue is an understanding of the ultrastructural links between cells and host fibers. Here, we identify a distinct type of junction that helps the cells to find anchorage in the three-dimensional environment, and we evaluate the phenotype of the resulting tissue. Neonatal rat cardiomyocytes were seeded in two different collagen scaffolds after pre-hydration of the scaffold. Conventional and electron microscopy were used to analyze the tissue microstructure. Viability was assessed by life/dead assay and physical properties of the resulting tissue were evaluated. The resulting tissue displayed high cellular viability, spontaneous contractions over 12 weeks, and responded to passive stretch similar to native rat myocardium. Contractile force responded physiologically to calcium (Ca), adrenaline, and stretch administration. Ultrastructural studies revealed a cell-to-fiber junction, as well as a background matrix configuration, which has not been described before in this context. The cells aligned along collagen fibers and engaged in complex intercalations. The cell-to-fiber affinity is essential for the phenotypical performance of bioartificial myocardial tissue equivalents. Moreover, given the appropriate porosity of the scaffold, pre-hydration promotes migration and affinity of cells to host structures
— id: 81122, year: 2004, vol: 26, page: 157, stat: Journal Article,

Insulin-like growth factor promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration
Kofidis, Theo; de Bruin, Jorg L; Yamane, Toshiyuki; Balsam, Leora B; Lebl, Darren R; Swijnenburg, Rutger-Jan; Tanaka, Masashi; Weissman, Irving L; Robbins, Robert C
2004 ;22(7):1239-1245, Stem cells
Insulin-like growth factor-1 (IGF-1) promotes myocyte proliferation and can reverse cardiac abnormalities when it is administered in the early fetal stage. Supplementation of a mouse embryonic stem cell (ESC) suspension with IGF-1 might enhance cellular engraftment and host organ-specific differentiation after injection in the area of acute myocardial injury. In the study reported here, we sought to enhance the restorative effect of ESCs in the injured heart by adding IGF-1 to the injected cell population. Green fluorescent protein (GFP)-labeled sv129 ESCs (2.5 x 10(5)) were injected into the ischemic area after left anterior descending (LAD) artery ligation in BalbC mice. Recombinant mouse IGF-1 (25 ng) was added to the cell suspension prior to the injection (n = 5). Echocardiography was performed before organ harvest 2 weeks later. The degree of restoration (ratio of GFP+ to infarct area), expression of cardiac markers by GFP+ cells, inflammatory response, and tumorigenicity were evaluated. Mice with LAD ligation only (n = 5) and ESC transfer without IGF-1 (n = 5) served as controls. ESCs formed viable grafts and improved cardiac function. Left ventricular wall thickness was higher in the IGF-1 group (p = .025). There was a trend toward higher fractional shortening in the IGF-treated group. Histological analysis demonstrated that IGF-1 promoted expression of alpha-sarcomeric actin (p = .015) and major histocompatibility complex class I (p = .01). IGF did not affect the cellular response to the donor cells or tumorigenicity. IGF-1 promotes expression of cardiomyocyte phenotype in ESCs in vivo. It should be considered as an adjuvant to cell transfer for myocardial restoration
— id: 81130, year: 2004, vol: 22, page: 1239, stat: Journal Article,

Superoxide dismutase mimetic m40401 reduces ischemia-reperfusion injury and graft coronary artery disease in rodent cardiac allografts
Murata, Seiichiro; Miniati, Douglas N; Kown, Murray H; Koransky, Mark L; Lijkwan, Maarten A; Balsam, Leora B; Robbins, Robert C
2004 Oct 27;78(8):1166-1171, Transplantation
BACKGROUND: The oxidative stress associated with ischemia-reperfusion (I/R) of cardiac allografts leads to production of injurious cytokines and expression of proinflammatory adhesion molecules. This is one of the most important alloantigen-independent factors associated with graft coronary artery disease (GCAD). M40401 is a newly developed cell permeable superoxide dismutase mimetic, which has been shown to scavenge superoxide anion with highly specific and enhanced catalytic activity. We hypothesized that M40401 would exert a protective effect in I/R injury of cardiac allografts and ameliorate the progression of GCAD. METHODS: Recipient ACI rats were pretreated with M40401 or vehicle control. PVG donor hearts were heterotopically transplanted into the abdomen of ACI recipients. Cardiac allografts were analyzed for adhesion molecule mRNA expression and tumor necrosis factor-alpha expression after 4 hr of reperfusion. Neutrophil infiltration was detected by myeloperoxidase activity. Intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1 mRNA were detected by reverse-transcriptase polymerase chain reaction. Immunohistochemical analysis of adhesion molecule expression was also performed. Additional grafts were procured 90 days after transplantation and assessed for the development of GCAD by computer-assisted image analysis. RESULTS: In the M40401-treated group, adhesion molecule expression was significantly less than in the vehicle control group. Treated grafts also had lower myeloperoxidase activity and tumor necrosis factor-alpha concentration compared with controls. Neointimal proliferation and intima to media ratios in M40401-treated allografts were significantly decreased compared with controls. CONCLUSIONS: Selective removal of superoxide anion by M40401 results in inhibition of I/R injury. Furthermore, M40401 treatment decreases the development of oxidative stress-associated GCAD. This treatment strategy may have broad cardioprotective applications for all cardiac operations in addition to cardiac transplantation
— id: 81129, year: 2004, vol: 78, page: 1166, stat: Journal Article,

Effects of AGI-1096, a novel antioxidant compound with anti-inflammatory and antiproliferative properties, on rodent allograft arteriosclerosis
Murata, Seiichiro; Sundell, Cynthia L; Lijkwan, Maarten A; Balsam, Leora B; Hammainen, Pekka; Coleman, Caroline; York, Chris; Luchoomun, Jayraz; Suen, Ki-Ling; Howard, Randy; Somers, Patricia K; Morris, Randall E; Robbins, Robert C
2004 May 27;77(10):1494-1500, Transplantation
BACKGROUND: AGI-1096 is a novel phenolic intracellular antioxidant with anti-inflammatory and antiproliferative properties. In vitro, AGI-1096 inhibited the inducible expression of vascular cell adhesion molecule (VCAM)-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 in endothelial cells and tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. It also inhibited serum-stimulated proliferation of aortic smooth-muscle cells. In vivo, AGI-1096 demonstrated anti-inflammatory properties in a murine delayed-type hypersensitivity model. Given these antioxidant, anti-inflammatory and antiproliferative properties, we reasoned that AGI-1096 may be able to prevent chronic allograft arteriosclerosis. This hypothesis was tested in a rodent aortic transplantation model. METHODS: Donor descending aortas from August-Copenhagen-Irish rats were heterotopically transplanted into Lewis rat abdomens in end-to-end fashion. Animals were assigned to six groups as follows: AGI-1096 0 mg/kg per day (vehicle, n = 10), 10 mg/kg per day (n = 10), 20 mg/kg per day (n = 10), 40 mg/kg per day (n = 10), positive control (cyclosporine A 10 mg/kg per day by oral gavage, n = 10), and isograft negative control (Lewis-to-Lewis, n = 5). AGI-1096 was administrated subcutaneously to recipient animals three days before the surgery and for 90 days thereafter. On day 90, the paraffin-embedded allograft sections were stained with Elastin-van Gieson's stain, and the intima/media (I/M) ratio and luminal narrowing (1%LN) was assessed by digital morphometry. RESULTS: AGI-1096 demonstrated dose-dependent lowering of the I/M ratio and %LN when compared with vehicle controls. CONCLUSION: This is the first study to show that treatment of allograft recipients with AGI-1096 decreases the incidence of transplant arteriosclerosis. These data suggest that AGI-1096 may be a promising new therapeutic agent for use in clinical transplantation
— id: 81124, year: 2004, vol: 77, page: 1494, stat: Journal Article,

Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts
Tanaka, Masashi; Mokhtari, Golnaz K; Terry, Raya D; Balsam, Leora B; Lee, Keun-Ho; Kofidis, Theo; Tsao, Philip S; Robbins, Robert C
2004 Sep 14;110(11 Suppl 1):II200-II206, Circulation
BACKGROUND: Ischemia-reperfusion injury is an important risk factor for graft coronary artery disease (GCAD). We hypothesized that overexpression of SOD1 in donor hearts would suppress ischemia-reperfusion injury and thereby reduce GCAD. METHODS AND RESULTS: In one series, donor hearts of C57BL/6 (H-2b) transgenic mice overexpressing human SOD1 or C57BL/6 wild-type mice were heterotopically transplanted into C57BL/6 recipients and procured after 4 hours of reperfusion (n=6 each). Superoxide, TNF-alpha, and MCP-1/CCL2 production were significantly reduced in the SOD1 transgenic donor heart recipients, and graft injury determined by serum CPK-MB levels was significantly decreased. Cardiomyocyte apoptosis and caspase-3 and caspase-9 activities were significantly decreased in these recipients; caspase-8 activity was unchanged. Fas ligand but not Fas expression was also reduced. In a second series, transgenic and wild-type hearts were transplanted into C-H-2bm12KhEg (H-2bm12) recipients, and then procured on day 56 (n=7 each). Cardiac graft beating was significantly better in the SOD1 transgenic donor heart recipients on days 28, 42, and 56 (but not day 14). Significant reduction in luminal narrowing, the intima/media ratio, and the percentage of diseased vessels was seen in the SOD1 transgenic donor heart recipients, and MCP-1/CCL2, ICAM-1, and VCAM-1 production were significantly reduced. CONCLUSIONS: Overexpression of SOD1 attenuates both apoptosis and the inflammatory response during ischemia-reperfusion injury and therefore mitigates against the subsequent development of GCAD
— id: 81127, year: 2004, vol: 110, page: II200, stat: Journal Article,

Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease
Tanaka, Masashi; Nakae, Susumu; Terry, Raya D; Mokhtari, Golnaz K; Gunawan, Feny; Balsam, Leora B; Kaneda, Hideaki; Kofidis, Theo; Tsao, Philip S; Robbins, Robert C
2004 Dec 1;104(12):3789-3796, Blood
After cardiac transplantation, graft damage occurs secondary to ischemia-reperfusion injury and acute rejection. This damage ultimately leads to the development of graft coronary artery disease (GCAD), which limits long-term graft survival. Apoptosis is directly involved in graft injury, contributing to the development of GCAD. To assess the role of the antiapoptotic factor Bcl-2 in the process of GCAD, we transplanted hearts from FVB transgenic mice overexpressing human Bcl-2 under the control of alpha-myosin heavy chain promoter into allogenic C57BL/6 mice. Bcl-2 overexpression led to reduced cytochrome c-mediated caspase-9-dependent cardiomyocyte apoptosis and local inflammation (neutrophil infiltration and proinflammatory cytokine production) in cardiac allografts during ischemia-reperfusion injury and also led to reduced immune responses (inflammatory cell infiltration, production of T(H)1 cytokines and chemokines, and expression of adhesion molecules) during acute and chronic rejection without affecting host CD4(+) and CD8(+) cell responses in the spleen. Thus, local Bcl-2 expression directly contributes to the modulation of local immune responses in allograft rejection, resulting in attenuated GCAD. In conclusion, our findings suggest that the modulation of Bcl-2 expression by pharmacologic up-regulation or gene transfer may be of clinical benefit in the short- and long-term function of cardiac allografts
— id: 81125, year: 2004, vol: 104, page: 3789, stat: Journal Article,

Antisense oligonucleotides: design, construction, and applications to cardiac allograft transfer
Balsam, Leora B; Miniati, Douglas N; Robbins, Robert C
2003 ;219:129-133, Methods in molecular biology
— id: 81112, year: 2003, vol: 219, page: 129, stat: Journal Article,

Novel index for invasively assessing the coronary microcirculation
Fearon, William F; Balsam, Leora B; Farouque, H M Omar; Caffarelli, Anthony D; Robbins, Robert C; Fitzgerald, Peter J; Yock, Paul G; Yeung, Alan C
2003 Jul 1;107(25):3129-3132, Circulation
BACKGROUND: A relatively simple, invasive method for quantitatively assessing the status of the coronary microcirculation independent of the epicardial artery is lacking. METHODS AND RESULTS: By using a coronary pressure wire and modified software, it is possible to calculate the mean transit time of room-temperature saline injected down a coronary artery. The inverse of the hyperemic mean transit time has been shown to correlate with absolute flow. We hypothesize that distal coronary pressure divided by the inverse of the hyperemic mean transit time provides an index of microcirculatory resistance (IMR) that will correlate with true microcirculatory resistance (TMR), defined as the distal left anterior descending (LAD) pressure divided by hyperemic flow, measured with an external ultrasonic flow probe. A total of 61 measurements were made in 9 Yorkshire swine at baseline and after disruption of the coronary microcirculation, both with and without an epicardial LAD stenosis. The mean IMR (16.9+/-6.5 U to 25.9+/-14.4 U, P=0.002) and TMR (0.51+/-0.14 to 0.79+/-0.32 mm Hg x mL(-1) x min(-1), P=0.0001), as well as the % change in IMR (147+/-66%) and TMR (159+/-105%, P=NS versus IMR % change), increased significantly and to a similar degree after disruption of the microcirculation. These changes were independent of the status of the epicardial artery. There was a significant correlation between mean IMR and TMR values, as well as between the % change in IMR and % change in TMR. CONCLUSIONS: Measuring IMR may provide a simple, quantitative, invasive assessment of the coronary microcirculation
— id: 81113, year: 2003, vol: 107, page: 3129, stat: Journal Article,

Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve
Fearon, William F; Farouque, H M Omar; Balsam, Leora B; Caffarelli, Anthony D; Cooke, David T; Robbins, Robert C; Fitzgerald, Peter J; Yeung, Alan C; Yock, Paul G
2003 Nov 4;108(18):2198-2200, Circulation
BACKGROUND: Thermodilution coronary flow reserve (CFRthermo) is a new technique for invasively measuring coronary flow reserve (CFR) with a coronary pressure wire and is based on the ability of the pressure transducer to also measure temperature changes. Whether CFRthermo correlates well enough with absolute flow-derived CFR (CFRflow) to replace Doppler wire-derived CFR (CFRDoppler) remains unclear. METHODS AND RESULTS: In an open-chest pig model, CFRthermo was measured in the left anterior descending (LAD) artery and compared with CFRDoppler and CFRflow, measured with an external flow probe placed around the LAD. In 9 pigs, CFR was measured simultaneously by all 3 means in the normal LAD and after creation of an epicardial LAD stenosis. To determine the added effect of microvascular disease, measurements of flow reserve were also performed after disruption of the coronary microcirculation with embolized microspheres. Intracoronary papaverine (20 mg) was used to induce hyperemia. In a total of 61 paired measurements, CFRthermo correlated strongly with the reference standard CFRflow (r=0.85, P<0.001). CFRDoppler correlated less well with CFRflow (r=0.72, P<0.001). Bland-Altman analysis showed a closer agreement between CFRthermo and CFRflow. CONCLUSIONS: CFRthermo correlates better with CFRflow than does CFRDoppler
— id: 81118, year: 2003, vol: 108, page: 2198, stat: Journal Article,

Clinically established hemostatic scaffold (tissue fleece) as biomatrix in tissue- and organ-engineering research
Kofidis, T; Akhyari, P; Wachsmann, B; Mueller-Stahl, K; Boublik, J; Ruhparwar, A; Mertsching, H; Balsam, L; Robbins, R; Haverich, A
2003 Jun;9(3):517-523, Tissue engineering
Various types of three-dimensional matrices have been used as basic scaffolds in myocardial tissue engineering. Many of those are limited by insufficient mechanical function, availability, or biocompatibility. We present a clinically established collagen scaffold for the development of bioartificial myocardial tissue. Neonatal rat cardiomyocytes were seeded into Tissue Fleece (Baxter Deutschland, Heidelberg, Germany). Histological and ultrastructural examinations were performed by DAPI and DiOC(18) staining and electron microscopy, respectively. Force measurements from the spontaneously beating construct were obtained. The constructs were stimulated with agents such as adrenalin and calcium, and by stretching. Passive stretch curves were obtained. Spontaneous contractions of solid bioartificial myocardial tissue (BMT), 20 x 15 x 2 mm, resulted. Contractions continued to week 12 (40% of BMTs) in culture. Histology revealed intercellular and also cell-fibril junctions. Elasticity was similar to that of native rat myocardium. Contractile force increased after topical administration of Ca(2+) and adrenaline. Stretch led to the highest levels of contractile force. In summary, bioartificial myocardial tissue with significant in vitro longevity, spontaneous contractility, and homogeneous cell distribution was produced using Tissue Fleece. Tissue Fleece constitutes an effective scaffold to engineer solid organ structures, which could be used for repair of congenital defects or replacement of diseased tissue
— id: 110809, year: 2003, vol: 9, page: 517, stat: Journal Article,

A few critical aspects--and Achilles heels--of tissue engineering approaches to restore injured myocardium
Kofidis, Theo; Balsam, Leora B; Robbins, Robert C
2003 Dec;126(6):2113-2114, Journal of thoracic & cardiovascular surgery
— id: 81119, year: 2003, vol: 126, page: 2113, stat: Journal Article,

Antegrade versus retrograde perfusion of the donor lung: impact on the early reperfusion phase
Kofidis, Theo; Struber, Martin; Warnecke, Gregor; Sommer, Sebastian; Leyh, Rainer G; Balsam, Leora B; Robbins, Robert C; Haverich, Axel
2003 Nov;16(11):801-805, Transplant international
Transpulmonary thermodilution was used to evaluate the effect of flush route during harvest on hemodynamic and respiratory function of the pulmonary graft in the early post-transplant phase. Single lung transplantation was performed in two piglet groups after 24 h of cold storage. Donor organs for group A underwent antegrade perfusion, and those for group R retrograde perfusion. PaO(2), compliance (C), airway resistance (R), extravascular lung water index (EVLWI), pulmonary blood volume index (PBVI), intrathoracic blood volume index (ITBVI), capillary leak (CL), and cardiac function index (CFI) were assessed by transpulmonary thermodilution at baseline, 1, 3, and 6 h after reperfusion. EVLWI was significantly lower in group R. Compliance and PaO(2) were higher in the same group. The two groups did not differ significantly with regard to CFI, PBVI, ITBVI, and airway resistance. Retrograde perfusion of the donor lung had a positive impact on graft function during early reperfusion. Transpulmonary hemodynamic monitoring can be a powerful tool for intra- and postoperative management of transplant patients
— id: 81114, year: 2003, vol: 16, page: 801, stat: Journal Article,

Elevated cyclic adenosine monophosphate ameliorates ischemia-reperfusion injury in rat cardiac allografts
Murata, Seiichiro; Miniati, Douglas N; Kown, Murray H; Koransky, Mark L; Balsam, Leora B; Lijkwan, Maarten A; Martens, Jasper M; Robbins, Robert C
2003 Jul;22(7):802-809, Journal of heart & lung transplantation
BACKGROUND: Oxidative stress after ischemia and reperfusion leads to leukocyte activation, the production of injurious cytokines, and increased expression of inflammatory adhesion molecules. This initial event is one of the most important alloantigen-independent factors associated with graft coronary artery disease (GCAD). Cyclic adenosine monophosphate (cAMP) is an important second messenger that inhibits the expression of tumor necrosis factor alpha (TNF-alpha), vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1) in vitro. Its levels decrease during organ preservation. We hypothesized that augmenting allograft cAMP levels with the water-soluble adenylate cyclase activator, NKH477, could decrease ischemia-reperfusion injury and inhibit the progression of GCAD. METHODS: PVG to ACI rat heterotopic cardiac allografts, treated with NKH477 solution or vehicle, were reperfused for 4 hours or 90 days after 60 minutes of ischemia. We analyzed grafts for intracellular adhesion molecule 1 (ICAM-1), VCAM-1, and ELAM-1 mRNA expression; TNF-alpha and interleukin-6 (IL-6) protein expression; and myeloperoxidase activity. We also performed immunohistochemical analysis for ICAM-1 and VCAM-1 protein expression. At post-operative Day 90, the progression of GCAD had increased morphometrically. RESULTS: NKH477-treated grafts had significantly decreased levels of myeloperoxidase activity compared with controls. In this group, TNF-alpha, IL-6, and VCAM-1 protein expression was inhibited; however, ICAM-1 and ELAM-1 expression did not alter. We found no differences in the degree of development of GCAD between groups. CONCLUSION: Although augmented intracellular cAMP prevented acute reperfusion injury, it was insufficient to prevent the development of GCAD. Intracellular adhesion molecule 1 and ELAM-1, whose expression NKH477 does not inhibit, may play important roles in the development of GCAD
— id: 81116, year: 2003, vol: 22, page: 802, stat: Journal Article,

Restoration of blood flow and evaluation of corresponding angiogenic events by scanning electron microscopy after a single dose of VEGF in a model of peripheral vascular disease
Kofidis, T; Nolte, D; Simon, A R; Metzakis, A; Balsam, L; Robbins, R; Haverich, A
2002 ;5(1-2):87-92, Angiogenesis
The angiogenic effect of vascular endothelial growth factor (VEGF) has typically been assessed by indirect methods, including microsphere injection and angiography. Here, we use 3-D scanning electron microscopy (SEM) to directly visualize patterns of angiogenesis after a single bolus administration of VEGF in a model of peripheral vascular ischemia. Hind limb ischemia was induced by subcutaneous turniquet implantation in adult Wistar rats. The control group (group A, n = 10) was left untreated, group B (n = 10) received a single dose of VEGF (50 microg) injected in the peroneus muscle. LASER Doppler was applied for blood flow measurements. Animals were sacrificed on day 14 after ischemia induction and vascular casting was performed. Angiogenetic events such as 'tiny lateral sprouts', arcus formations', confluences and the angle of sprouting were assessed by SEM. Significant capillary sprouting was observed in both groups. VEGF-treated limbs demonstrated higher degrees of capillary growth (P = 0.01) and flow recovery (P = 0.028). 3-D-SEM showed sprouts to be more frequent in group B. Tiny lateral sprouts, which always left the mother vessel at an angle of 90 degrees and which were of small diameter and lacked imprints of endothelial cell nuclei, were more frequent in the VEGF-treated group (P = 0.018). Arcus formation was significantly higher in the treated group (P = 0.02). We have developed a simple and effective experimental model of ischemia. For the study of angiogenic phenomena, 3-D imaging of the microvasculature offers a direct and conclusive method for the study of angiogenic events
— id: 110810, year: 2002, vol: 5, page: 87, stat: Journal Article,

Functional mapping of CD11b/CD18 epitopes important in neutrophil-epithelial interactions: a central role of the I domain
Balsam, L B; Liang, T W; Parkos, C A
1998 May 15;160(10):5058-5065, Journal of immunology
In the intestine, lung, and urinary tract, neutrophil (polymorphonuclear leukocyte, PMN) transepithelial migration is dependent on the leukocyte beta2 integrin CD11b/CD18. While the regions of CD11b involved in recognition of several soluble ligands are known, those that mediate PMN-epithelial interactions have not been investigated. In this study, mAbs reactive with four extracellular regions on CD11b, the NH2-terminal region, I (inserted) domain, cation-binding region, and region proximal to the transmembrane domain (C domain), were analyzed for the ability to block CD11b/CD18-mediated interactions with T84 intestinal epithelial cells. In such a manner, epitope mapping was applied to the complex interactions between CD11b/CD18 and a cell-based ligand system. I domain Abs strongly inhibited both adhesion of PMN to epithelial cells and PMN migration across T84 epithelial monolayers. However, the profile of inhibition was distinct from that of other known ligands of CD11b/CD18. CBRM1/32, an Ab to a discontinuous epitope residing within the NH2- and cation-binding domains, strongly inhibited both adhesion and transmigration responses. C domain Abs had minimal effects on adhesion and transmigration. These findings appear applicable to other epithelia, since similar results were obtained in transmigration experiments with CF15 human airway epithelial cells. Finally, Ab inhibition profiles were confirmed with adhesion assays of isolated epithelial cells to purified CD11b/CD18. These findings demonstrate the central role of the I domain and the participation of a discontinuous region shared by the NH2- and cation-binding domains in mediating PMN-adhesive interactions with epithelial cells
— id: 81154, year: 1998, vol: 160, page: 5058, stat: Journal Article,

Streptococcus anginosus spondylodiskitis
Balsam, L B; Shepherd, G M; Ruoff, K L
1997 Jan;24(1):93-94, Clinical infectious diseases
— id: 81153, year: 1997, vol: 24, page: 93, stat: Journal Article,

Activating transcription factor-3 stimulates 3',5'-cyclic adenosine monophosphate-dependent gene expression
Chu, H M; Tan, Y; Kobierski, L A; Balsam, L B; Comb, M J
1994 Jan;8(1):59-68, Molecular endocrinology
Activating transcription factor-3 (ATF-3) is one member of a large family of leucine zipper transcription factors which bind to promoters responsive to cAMP and phorbol ester at the related cAMP (CRE) and phorbol ester response elements. We report here that ATF-3 is coexpressed with the neuropeptide precursor proenkephalin in human neuroblastoma SK-N-MC cells. Cotransfection experiments indicate that activation of proenkephalin gene expression by ATF-3 is dependent upon both the catalytic subunit of the cAMP-dependent protein kinase and the CRE-2 element. The CRE-2 element is essential for second messenger-inducible expression and is known to bind AP-1-like transcription factors. ATF-3 expressed in bacteria or from rabbit reticulocyte lysates binds to the proenkephalin CRE-2 element as a homodimer and as a heterodimer with Jun-D, another activator of proenkephalin transcription. ATF-3 stimulates binding of Jun-D to the proenkephalin CRE-2 element and acts synergistically with Jun-D to induce proenkephalin gene expression. Sequential immunoprecipitations of ATF-3 from SK-N-MC cells expressing proenkephalin indicate that ATF-3 is complexed with Jun-D in vivo and that both proteins are highly phosphorylated. Together, our results suggest that ATF-3 may play an important role in the regulation of gene expression by cAMP-dependent intracellular signaling pathways
— id: 81152, year: 1994, vol: 8, page: 59, stat: Journal Article,