Treatment of esophageal perforation in octogenarians: a multicenter study.

Esophageal perforation is associated with significant mortality, and this may markedly increase with advanced age. This multicenter study investigates this issue in patients older than 80 years. Data on 33 patients >80 years old who underwent conservative (10 patients), endoclip (one patient), stent grafting (11 patients), or surgical treatment (11 patients) for esophageal perforation were collected from nine centers. Surgical repair consisted of repair on drain in one patient, primary repair in seven patients, and esophagectomy in two patients. Among patients who underwent stent grafting, one required repeat stenting and another stent graft repositioning. One patient was converted to surgical repair after stent grafting. Thirteen patients (39.4%) died during the 30-day and/or in-hospital stay. Their mortality was significantly higher than in a series of patients<80 years old (13.0%, 21/161 patients, P=0.001). Three patients (30.0%) died after conservative treatment, one (100%) after treatment with endoclips, five (45.5%) after stent grafting, and four (36.4%) after surgical repair (P=0.548). Early survival with salvaged esophagus was 42.4% (conservative treatment: 70.0% endoclips 0%, stent grafting: 54.5%, and surgical repair: 54.5%, respectively, P=0.558). Estimated glomerular filtration rate<60 mL/minute/1.73 m2 (70.0% vs. 25.0%, P=0.043) and sepsis (100% vs. 32.1%, P=0.049) at presentation were associated with increased risk of early mortality in univariate analysis. Esophageal perforation in octogenarians is associated with very high early and intermediate high mortality irrespective of the treatment method used.

Postconditioning and remote postconditioning of ischemic rat cardiac grafts.

BACKGROUND: Global warm ischemia of transplanted cardiac grafts is associated with apoptosis and subsequent tissue necrosis. It is suggested that postconditioning (PostC) may ameliorate the early outcome of cardiac grafts after ischemia-reperfusion. We investigated whether PostC and remote postconditioning (RPostC) have a histopathologic impact after transplantation of warm ischemic rat cardiac grafts. MATERIALS AND METHODS: Thirteen rats were randomized to undergo either PostC or RPostC after heterotopic transplantation of ischemic cardiac grafts. Six rats without intervention besides transplantation served as controls (control). The recipient rats were sacrificed 24 h after transplantation to evaluate histopathology and apoptotic index. RESULTS: No significant differences were observed between the study groups in terms of graft heat shock protein 70 and oxygen radical absorbing capacity, an indicator of antioxidant capacity. While apoptosis and PCARB, a marker of protein oxidation and oxidative stress, decreased after RPostC (p < 0.05), contraction band necrosis was less prominent in both PostC and RPostC. CONCLUSION: Both PostC and RPostC have a histopathologic impact after 24 h of reperfusion of warm ischemic rat cardiac grafts.

Aprotinin Impacts 8-Isoprostane after Coronary Artery Bypass Grafting.

BACKGROUND AND AIMS:: The lungs participate in the modulation of the circulating inflammatory factors induced by coronary artery bypass grafting. We investigated whether aprotinin-which has been suggested to interact with inflammation-influences lung passage of key inflammatory factors after coronary artery bypass grafting. MATERIAL AND METHODS:: A total of 40 patients undergoing coronary artery bypass grafting were randomized into four groups according to aprotinin dose: (1) high dose, (2) early low dose, (3) late low dose, and (4) without aprotinin. Pulmonary artery and radial artery blood samples were collected for the evaluation of calculated lung passage (pulmonary artery/radial artery) of the pro-inflammatory factors interleukin 6 and interleukin 8, 8-isoprostane, myeloperoxidase and the anti-inflammatory interleukin 10 immediately after induction of anesthesia (T1), 1 min after releasing aortic cross clamp (T2), 15 min after releasing aortic cross clamp (T3), 1 h after releasing aortic cross clamp (T4), and 20 h after releasing aortic cross clamp (T5). RESULTS:: Pulmonary artery/radial artery 8-isoprostane increased in patients with high aprotinin dose as compared with lower doses (1.1 range 0.97 vs 0.9 range 1.39, p = 0.001). The main effect comparing high aprotinin dose with lower doses was significant (F(1, 38) = 7.338, p = 0.01, partial eta squared = 0.16) further supporting difference in the effectiveness of high aprotinin dose for pulmonary artery/radial artery 8-isoprostane. CONCLUSION:: According to the pulmonary artery/radial artery equation, the impact of aprotinin on 8-isoprostane after coronary artery bypass grafting is dose dependent. Aprotinin may aid the lung passage of circulating factors toward a beneficial anti-inflammatory milieu.

The Impact of Lung Ventilation on Some Cytokines after Coronary Artery Bypass Grafting.

BACKGROUND AND AIMS: Cardiopulmonary bypass induces a systematic inflammatory response, which is partly understood by investigation of peripheral blood cytokine levels alone; the lungs may interfere with the net cytokine concentration. We investigated whether lung ventilation influences lung passage of some cytokines after coronary artery bypass grafting. MATERIAL AND METHODS: In total, 47 patients undergoing coronary artery bypass grafting were enrolled, and 37 were randomized according to the ventilation technique: (1) No-ventilation group, with intubation tube detached from the ventilator; (2) low tidal volume group, with continuous low tidal volume ventilation; and (3) continuous 10 cm H2O positive airway pressure. Ten selected patients undergoing surgery without cardiopulmonary bypass served as a referral group. Representative pulmonary and radial artery blood samples were collected for the evaluation of calculated lung passage (pulmonary/radial artery) of the pro-inflammatory cytokines (interleukin 6 and interleukin 8) and the anti-inflammatory interleukin 10 immediately after induction of anesthesia (T1), 1 h after restoring ventilation/return of flow in all grafts (T2), and 20 h after restoring ventilation/return of flow in all grafts (T3). RESULTS: Pulmonary/radial artery interleukin 6 and pulmonary/radial artery interleukin 8 ratios ( p = 0.001 and p = 0.05, respectively) decreased, while pulmonary/radial artery interleukin 10 ratio ( p = 0.001) increased in patients without cardiopulmonary bypass as compared with patients with cardiopulmonary bypass. CONCLUSIONS: The pulmonary/radial artery equation is an innovative means for the evaluation of cytokine lung passage after coronary artery bypass grafting. The mode of lung ventilation has no impact on some cytokines after coronary artery bypass grafting in patients treated with cardiopulmonary bypass.

Ultrarapid Ki-67 immunostaining in frozen section interpretation of gliomas.

BACKGROUND: Astrocytic tumours, the most common gliomas, are often classified intraoperatively using standard morphological staining. The final diagnosis and grading of gliomas on paraffin wax sections is often assisted by Ki-67 immunohistochemistry, but standard immunostaining protocols take too long to be used intraoperatively. AIMS: To investigate a new rapid Ki-67 immunohistochemical test for its use in an intraoperative setting. METHODS: The new Ki-67 immunostaining (Ultrarapid-Ki67) method on frozen sections can be carried out in 10 minutes. Thirty four pilocytic and diffuse astrocytomas were immunostained by rapid Ki-67 and results were compared with corresponding MIB-1 staining, histological grading, and prognosis. RESULTS: The staining protocol was practical to perform and the results were morphologically and quantitatively indistinguishable from those after immunostaining with MIB-1, an antibody recognising Ki-67 in paraffin wax embedded tissue. A comparison of Ultrarapid-Ki67 and MIB-1 immunostaining of paraffin wax sections showed almost identical quantitative correlation in astrocytic gliomas (r = 0.916; p<0.001). The Ultrarapid-Ki67 indices (percentage of positive cells) of low grade (I/II) astrocytomas ranged from 0% to 6.1%, whereas those of representative high grade (III/IV) tumours were significantly higher (range, 5.6-45%; p<0.001). The best prognostic cutoff point for Ultrarapid-Ki67 was 7.5%, which divided diffuse grade II-IV astrocytomas into significantly differing subsets (p = 0.0008). CONCLUSION: Ultrarapid-Ki67 immunostaining is a useful adjunct to morphological diagnosis and grading of astrocytic tumours, and as a fast test (approximately 10 minutes for staining plus three to four minutes for scoring), it could be used in routine intraoperative diagnosis of gliomas and other neoplastic diseases.

Reversibility of allograft arteriosclerosis after retransplantation to donor strain.

The rat aortic transplant model was modified to investigate whether the vascular wall changes on chronic rejection are reversible. DA (RT1a) aortas were first transplanted to WF (RT1a) recipients. The first transplantation was accompanied, as described earlier, by an increase in intimal cellularity and thickness and typical arteriosclerotic changes of chronic rejection in the allograft intima. A second transplantation was made to DA, WF or to (DAxWF)F1 recipients 10 days-2 months after the first transplantation. In all retransplantations performed at any one of the indicated timepoints, the thickness and number of nuclei of the intima continued to increase. These observations demonstrate that, after an initial trigger, allograft arteriosclerosis proceeds and is irreversible despite elimination of histoincompatibility.

Chronic rejection in the rat aortic allograft. V. Mechanism of the angiopeptin (BIM23014C) effect on the generation of allograft arteriosclerosis.

Synthetic cyclic octapeptide analogues of somatostatin, such as angiopeptin (BIM23014C; AP) inhibit myointimal proliferation in chronically rejecting rabbit and rat allografts and following angioplasty in rabbits. We have investigated the mechanism of angiopeptin inhibition of allograft arteriosclerosis. DA (RT1a) aortic allografts were transplanted to WF (RT1v) recipients, which either received 80 micrograms/kg/day of AP (Alzet mini-pumps, s.c., 0-180 days) or were left untreated. AP administration did not affect the intensity of adventitial inflammation, nor reduced the disappearance of smooth-muscle cell nuclei from the media (media necrosis); however, it reduced their appearance in the intima and intimal thickening. The effect disappeared, however, from the 3rd month onward. In vivo labeling with tritiated thymidine and autoradiograms demonstrated that AP reduced slightly the proliferation of the inflammatory cells in adventitia and of smooth-muscle cells in the media, and reduced strongly and significantly (P < 0.01) the proliferation of smooth-muscle cells in the intima. Analysis of the major chronic-rejection associated eicosanoids from the vascular wall showed that AP had no effect on the release of the pro-inflammatory thromboxane B2 from the allograft. As AP did not reduce the intensity of perivascular inflammation, reduced only slightly the proliferation of inflammatory cells, and did not affect the release of thromboxane B2 from the inflammatory macrophages, it is likely that the AP effect is not directed to the inflammatory cells. As previous in vitro studies have demonstrated that vascular smooth-muscle cells proliferate in response to several growth factors, and as somatostatin analogues are inhibitory to their action, our data suggest that the action of AP on allograft arteriosclerosis is due to a direct effect on smooth-muscle-cell proliferation.

Signal transduction during in vitro lymphocyte homing.

Lymphocyte binding to endothelium is a necessary prerequisite for lymphocyte homing through endothelium. This is mediated by the binding of ligands on endothelial cells to lymphocyte surface homing receptors. We show in this paper that the intracellular second messenger pathways involved in interferon gamma-induced intercellular adhesion molecule 1 upregulation on endothelial cells are protein kinase C and calcium dependent. Lymphocyte binding to endothelial cells is enhanced by both platelet activating factor and interleukin 1 alpha. Platelet activating factor added to endothelial cultures increases lymphocyte binding within 10 min and operates via protein kinase C but not via cAMP. On the other hand interleukin 1 alpha increases binding within 4 hr and operates via cAMP but not via protein kinase C. These results imply that different mediators of inflammation can activate different signal transduction pathways but lead to similar increases in lymphocyte binding.

Leukocyte filtration improves brain protection after a prolonged period of hypothermic circulatory arrest: A study in a chronic porcine model.

BACKGROUND: Ischemic cerebral injury follows a well-attested sequence of events, including 3 phases: depolarization, biochemical cascade, and reperfusion injury. Leukocyte infiltration and cytokine-mediated inflammatory reaction are known to play a pivotal role in the reperfusion phase. These events exacerbate the brain injury by impairing the normal microvascular perfusion and through the release of cytotoxic enzymes. The aim of the present study was to determine whether a leukocyte-depleting filter (LeukoGuard LG6, Pall Biomedical, Portsmouth, United Kingdom) could improve the cerebral outcome after hypothermic circulatory arrest. METHODS: Twenty pigs (23-30 kg) were randomly assigned to undergo cardiopulmonary bypass with or without a leukocyte-depleting filter before and after a 75-minute period of hypothermic circulatory arrest at 20 degrees C. Electroencephalographic recovery, S-100beta protein levels, and cytokine levels (interleukin 1beta, interleukin 8, and tumor necrosis factor alpha) were recorded up to the first postoperative day. Postoperatively, all animals were evaluated daily until death or until electively being put to death on day 7 by using a quantitative behavioral score. A postmortem histologic analysis of the brain was carried out on all animals. RESULTS: The rate of mortality was 2 of 10 in the leukocyte-depletion group and 5 of 10 in control animals. The risk for early death in control animals was 2.5 (95% confidence interval, 0.63-10.0) times higher than that of the leukocyte-depleted animals. The median behavioral score at day 7 was higher in the leukocyte-depletion group (8.5 vs 3.5; P =.04). The median of total histopathologic score was 8.5 in the leukocyte-depletion group and 15.5 in the control group (P =.005). CONCLUSION: A leukocyte-depleting filter improves brain protection after a prolonged period of hypothermic circulatory arrest.

Endothelialitis and accelerated arteriosclerosis in human heart transplant coronaries.

We have analyzed the autopsy material of 11 cardiac allograft recipients, whose grafts became nonfunctional less than 1 year after transplantation. All patients had received routine triple-drug immunosuppression. Two of these patients showed accelerated transplant arteriosclerosis; the graft loss was associated with strong intimal proliferative response affecting the first-order and second-order intramuscular branches of the major coronary vessels. Histologic evidence showed only a slight inflammatory reaction in the vascular adventitia. The media was mostly intact, and the internal elastic lamina showed occasional breaks. A very prominent inflammatory reaction was noted in the subendothelial space in the intima. Immunohistochemistry with monoclonal antibodies revealed that the luminal part of the intima was invaded by anti-leukocyte common antigen and anti-UCHL1 positive T lymphocytes, whereas the abluminal part consisted mostly of anti-smooth muscle alpha-actin-positive smooth muscle cells. We call this subendothelial accumulation of lymphocytes endothelialitis. The suggestion has been made that accelerated arteriosclerosis may be associated with cyclosporine treatment. Correlation with the recipient's cytomegalovirus status in this study suggests that cytomegalovirus infection may contribute to the development of endothelialitis and accelerated arteriosclerosis in heart transplant recipients.

Chronic rejection in rat aortic allografts. IV. Effect of hypercholesterolemia in allograft arteriosclerosis.

Rat aortic allografts transplanted across histoincompatible strains develop arteriosclerotic alterations in the vascular wall that are virtually indistinguishable from those observed in human heart allografts during chronic rejection. In this study we have investigated whether hypercholesterolemia in the recipient rat accelerates allograft arteriosclerosis. Hypercholesterolemia was induced by a 4% cholesterol and 0.5% cholic acid diet, added to the normal rat diet. The cholesterol and cholic acid diet increased the level of serum total cholesterol from 1.3 +/- 0.0 to 4.8 +/- 0.9 (+/- SD) mmol/L and the level of low-density lipoprotein cholesterol from 0.3 +/- 0.0 to 2.6 +/- 1.0 mmol/L (p < 0.05) but caused no change in the level of high-density lipoprotein cholesterol, 1.0 +/- 0.1 versus 0.7 +/- 0.3 mmol/L. The level of plasma triglycerides remained also unchanged. Quantitation of two major chronic rejection-associated eicosanoids from the allograft vascular wall showed a significant increase in the synthesis of thromboxane B2 in the hyperlipidemic animals from 6.0 +/- 5.0 to 8.0 +/- 5.0 ng/mg dry weight and a slight reduction in the synthesis of 6-keto-prostaglandins F1 alpha. In vivo labeling of the recipient rat with tritiated thymidine and autoradiography showed that hypercholesterolemia did not affect the proliferation of inflammatory cells in the allograft adventitia, slightly increased the proliferation of smooth muscle cells in the media from 23 +/- 14 cells to 34 +/- 13 cells (+/- SEM) per cross section (p = ns), but slightly reduced the proliferation of smooth muscle cells in the intima from 13 +/- 6 to 6.2 +/- 1.5 (p = ns). Hypercholesterolemic recipients did not show any significant enhancement but, in fact, showed a delay in the generation of arteriosclerotic changes in the allograft intima. We conclude that although hypercholesterolemia, in the absence of hypertriglyceridemia, induces significant alterations in the eicosanoid metabolism and minor alterations in smooth muscle cell proliferation in the transplant vascular wall, it does not enhance arteriosclerotic alterations in chronically rejecting rat aortic allografts.

Does technical failure of revascularization during coronary artery bypass grafting predict severity of poststernotomy mediastinitis?

BACKGROUND AND AIMS: To assess the impact of unsuccessful revascularization in relation to poststernotomy mediastinitis (PSM), which affects long-term outcome after coronary artery bypass grafting (CABG). MATERIAL AND METHODS: An active approach for the follow-up of PSM involved a step by step treatment protocol of conventional surgery and plastic reconstructive surgery. 47 patients treated for PSM after CABG were identified and further evaluated. Complete revascularization was considered unsuccessful when technical hazards were reported during CABG. When PSM subsided after thorough debridement and sternal refixation without plastic reconstructive surgery, such as omentoplasty or muscle transposition, PSM was categorized as mild PSM. If treatment required plastic reconstructive surgery, PSM was categorized as severe PSM. Preoperative coronary artery angiographic status and success of revascularization were compared to postoperative outcome in relation to mild and severe PSM. RESULTS: 36 patients suffered from mild PSM and 11 patients from severe PSM. Preoperative clinical status did not differ among patients. Two patients (4.3 %) died during hospitalization. The need for plastic reconstructive surgery was significant (p < 0.05) among patients with unsuccessful revascularization. 35 out of 41 patients (85 %) without problems of graft anastomosis during CABG (successful revascularization) were associated with mild PSM, whereas only 6 out of 41 patients (15 %) with successful revascularization during CABG required plastic reconstructive surgery (p < 0.05). Technical failure of graft anastomosis (3 cases) or poor outflow of internal thoracic artery (2 cases) were statistically associated with severe PSM. CONCLUSION: Technical failures of revascularization during CABG may delay recovery from PSM.

Prolonged cardiac allograft survival using iodine 131 after human sodium iodide symporter gene transfer in a rat model.

BACKGROUND: Radioiodine is efficiently concentrated by tissues expressing the human sodium iodide symporter (hNIS). OBJECTIVE: To analyze the effects of iodine 131 on acute cardiac allograft rejection after ex vivo hNIS gene transfer in a rat model of cardiac allotransplantation. MATERIALS AND METHODS: Hearts from Brown Norway rats were perfused ex vivo either with UW (University of Wisconsin) solution (n = 9) or UW solution containing 1 x 10(9) pfu/mL of adenovirus 5 plus NIS (Ad-NIS) (n = 18). Donor hearts were transplanted heterotopically into the abdomen of Lewis rats, and recipients were treated on postoperative day 3 with either 15,000 microCi of (131)I or saline solution. The hearts were explanted when no longer beating, and were evaluated histologically for evidence of rejection and other changes. RESULTS: Grafts perfused with the Ad-NIS vector survived significantly longer in recipients injected with (131)I (mean [SD], 11.3 [1.9] days) compared with control animals not treated with (131)I (5.7 [0.65] days) (P < .001). Treatment with (131)I did not prolong graft survival in recipients of hearts that were not perfused with Ad-NIS (5.5 [1.0] vs 5.3 [0.8] days). In Ad-NIS (131)I-treated transplants, the level of myocardial damage on day 6 after surgery, when control hearts were rejected, was significantly lower (60.8 [28.0] vs 99.7 [0.8]; P < .05). CONCLUSION: Our findings indicate that (131)I, after NIS gene transfer, can effectively prolong cardiac allograft survival. To our knowledge, this is the first report of the use of NIS-targeted (131)I therapy in cardiac transplantation. Further studies are required to determine the mechanism of this effect and its potential for clinical application.