The radial artery in reoperative coronary bypass surgery:.

BACKGROUND: Failure of saphenous vein grafts (SVG) is a significant cause for coronary reoperation (redo CABG). The radial artery (RA) because of its availability, and versatility is well suited to use (together with internal thoracic arteries (ITA) in redo CABG, especially to replace failed SVG. We evaluated our experience where the RA was a major conduit in redo CABG over the past 5 years. METHODS: From July 1996 to June 2002, 590 consecutive patients underwent redo CABG where one or both RA(s) were used, together with LITA or RITA. The mean age was 67.3 years, 82% were male, and 19% diabetic, 419 (71%) had Class III or IV angina, 135 (23%) had left main stenosis, and 210 (36%) had an LVEF < 0.50. There were a total of 877 RA conduits (303 single, 287 bilateral), 518 new LITA or RITA. A mean of 2.8 new distal anastomoses constructed 92% (2.6 per patient)of the arterial grafts. Follow-up was at 1 month, 3 months, and then yearly. The results were compared with 6466 primary CABG performed in the same time frame, and with a prior cohort of 741 consecutive patients having redo CABG without an RA in which identical operative techniques had otherwise been used. RESULTS: The 30-day mortality was 3.9% (23 patients). Morbidity was low. Perioperative myocardial infarction occurred in 16 (2.7%) patients, stroke in 10 (1.7%), sternal infection in 10 (1.7%), donor site infection in 2 (0.3%), and IABP use in 23 patients (3.9%)-including 10 preoperatively. The results were better when compared to a prior cohort of 741 patients with redo CABG (1991 to 1996) without use of the RA. The results were inferior to that of the contemporary primary CABG. Operative mortality was 3.9% versus 0.9%, p = 0.002, myocardial infarction 2.7% versus 0.8%, p = 0.03. CONCLUSION: The use of the RA (together with ITA) in redo CABG achieved total arterial revascularization in 92% of cases and is associated with excellent results, at least equal to or superior to those achieved previously.

The radial artery in coronary re-operations.

OBJECTIVES: Vein graft (VG) failure often leads to coronary re-operation (re-do coronary artery bypass grafting (CABG)). As the internal thoracic artery (ITA(s)) and VG have often already been used and as the VG has usually failed, the radial artery (RA) is ideally suited for use in re-do CABG. We evaluated our experience where the RA(s) was a key conduit in re-do CABG to determine the safety and efficacy and compared this to re-operations where the RA was not used. METHODS: Three hundred and fifty-two consecutive patients who had re-do CABG using the RA(s) from July 1995 to March 1999 were studied: mean age 67.3 years, 209 (60%) angina Class III or IV, past acute myocardial infarction (AMI) in 201 (57%), left ventricular ejection fraction <50% in 109 (31%). Five hundred and thirty-two RAs were used (bilateral in 180 (51%) patients). Additionally, 232 new left ITAs (66% of patients) and 71 new right ITAs (20% of patients) were placed. A total of 1022 distal anastomoses were performed (mean of 2.9 per patient). Follow-up was at 1 month, 3 months, and yearly. The results were also compared to 730 patients having re-do CABG without an RA (January 1990 to June 1995) using identical operative and myocardial protection techniques. RESULTS: RA spasm was noted intra-operatively in four (1.1%) patients, operative mortality was noted in 14 (3.9%) patients, peri-operative myocardial infarction was noted in ten (2.8%) patients, intra-aortic balloon pump was used in nine (2.6%) patients, stroke was noted in six (1.7%) patients, deep sternal infection was noted in two (0.6%) patients, and re-operation for haemorrhage was performed in seven (2.0%) patients. There was only one (0.3%) forearm infection, and two (0.6%) forearm haematomas required drainage. There was no hand ischaemia. When compared to 730 re-do CABG patients without RA, there were significant differences in arterial grafts used (2.6 vs. 1.2, P=0.01), in deep sternal infection (0.6% vs. 2.6%, P=0.01) and donor site infection (0.3% vs. 2.7%, P=0.005) favouring the RA group. Three-year actuarial survival was 89.2% in the RA group and 88.5% in the non-RA group (P=1.0). CONCLUSIONS: Use of the RA in re-do CABG is safe, effective, allows additional conduit choice, reduces donor site and sternal infections, and may avoid further late VG failure.

Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents.

Dendritic cells (DCs) can efficiently acquire foreign antigen(s) from apoptotic cells and induce MHC class I-restricted, antigen-specific CTLs. An accumulation of DCs within solid tumor masses in situ has been associated indirectly with a more favorable prognosis. Therefore, DCs may offer an efficient means for triggering immune responses within tumors, particularly in those masses containing significant apoptosis. We examined whether delivery of DCs could, alone, impact on the progressive growth of a tumor with a relatively high apoptotic index. We detected significant early apoptosis within the mass of a s.c. growing murine MT-901 breast carcinoma. DCs could efficiently engulf MT-901 tumor apoptotic cells in vitro. Intratumoral injections of syngeneic but not allogeneic DCs resulted in significant inhibition of MT-901 tumor growth. Histological examination of the tumor revealed intense mononuclear cell infiltration during and after DC injections. Tumor growth inhibition was relatively radiosensitive and dependent on host-derived CD8+ T cells. The baseline level of tumor apoptosis could be increased substantially by tumor necrosis factor alpha administration, leading to a greater DC-mediated antitumor effect. The antitumor effect could also be enhanced by first pulsing DCs with the foreign helper protein, keyhole limpet hemocyanin, prior to intratumoral delivery and combining it with the systemic administration of interleukin 2. Splenocytes from treated animals showed heightened levels of specific CTL activity and production of cytokines. The level of in situ tumor apoptosis appears to play a critical role in DC-mediated antitumor effects. The potential implication of these findings in DC-based tumor therapy strategies is discussed.

Urokinase receptor-deficient mice have impaired neutrophil recruitment in response to pulmonary Pseudomonas aeruginosa infection.

Leukocytes express both urokinase-type plasminogen activator (uPA) and the urokinase receptor (uPAR, CD87). Evidence in vitro has implicated uPAR as a modulator of beta2 integrin function, particularly CR3 (CD11b/CD18, Mac-1). Pseudomonas aeruginosa infection has been demonstrated to recruit neutrophils to the pulmonary parenchyma by a beta2 integrin-dependent mechanism. We demonstrate that mice deficient in uPAR (uPAR-/-) have profoundly diminished neutrophil recruitment in response to P. aeruginosa pneumonia compared with wild-type (WT) mice. The requirement for uPAR in neutrophil recruitment is independent of the serine protease uPA, as neutrophil recruitment in uPA-/- mice is indistinguishable from recruitment in WT mice. uPAR-/- mice have impaired clearance of P. aeruginosa compared with WT mice, as demonstrated by CFU and comparative histology. WT mice have diminished neutrophil recruitment to the lung when an anti-CD11b mAb is given before inoculation with the pathogen, while recruitment of uPAR-/- neutrophils is unaffected. We conclude that uPAR is required for the recruitment of neutrophils to the lung in response to P. aeruginosa pneumonia and that this requirement is independent of uPA. Further, we show that uPAR and CR3 act by a common mechanism during neutrophil recruitment to the lung in response to P. aeruginosa. This is the first report of a requirement for uPAR during cellular recruitment in vivo against a clinically relevant pathogen.

Family stressors as predictors of codependency.

Codependency has been defined as an extreme focus on relationships, caused by a stressful family background (J. L. Fischer, L. Spann, & D. W. Crawford, 1991). In this study the authors assessed the relationship of the Spann-Fischer Codependency Scale (J. L. Fischer et al., 1991) and the Potter-Efron Codependency Assessment (L. A. Potter-Efron & P. S. Potter-Efron, 1989) with self-reported chronic family stress and family background. Students (N = 257) completed 2 existing self-report codependency measures and provided family background information. Results indicated that women had higher codependency scores than men on the Spann-Fischer scale. Students with a history of chronic family stress (with an alcoholic, mentally ill, or physically ill parent) had significantly higher codependency scores on both scales. The findings suggest that other types of family stressors, not solely alcoholism, may be predictors of codependency.

Urokinase is required for T lymphocyte proliferation and activation in vitro.

We have previously demonstrated that urokinase-deficient (uPA-/-) mice do not increase lung T lymphocyte number and fail to mount protective immune responses during pulmonary Cryptococcus neoformans infection. These observations suggest a previously unconsidered role for urokinase-type plasminogen activator (uPA) in T lymphocyte-mediated immune responses. Accordingly, we sought to determine whether uPA is required for T cell receptor-mediated (TCR-mediated) lymphocyte proliferation and activation. Splenocytes from uPA-/- and uPA+/+ mice were stimulated with concanavalin A (Con A). The uPA-/- mice had diminished T cell proliferation as compared with uPA+/+ mice. Coculturing uPA-/- T cells with uPA+/+ accessory cells led to the restoration of proliferation. Similarly, T cell proliferation induced by CD3 cross-linking was diminished in uPA-/- mice as compared with uPA+/+ mice. T lymphocyte activation, defined as the induced expression of antigens and the elaboration of cytokines, was determined. The expression of CD69 and that of CD49d were diminished in response to Con A stimulation in uPA-/- mice as compared with uPA+/+ mice. The elaboration of cytokines in response to Con A was also altered in the uPA-/- mice. The production of the Th1 cytokines interferon-gamma and interleukin-12 was diminished in uPA-/- mice as compared with uPA+/+ mice. The uPA-/- mice produced increased amounts of interleukin-10, a Th2 cytokine. We conclude that the lack of uPA results in impaired T cell activation and proliferation in response to TCR-mediated signaling and the expression of a less Th1-polarized profile of cytokines. These findings suggest that the inability of uPA-/- mice to combat Cryptococcus neoformans infection may be caused by the impairment of T lymphocyte immune responses in the absence of uPA.

Total arterial coronary revascularization: techniques and results in 3,220 patients.

BACKGROUND: To overcome the problems of late vein graft atherosclerosis, occlusion and need of coronary reoperations, we have adopted a strategy of total arterial coronary revascularization. We evaluated our experience with this strategy to establish its safety and efficacy. METHODS: All 3,220 consecutive patients who had total arterial coronary revascularization from January 1988 to June 1998 were evaluated. Data were collected prospectively. The mean age was 62.2 years. Of the patients, 595 (18.8%) had diabetes; 739 (23%) had a left ventricular ejection fraction of less than 0.50; and 484 (15%) were classified unstable/urgent. The conduits included 3,140 left internal thoracic arteries, 1,224 right internal thoracic arteries, and 2,417 radial arteries, 654 of which were bilateral. A Y or T graft with the left internal thoracic artery was used in 467 patients. Patients were followed up at 1 month, 3 months, and yearly thereafter. Postoperative angiography was performed for symptoms or as part of an ethics committee-approved prospective study. RESULTS: The operative mortality rate was 0.7% (21 patients). Complications included stroke in 26 patients (0.8%), myocardial infarction in 27 (0.8%), sternal infection in 35 (1.1%), and reoperation for hemorrhage in 23 (0.7%). The peak level of the myocardial enzyme of creatine kinase was 16.4+/-14.9 IU/L. Twenty-five patients (0.8%) required intraoperative or postoperative intraaortic balloon pump support. Mortality and stroke rates were higher in patients having reoperation (0.6% versus 1.8%; p = 0.11; and 0.7% versus 2.2%; p = 0.07, respectively). Postoperative angiographic patency was 97% at 5 years for the left internal thoracic artery (620 grafts), 89% at 5 years for the right internal thoracic artery (276 grafts), and 91% at 1 year for the radial artery (65 grafts). CONCLUSIONS: Total arterial coronary revascularization can be performed safely with good patency rates in a large number of patients and may potentially avoid the sequelae of vein graft atherosclerosis.

Ross procedure. Inserting the autograft using a fully supported root replacement method; techniques and results.

BACKGROUND AND AIM OF THE STUDY: The root replacement (RR) method for insertion of the pulmonary autograft (PA) has resulted in improved immediate aortic valve competence. However, the unsupported pulmonary artery wall is thinner, more elastic, and thus more prone to dilatation than the normal aortic root. This might predispose to late aortic regurgitation (AR) due to splaying of the aortic commissures, similar to the mechanism of AR in Marfan's syndrome. METHODS: A fully supported root replacement (FSRR) method was designed and implemented in 78 patients, with preservation of the aortic root and proximal ascending aortic remnant fully to surround and support the PA root. Additional aortic annulus reduction was performed in 29 patients, and adjustment of the sinotubular diameter in 27. RESULTS: Seventy-eight patients were analyzed with sequential Doppler echocardiography. The maximal neoaortic sinus diameter remained constant for up to three years after surgery (mean 34.3 +/- 4.0 mm) compared with before surgery (35.2 +/- 4.0 mm). There was one early death, no late deaths or reoperations, and at last follow up AR was nil/trivial in 72% of patients, mild in 27% and moderate in 1%. There was no progression of AR over four years' follow up. By comparison, four patients previously underwent unsupported RR for insertion of the PA; in these patients, mean neoaortic sinus diameter increased significantly from 31 +/- 6 mm to 41 +/- 3 mm at three years after surgery (p = 0.005). CONCLUSIONS: Insertion of the PA using a FSRR method prevents dilatation of the neoaortic sinuses and sinotubular junction without need for prosthetic material, and provides similar results to conventional RR with regard to aortic valve competence. Retaining the advantages of RR in this manner and maintaining aortic root size may prove valuable in the longer term.

Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells.

Previous studies have demonstrated that IL-15 administration after cyclophosphamide (CY) injection of C57BL/6J mice bearing the i.m. 76-9 rhabdomyosarcoma resulted in a significant prolongation of life. In the present study, we investigated the immune response against the 76-9 experimental lung metastases after CY + IL-15 therapy. Administration of CY + IL-15, but not IL-15 alone, induced prolongation of life and cures in 32% of mice bearing established experimental pulmonary metastases of 76-9 tumor. The CY + IL-15 therapy resulted in increased levels of NK1.1+/LGL-1+ cells, and CD8+/CD44+ T cells in PBL. In vitro cytotoxic assay of PBL indicated the induction of lymphokine-activated killer cell activity, but no evident tumor-specific class I-restricted lytic activity. Survival studies showed that the presence of NK and T lymphocytes is necessary for successful CY + IL-15 therapy. Experiments using knockout mice implied that either alphabeta or gammadelta T cells were required for an antitumor effect induced by CY + IL-15 therapy. However, mice lacking in both alphabeta and gammadelta T cells failed to respond to combination therapy. Cured B6 and alphabeta or gammadelta T cell-deficient mice were immune to rechallenge with 76-9, but not B16LM tumor. B cell-deficient mice showed a significant improvement in the survival rate both after CY and combination CY + IL-15 therapy compared with normal B6 mice. Overall, the data suggest that the interaction of NK cells with tumor-specific alphabeta or gammadelta T lymphocytes is necessary for successful therapy, while B cells appear to suppress the antitumor effects of CY + IL-15 therapy.

Bilateral internal thoracic artery grafting may improve outcome of coronary artery surgery. Risk-adjusted survival.

BACKGROUND: Excellent clinical results of the patients with single left internal thoracic artery (ITA) grafting compared with saphenous vein grafting have prompted surgeons to use both ITAs. However, long-term benefits of the bilateral ITA grafting have not been proven. METHODS AND RESULTS: We reviewed our experience of 2826 patients (age 62 +/- 9 years [mean +/- 1 SD], 2350 men, mean follow-up 52 months) who underwent surgery with ITAs, supplemented by saphenous vein grafts when required, between 1985 and 1995. Single ITA grafting (n = 1557) was compared with double (n = 1269), by means of the Cox proportional hazards model. Significant predictors of all-cause mortality were as follows: (1) peripheral vascular disease, rate ratio (RR) = 2.4 (1.7 to 3.4 [95% CI]); (2) prior myocardial infarction, RR = 2.1 (1.5 to 3.1); (3) severe left ventricular dysfunction, RR = 3.9 (2.6 to 5.9) and moderate left ventricular dysfunction, RR = 2.0 (1.5 to 2.6); (4) age > or = 70 years, RR = 3.4 (2.4 to 4.8), and age 60 to 69 years, RR = 1.7 (1.3 to 2.4); (5) diabetes mellitus, RR = 1.7 (1.3 to 2.4); (6) carotid disease, RR = 1.7 (1.2 to 2.4); and (7) single ITA (versus bilateral ITA), RR = 1.4 (1.1 to 1.8). Number of vessels diseased, surgical status (i.e., urgent versus elective), hypertension, and sex were not significant predictors. Unadjusted actuarial survival rates at 10 years were 86 +/- 3% (mean +/- 95% CI) for bilateral ITA group and 71 +/- 5% for single ITA. Single ITA was also a predictor of all-cause mortality, late myocardial infarction, or late reoperation (RR = 1.3 [1.1 to 1.6]). CONCLUSIONS: Bilateral ITA grafting may improve long-term survival and freedom from late myocardial infarction or reoperation after coronary artery surgery. Mathematical modeling may assist in developing a strategy for use of bilateral ITA grafts.

CSF-1 regulation of Il6 gene expression by murine macrophages: a pivotal role for GM-CSF.

We test the hypothesis that the monocyte-macrophage colony-stimulating factor (CSF-1 or M-CSF) plays a major role in the inflammatory responses of Mphi by acting as a priming agent that heightens their responsiveness to secondary stimulation by other mediators. We previously reported that CSF-1 induced peritoneal Mphi (PMphi) to transcribe several genes including interleukin-6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm). It was reported that the Il6 and Csfgm genes were individually regulated by different pathways but it was not clear to what extent the two genes interacted during Mphi-mediated inflammatory responses. We now show that CSF-1 induces the release of bioactive GM-CSF from mouse resident PMphi. GM-CSF induces Il6 gene expression and synergizes with CSF-1 to induce the release of large amounts of IL-6. PMphi from C57BL/6J-Csfgm(null) mice were shown to release minimal IL-6 in response to CSF-1 and to express a much reduced response to the highly stimulatory combination of CSF-1 and lipopolysaccharide (LPS). Exogenous recombinant GM-CSF restored the IL-6 response of GM-CSF null PMphi to a great extent but not completely. As controls, three other recombinant proteins were tested but of these only tumor necrosis factor alpha (TNF-alpha) was shown to synergize with both CSF-1 and GM-CSF. Using PMphi from mice deficient in the expression of the Il6 gene, it was shown that they released two- to threefold more GM-CSF in response to CSF-1 than their control counterparts. However, an exogenous supply of recombinant IL-6 had no effect on GM-CSF release. The data indicate that the pathways regulating Il6 gene expression are under the control of a complex network of cytokine interactions involving at least CSF-1, GM-CSF, and TNF-alpha, with the added possibility that IL-6 may exert modulatory activity within this network.

Comparative analysis of murine dendritic cells derived from spleen and bone marrow.

In order to improve upon preclinical tumor vaccine strategies that employ dendritic cells (DC), we now have compared short-term cultures of spleen- and GM-CSF/IL-4-stimulated bone marrow (BM) to determine if differences exist in phenotype and function of murine DC derived from primary and secondary hematolymphoid organs. Although cultures of BM contained a lower percentage of DC compared to spleen, their capacity to stimulate a primary allogeneic mixed leukocyte reaction (MLR) and to uptake fluorescent dextran was substantially greater. In addition, the overall yields of DC per animal was at least twofold greater from BM compared to spleen. Cultures of BM harvested at day 3, 6, or 9 stimulated comparable levels of primary allo-MLR on a per-cell basis. However, there was a consistent loss (at least twofold) of all cells occurring beyond day 6 as compared with cell yields from earlier time points. Importantly, we also improved on methods to rapidly obtain highly enriched DC (> 90%) from BM, which has obviated the reported prior need for complex antibody and complement treatments to remove contaminating mature T and B lymphocytes, Ia-bearing cells, and granulocytes before DC generation. In contrast, although similar purity of DC with similar phenotype and function could be obtained from the spleen, substantial loss in yield occurred, suggesting a further difference in DC between the two tissue sources. The overall yield of DC derived from spleen and BM cultures could be substantially increased by in vivo pretreatment of the donor animals with recombinant Flt3-L. Collectively, these studies demonstrate that notable differences exist in DC preparations derived from spleen vs. BM and that BM provides the preferred source of DC that can be rapidly enriched to high purity for use in further vaccine development.

Bilateral radial artery grafts in coronary reconstruction: technique and early results in 261 patients.

BACKGROUND: To achieve arterial myocardial revascularization we have progressively used more single and bilateral internal thoracic artery and radial artery (RA) grafts. We evaluated our early experience with bilateral radial artery to coronary grafts. METHODS: As part of their coronary reconstruction, 261 patients had 522 bilateral RA grafts from March 1995 to June 1997. Mean age was 61.1 years. There were 70 (27%) patients with non-insulin-dependent diabetes and 13 (5%) with insulin-dependent diabetes. Unstable angina was seen in 54 (21%) patients. Left ventricular ejection fraction less than 50% was noted in 74 (28.4%) patients. Coronary revascularization was completed with additional single internal thoracic artery in 229 patients (88%), bilateral internal thoracic artery in 25 patients (9.6%), and vein grafts in 13 patients (5%). Intraluminal 1% papaverine in blood was used. There were 3.6 +/- 0.7 distal anastomoses per patient, with a total of 939, 921 (98%) with arterial conduits and 18 with vein grafts. Five hundred ninety-four (63%) of the anastomoses were with RAs. Of the 522 RA grafts 72 (13.8%) were used sequentially. The RA was most frequently placed to the circumflex marginals (261 patients, 100%) and posterior descending (169 patients, 65%). Proximal RA anastomosis was directly to the aorta in 472 patients, the internal thoracic artery in 42, or another RA in 8. All anastomoses were constructed during a single cross-clamp period (mean, 74.2 +/- 26.6 minutes). RESULTS: Operative mortality was 2 patients (0.8%). Complications included stroke in 2 patients (0.8%), deep internal infection in 2 (0.8%), reoperation for hemorrhage in 1 (0.4%), and myocardial infarction in 2 (0.8%). Mean peak creatine kinase-MB was 13.2 +/- 11.6 IU/L. There were no forearm infections or hand ischemia, but there were 4 (1.6%) hematomas, 1 requiring drainage. Angiography was done on 16 patients with RA grafts, a mean of 4.2 months postoperatively. Twenty of 22 distal anastomoses were patent (91%), and there was 1 occlusion and 1 string sign. CONCLUSIONS: Bilateral RA to coronary grafting extends the scope of arterial myocardial revascularization, and is safe. Late angiographic results are required.

Evolution of complete arterial grafting. For coronary artery disease.

Arterial grafting for the correction of coronary artery disease preceded the use of saphenous vein grafts, but the overwhelming popularity of the saphenous vein from 1970 to 1985 left the development of arterial grafting dormant. Excellent graft patency results from pedicled internal thoracic artery grafting and continued saphenous vein graft failure prompted our unit to explore complete arterial grafting with internal thoracic artery and radial artery grafts. One thousand and fifty-three patients who received a combination of internal thoracic artery and radial artery grafts were compared with 1,156 patients who received internal thoracic artery and saphenous vein grafts. All patients underwent primary coronary artery bypass surgery between 1995 and 1998. The early mortality and morbidity and the probability of survival at 2 years were similar in both groups of patients. Early graft patency studies of 35 radial artery grafts showed 33 (94%) were patent at a mean of 12 months. Complete arterial grafting using internal thoracic and radial arteries is safe and may provide a long-term benefit.

Results of 1,454 free right internal thoracic artery-to-coronary artery grafts.

BACKGROUND: After beginning our use of bilateral internal thoracic artery grafts in 1985, we found the pedicled right internal thoracic artery grafts limiting, and expanded the application of the right internal thoracic artery by elective use as a free graft. We evaluated the results of patients having a free right internal thoracic artery (FRITA)-to-coronary artery graft as part of their coronary revascularization. METHODS: From 1986 to 1995, 1,454 patients had a FRITA graft. Preoperative characteristics included mean age, 58.8 years (range 29 to 84 years); non-insulin-dependent diabetes, 116 (8%); insulin-dependent diabetes, 7 (0.5%); left ventricular ejection fraction from 0.30 to 0.40, 159 (11%); left ventricular ejection fraction less than 0.30, 14 (1%); and unstable angina, 144 (9.9%). In 11 patients the FRITA was the only graft, in 1,443 a left internal thoracic graft was also used and revascularization completed with additional arterial and vein grafts. There were 3.3 +/- 1.1 distal anastomoses per patient, the aortic clamp time was 49 +/- 12 minutes, and bypass time was 69 +/- 16 minutes. The FRITA was used to reach the circumflex marginal arteries in 718 patients (49.5%), posterior descending artery in 286 (19.7%), diagonal or intermediate in 172 (11.8%), left anterior descending artery in 119 (8.1%), right coronary artery in 115 (7.9%), and left ventricular branch of right coronary artery in 44 (3%). The proximal anastomosis was directly on the aorta in 1,441, other arterial graft in 8, and vein graft in 5. RESULTS: Operative mortality was 13 patients (0.9%); stroke occurred in 14 patients (1%) and myocardial infarction in 19 (1.3%). The peak creatine kinase myocardial isoenzyme serum level was 20.6 +/- 13.6 IU/L. Complications included sternal infection in 18 patients (1.2%) and reoperation for hemorrhage in 23 (1.6%). Survival at 5 and 7 years, respectively, was 96% +/- 2.1% and 94% +/- 2.5%. In 71 patients with a FRITA studied at a mean of 41.5 +/- 14 months postoperatively for recurrent symptoms, 67 FRITA grafts were widely patent (94.5%), 3 displayed a string sign, and 1 was totally occluded. CONCLUSIONS: Use of the right internal thoracic artery as a free graft is safe and effective and allows greater flexibility in arterial coronary revascularization.

Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes.

Recent data have indicated that resident mouse peritoneal macrophages (PMo) transcribed the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes in response to stimulation with the monocyte-macrophage colony-stimulating factor (CSF-1) but only Il6 mRNA was translated into secreted protein. In this paper, we extend these observations. It is shown that resident PMo incubated with protein kinase (PK)C inhibitors, staurosporine (SP) and its derivative GF109203-X, showed a several fold increase in the levels of Il6 mRNA in control and CSF-1-primed PMo and a parallel release of large amounts of protein. In contrast, SP was shown to have no effect on the release of GM-CSF from control or CSF-1-primed PMo, although it increased by approximately twofold the amount of Csfgm mRNA in CSF-1-primed Mo. When SP was added 4 h after CSF-1 priming to block CSF-1-induced protein kinase pathways, an increased amount of IL-6 release was again seen but without any increase in Il6 mRNA levels. Under these conditions, Csfgm gene expression was relatively unaffected. Activation of PKC by phorbol myristate acetate (PMA) also resulted in increased Il6 gene expression by control and CSF-1-primed PMo. PMA had no apparent effect on Csfgm transcription but appeared to influence translation at a low level, as measured by the release of small amounts of GM-CSF protein. The addition of lipopolysaccharide (LPS) to CSF-1-primed PMo resulted in a synergistic increase in the expression of both genes at the levels of transcription and protein release. The addition of SP to CSF-1-primed Mo before LPS, however, further enhanced IL-6 release but not GM-CSF release from the cells. The data indicate that CSF-1-priming drives a number of pathways involved in the regulation of expression of both genes and renders PMo highly susceptible to appropriate secondary stimulatory agents that transform the PMo into secretory inflammatory cells.

IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: the potential role of NK cell subpopulations.

The daily administration of IL-15 to cyclophosphamide (CY)-injected mice bearing the 76-9 rhabdomyosarcoma was shown to prolong the period of remission induced by CY. In addition, IL-15 was shown to enhance the efficacy of adoptive immunotherapy. Cytotoxicity assays using spleens from normal and tumor-bearing mice indicated that IL-15 enhanced NK cell activity but there was no evidence for class I-restricted cytolytic T cell activity. To determine whether IL-15 was likely to induce different cytotoxic effectors at the tumor site compared with the spleen, tumors were removed after CY injection and cell suspensions were incubated with IL-15 in parallel with isolated spleen cells. Both populations were seen to expand to yield predominantly cells coexpressing NK1.1 and B220 antigens. However, tumor-associated NK cells were shown to differ from expanded spleen NK cells in terms of the proportions of LGL-1+ cells and cells expressing early and late NK cell differentiation antigens. Both expanded populations expressed high NK cell cytotoxic activity but only the spleen cells expressed lymphocyte-activated killer cell activity. It was apparent that the expanded tumor-associated NK cells expressed low-level class I-restricted lytic activity. The potential of activated NK cells in the circulation to exert anti-tumor effects was shown by the adoptive transfer of expanded NK cells to tumor-bearing mice after CY injection when significant prolongation of life was seen in all cases. The data indicate that IL-15 may serve as a useful anti-cancer adjuvant by activating initially the NK cell arm of the immune network.

CSF-1-induced and constitutive Il6 gene expression in mouse macrophages: evidence for PKC-dependent and -independent pathways.

It has been recently shown that CSF-1 enhanced the constitutive expression of the Il6 gene in resident mouse peritoneal macrophages (PM phi) but little is known about the pathways involved. In this report, we show that both constitutive and CSF-1-induced IL-6 release were enhanced and prolonged in the presence of the PKC inhibitors, staurosporine (SP) and its derivative, GF-109203X. Enhancement of constitutive IL-6 release required higher concentrations of inhibitors, while enhanced CSF-1-induced release was diminished when inhibitor concentrations exceeded defined limits. SP was also shown to activate constitutive IL-6 release by blood monocytes and elicited PM phi but had no effect on their responsiveness to CSF-1. Activation of PKC by exposure of resident PM phi to phorbol myristate acetate (PMA) also resulted in enhanced IL-6 release and PMA was shown to synergize with CSF-1. These data indicate that CSF-1 does not induce Il6 gene expression by amplifying the constitutive pathway in all mononuclear phagocyte subpopulations. It exerts its effects independently of PKC, which may activate Il6 gene expression in its own right by an alternative pathway. While CSF-1 and PKC are involved in separate pathways, the synergistic IL-6 response seen when PMA and CSF-1 interact suggests convergence of the two pathways. It is also apparent that multiple PKs, excluding PKC, may be involved in repressing constitutive and CSF-1-induced Il6 gene expression.

Differential sensitivity of mouse mononuclear phagocytes to CSF-1 and LPS: the potential in vivo relevance of enhanced IL-6 gene expression.

In this report, we compared the responsiveness of subpopulations of mononuclear phagocytes (MNP) to the actions of the monocyte-macrophage colony-stimulating factor (CSF-1) and lipopolysaccharide (LPS), as measured by the expression of the IL-6 (Il6) gene. It was seen that neither monocytes nor elicited peritoneal macrophages (PMphi) responded directly to CSF-1 compared with resident PMphi that were induced to express high levels of Il6 mRNA and release IL-6 protein. Resident PMphi released basal (constitutive) amounts of IL-6, while constitutive release by monocytes and elicited PMphi was barely detectable. Monocytes and elicited PMphi expressed similar levels of sensitivity to LPS, as measured by IL-6 release, and were less reactive than resident PMphi. When CSF-1 and LPS were added simultaneously to resident PMphi, a dose-dependent synergistic release of IL-6 was seen. Elicited PMphi also responded synergistically but required higher levels of CSF-1 and LPS, while monocytes failed to respond synergistically under any conditions. A similar synergistic effect was also seen in vivo when mice were injected with CSF-1 and LPS. Under these conditions, only resident peritoneal cells were shown to release IL-6 ex vivo while blood leukocytes and spleen cells released minimal amounts. These findings indicate that the stage of differentiation/maturation of MNP may be important for the ability of CSF-1 to render the cells sensitive to secondary stimulation, such as by LPS, and determines to what extent MNP subpopulations contribute to inflammatory responses in vivo.