Comprehensive validation of early diagnostic algorithms for myocardial infarction in the emergency department.

OBJECTIVE: To comprehensively evaluate diagnostic algorithms for myocardial infarction using a high-sensitivity cardiac troponin I (hs-cTnI) assay. PATIENTS AND METHODS: We prospectively enrolled patients with suspected myocardial infarction without ST-segment elevation from nine emergency departments in Japan. The diagnostic algorithms evaluated: (i) based on hs-cTnI alone, such as the European Society of Cardiology (ESC) 0/1-h or 0/2-h and High-STEACS pathways; or (ii) used medical history and physical findings, such as the ADAPT, EDACS, HEART, and GRACE pathways. We evaluated the negative predictive value (NPV), sensitivity as safety measures, and proportion of patients classified as low or high-risk as an efficiency measure for a primary outcome of type 1 myocardial infarction or cardiac death within 30 days. RESULTS: We included 437 patients, and the hs-cTnI was collected at 0 and 1 hours in 407 patients and at 0 and 2 hours in 394. The primary outcome occurred in 8.1% (33/407) and 6.9% (27/394) of patients, respectively. All the algorithms classified low-risk patients without missing those with the primary outcome, except for the GRACE pathway. The hs-cTnI-based algorithms classified more patients as low-risk: the ESC 0/1-h 45.7%; the ESC 0/2-h 50.5%; the High-STEACS pathway 68.5%, than those using history and physical findings (15-30%). The High-STEACS pathway ruled out more patients (20.5%) by hs-cTnI measurement at 0 hours than the ESC 0/1-h and 0/2-h algorithms (7.4%). CONCLUSIONS: The hs-cTnI algorithms, especially the High-STEACS pathway, had excellent safety performance for the early diagnosis of myocardial infarction and offered the greatest improvement in efficiency.

Development of articular cartilage grafts using organoid formation techniques.

In order to develop articular cartilage grafts, one must control shape and safety. We have developed scaffold-free culture methods in which the cells form multicellular aggregates (organoids). In this study, we applied the organoid culture method to chondrocytes attempting to reconstitute articular cartilage grafts. Primary rat costal chondrocytes and subcultured human articular chondrocytes were immobilized in hollow fibers by centrifugation at a density of 3 x 10(8) cells/cm3 to induce the formation of cylindrical-shaped organoids. To improve convenience, we developed a culture device to form sheet-shaped organoids (organoid-sheet). Primary bovine articular chondrocytes were cultured in this device. These organoids were evaluated by histological and gene expression analyses. In the primary rat culture system, chondrocytes formed cylindrical organoids in hollow fibers. Histochemical analysis revealed the presence of extracellular matrix (collagen and proteoglycan). The organoid maintained cartilage-specific gene expression (type II collagen, aggrecan) for 1 month of culture. In the subcultured human chondrocyte system, the organoid regained the decreased cartilage-specific gene expression. In the primary bovine culture system, the cells formed a 300 microm thickness organoid-sheet including abundant extracellular matrix. In conclusion, our organoid formation method was effective to form cartilage-like tissue. This result suggested that the technique may be applicable for the development of an articular cartilage graft.

Development of a cascade arc discharge source for an atmosphere-vacuum interface device.

To realize a novel vacuum-atmosphere interface that does not require a large differential pumping system, a robust cascade arc discharge source called a plasma window is constructed and tested for long-term operation. By modifying a test plasma with a direct current discharge, a vacuum interface with a high gas pressure ratio of 1/407 between the discharge and expansion sections is demonstrated for currents as high as 20 A. No significant damage to the electrodes is observed during the operation. Analysis of the visible emission spectra reveals that a stationary, stable argon plasma having a temperature of 1 eV and a density of 1.5 × 10(16) cm(-3) is generated in the plasma channel.

Quantitative rest technetium-99m tetrofosmin imaging in predicting functional recovery after revascularization: comparison with rest-redistribution thallium-201.

OBJECTIVES: This study was undertaken to 1) compare the regional myocardial tracer distributions between rest technetium (Tc)-99m tetrofosmin and rest-redistribution thallium (Tl)-201 images in patients with coronary artery disease and left ventricular dysfunction; and 2) assess the comparative values of these agents for predicting functional recovery after revascularization. BACKGROUND: Tc-99m tetrofosmin is a new myocardial perfusion imaging agent, but its role for detecting viable myocardium is still unclear. METHODS: Thirty-six patients with coronary artery disease and left ventricular dysfunction underwent rest Tc-99m tetrofosmin, rest-redistribution Tl-201 and gated blood pool scintigraphy. In 21 patients with successful revascularization confirmed by follow-up angiography, gated blood pool scintigraphy was repeated after revascularization. Optimal threshold cutoffs to separate reversible from irreversible dysfunction were determined by receive operating characteristic analysis. RESULTS: Regional Tc-99m tetrofosimin activity highly correlated with redistribution Tl-201 activity (r = 0.93). The diagnostic performance for predicting functional recovery, as measured by the area under the receiver operating characteristic curves, measured 0.66 +/- 0.07 (mean +/- SD) for Tc-99m tetrofosmin and 0.67 +/- 0.07 for Tl-201 (p = 0.60, 96.7% power to detect difference in area of 0.10). The optimal threshold cutoffs for viability were considered to be 50% of peak activity for Tc-99m tetrofosmin and 55% of peak activity for Tl-201. The positive and negative predictive values for reversible dysfunction were, respectively, 69% and 82% for Tc-99m tetrofosmin and 69% (p = 0.99 vs. Tc-99m tetrofosmin) and 71% (p = 0.66 vs. Tc-99m tetrofosmin) by Tl-201. CONCLUSIONS: The diagnostic performance of quantitative rest Tc-99m tetrofosmin imaging in predicting functional recovery after revascularization is comparable to that of rest-redistribution Tl-201.

Autologous dendritic cells or cells expressing both B7-1 and MUC1 can rescue tumor-specific cytotoxic T lymphocytes from MUC1-mediated apoptotic cell death.

We attempted to induce MUC1-specific cytotoxic T lymphocytes (CTLs) by mixed-lymphocyte tumor cell culture (MLTC) using two allogeneic MUC1-positive cancer cell lines, T-47D and MCF7. The induced CTLs exhibited MUC1-specific cytotoxicity 16 days after the initial stimulation. However, these CTLs underwent apoptotic death within 16 days. To examine whether the B7-1 molecule is required for the expansion of the responder cells, a B7-1(+)/MUC1(-) cell line was transfected with MUC1 cDNA, and the resulting transfectant was employed as a stimulator in an autologous MLTC. The CTLs exhibited MUC1 specificity but also continued to propagate. In parallel, autologous dendritic cells (DCs) were added to an MLTC containing peripheral blood lymphocytes (PBLs) and the allogeneic MUC1-positive stimulators. The CTLs demonstrated MUC1 specificity and their number increased. This suggests that the B7-1 molecule is required for rescuing CTLs from MUC1-mediated apoptotic death, but not for the induction of MUC1-specific responsiveness. This strategy to obtain the CTLs efficiently may be useful for adoptive immunotherapy against cancer.

A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) was measured using a competitive radioligand binding assay in membrane preparations from 74 primary human non-small cell lung cancer (NSCLC) tissues and 20 pathologically normal peripheral lung tissues. The mean EGFR level in tumours was 30.38 fmol/mg (+/-41.95 S.D.) of membrane protein (mg.p), significantly higher (P = 0.00016) than in normal tissues (mean, 10.26 +/- 10.02 fmol/mg.p). The mean EGFR concentration was also significantly higher in pathological stage IV tissue than in stages I (P = 0.049) and II (P = 0.040), and the mean EGFR concentration was significantly higher in cases with mediastinal involvement than in cases without it (P = 0.029). The mean EGFR level was higher in DNA aneuploid and multiploid cases than in DNA diploid cases, but there was no significant difference. No significant relationships were found to exist between receptor concentrations and pathological tumour size or histological type, or patient gender or age. From the above findings, a possible prognostic role for EGFR in primary NSCLC should be investigated.

(99m)Tc-sestamibi retention characteristics during pharmacologic hyperemia in human myocardium: comparison with coronary flow reserve measured by Doppler flowire.

UNLABELLED: The aim of the study was to investigate the increase in myocardial (99m)Tc-methoxyisobutylisonitrile (sestamibi) retention in humans during pharmacologic vasodilation. METHODS: For calculation of the increase in (99m)Tc-sestamibi retention during hyperemia, baseline and adenosine triphosphate (ATP)-induced hyperemic stress sestamibi studies were performed using a same-day rest-stress protocol. On the injection of sestamibi, left ventricular dynamic data were obtained for 90 s. The increase in sestamibi retention from baseline to hyperemia was calculated by the formula [abstract: see text] where Cm(h)(t) and Cm(b)(t) are myocardial counts on the tomographic image, and Cb(b)(tau) and Cb(h)(tau) are the left ventricular blood-pool counts during the first transit of sestamibi at baseline and during hyperemia, respectively. Coronary flow increase during intravenous ATP stress was measured using intracoronary Doppler flow guide wire and compared with the scintigraphic results of 28 measurements in 22 patients. RESULTS: Sestamibi retention increased as coronary flow velocity increased but plateaued at >2.5-3 times baseline flow velocity. The relationship between the increase in sestamibi retention (Y) and the increase in flow (X) is expressed as follows: Y = 0.44 + 0.60X - 0.068X(2) (r = 0.82). CONCLUSION: In humans, the increase in (99m)Tc-sestamibi myocardial retention underestimates coronary flow reserve, particularly at high flow rates. Knowledge of these tracer retention characteristics will contribute to a more comprehensive understanding of the manner and interpretation of stress sestamibi imaging.

Significance of late redistribution thallium-201 imaging after rest injection for detection of viable myocardium.

UNLABELLED: The aim of this study was to determine whether late redistribution imaging after rest injection of 201Tl would provide further information on myocardial viability over conventional rest-early redistribution 201Tl imaging. METHODS: Twenty-nine patients with coronary artery disease and left ventricular dysfunction underwent rest, early (3-4 hr) and late (20-24 hr) redistribution 201Tl and gated blood pool studies. In 14 patients with successful revascularization, gated blood pool study was repeated after the coronary intervention. RESULTS: Nine of 29 patients showed early redistribution, and six additional patients showed further redistribution on the late images. Of 136 segments with initial 201Tl defects, 18 showed early redistribution, and 10 showed late redistribution. When a threshold of 60% of peak activity was used as an index of myocardial viability, only a small fraction (3%) of the initial 201Tl defects were additionally considered viable by the late images. In 14 patients who underwent revascularization, the positive (69%) and negative (87%) predictive values of the early redistribution images for functional recovery were similar to those obtained by the late images (68% and 86%, respectively). CONCLUSION: Although late redistribution after rest injection of 201Tl occasionally occurs, most of the clinically relevant information on myocardial viability may be obtained by conventional rest-early redistribution 201Tl imaging when the defect severity is considered an index of tissue viability.

Early and delayed technetium-99m-tetrofosmin myocardial SPECT compared in normal volunteers.

UNLABELLED: This study was performed to test the feasibility of early SPECT imaging with 99mTc-tetrofosmin with the presence of high hepatic activity. METHODS: Thirteen normal volunteers were injected 600-740 MBq of 99mTc-tetrofosmin at rest and were imaged at 10 min and 1 hr after injection. The SPECT images were reconstructed for 180 degrees 360 degrees data. The early and delayed SPECT and anterior planar projection images were analyzed. RESULTS: After excluding one subject because of high hepatic activity overlapping to the myocardium, 4 of 12 subjects (33%) had abnormal scans with reduced uptake in the inferior wall on the early 180 degrees SPECT image. In contrast, only one (8%) showed equivocally reduced uptake on the 360 degrees SPECT image. In the delayed images, all subjects had a normal 180 degrees and 360 degrees SPECT scan. Quantitative data showed reduced regional activities in the inferior wall on the early SPECT scan, especially in the 180 degrees data. There were no changes in the mean anterior-to-inferior ratio in the anterior planar projection images over time, suggesting that the reduced activity in the early SPECT images reflected an artifactual effect. CONCLUSION: Our data indicate that it would be best to perform late imaging in patients with suspected coronary artery disease using 99mTc-tetrofosmin.

Myocardial viability assessment with technetium-99m-tetrofosmin and thallium-201 reinjection in coronary artery disease.

UNLABELLED: Exercise-rest 99mTc-tetrofosmin myocardial perfusion images with a 2-day protocol was compared to exercise-redistribution-reinjection 201Tl images to assess the ability of 99mTc-tetrofosmin to detect viable myocardium. METHODS: We studied 25 patients with coronary artery disease and regional or global left ventricular dysfunction. Myocardial SPECT images with 99mTc-tetrofosmin were obtained 10 min after injection during exercise and 1 and 3 hr after rest injection. Within 1 wk of the 99mTc-tetrofosmin study, exercise-redistribution-reinjection 201Tl SPECT imaging was performed. RESULTS: Visual analysis demonstrated concordance between 201Tl and 99mTc-tetrofosmin imaging for defect reversibility in 126 of 209 segments (60%), with initial defects on both exercise 201Tl and 99mTc-tetrofosmin images. In the remaining discordant 83 segments (40%), 73 (88%) appeared nonreversible on 99mTc-tetrofosmin imaging but were reversible on 201Tl imaging. CONCLUSION: On the basis of defect reversibility by visual analysis, exercise-rest 99mTc-tetrofosmin imaging underestimates myocardial viability compared to 201Tl reinjection imaging. The identification of viable myocardium with both 99mTc-tetrofosmin and 201Tl can be greatly enhanced to a similar degree if the severity of reduction in activity within nonreversible defects is considered. These two agents may provide comparable information about myocardial viability by quantitative analysis of defect severity.

Comparison of defect size between thallium-201 and technetium-99m tetrofosmin myocardial single-photon emission computed tomography in patients with single-vessel coronary artery disease.

Defect size on exercise-rest technetium (Tc)-99m tetrofosmin myocardial perfusion imaging was compared with that on exercise-reinjection thallium-201 imaging with 20 patients with 1-vessel coronary artery disease. In each patient, exercise-reinjection thallium-201 single-photon emission computed tomography (SPECT) and exercise-rest Tc-99m tetrofosmin SPECT imaging were performed. For visual analysis of the obtained SPECT images, the left ventricular myocardium was divided into 20 segments based on 3 short-axis slices from the apical, middle, and basal ventricular levels. For quantitative analysis, a square region of interest was placed on the center of each segment which was used for visual analysis, and relative regional activity to the normal reference region was calculated for each segment. By visual interpretation of the images, exercise Tc-99m tetrofosmin imaging showed a smaller defect size than exercise thallium-201 imaging (6.9 +/- 3.9 vs 8.8 +/- 3.0 segments, p <0.01). In contrast, rest Tc-99m tetrofosmin imaging showed a defect size similar to that on reinjection thallium-201 imaging (5.9 +/- 3.6 vs 5.6 +/- 3.9 segments, p = NS). Similarly, the mean defect sizes during exercise determined by quantitative analysis were smaller on Tc-99m tetrofosmin SPECT than those on thallium-201 SPECT at all tested threshold cutoff points ranging from 50% to 70%, whereas there were no significant differences in defect sizes between rest Tc-99m tetrofosmin and reinjection thallium-201 imaging. These data indicate that exercise Tc-99m tetrofosmin SPECT defect size determined either by visual analysis or by quantitative analysis may be smaller than on exercise thallium-201 SPECT.

Association of p53 protein expression in stage I lung adenocarcinoma with reference to cytological subtypes.

Since the nuclear accumulation of p53 protein is known to correspond well with mutation of the p53 tumor-suppressor gene, we analyzed the p53 protein immunohistochemically with the anti-p53 mouse monoclonal antibody, DO-7, in 105 stage I lung adenocarcinomas. The p53 immunoreactivity was detected in the nuclei of cancer cells in 51 cases (49%). The p53-positive cases had a significantly poorer prognosis compared with the p53-negative cases (log-rank test; P < .001) When p53 expression was compared among the cytological subtypes of adenocarcinoma, the incidence of p53 expression in the bronchial surface epithelial cell type (11 of 15) was significantly higher than in the goblet cell type (1 of 6) and tended to be higher than the Clara cell/alveolar type II pneumocyte type (27 of 59). These findings indicate that immunohistochemical examination of the p53 protein is a potential prognostic factor in stage 1 lung adenocarcinomas, and that p53 expression has been associated with the cytological subtype.

Role of transforming growth factor-beta1 and decorin in development of central fibrosis in pulmonary adenocarcinoma.

Transforming growth factor-beta1 (TGF-beta1) is known as the growth factor that stimulates the synthesis of extracellular matrix. Recently, TGF-beta has been found to control the growth of cancer cells. Small chondroitin-dermatan sulfate (decorin) is an abundant extracellular matrix component. TGF-beta1 stimulates the synthesis of decorin, and decorin is considered to bind TGF-beta1. The activity of decorin in neutralizing TGF-beta1 activity suggests that decorin serves as a negative-feedback regulator of TGF-beta1 activity. To investigate the role and relationship of TGF-beta1 and decorin in the formation of central fibrosis in pulmonary adenocarcinoma, we performed an immunohistochemical study of TGF-beta1 and decorin in 61 cases of T1 pulmonary adenocarcinoma. Positive stainings for TGF-beta1 were shown in 40 cases and negative in 21 cases. Twenty-seven of 32 cases with central fibrosis were positive for TGF-beta1. Positive staining for TGF-beta1 was significantly related to the appearance of central fibrosis in pulmonary adenocarcinoma. When central fibrosis was composed of proliferative connective tissue with loose staining for decorin, cancer cells showed intense staining for TGF-beta1. When central fibrosis was composed of old fibrotic tissue with dense staining for decorin, cancer cells showed weak staining for TGF-beta1. Our results suggest that TGF-beta1 has an important role in the formation of central fibrosis in pulmonary adenocarcinoma, and decorin may play a role as a negative feedback regulator in the production of TGF-beta1 in pulmonary adenocarcinoma.

An experimental study on direct revascularization of bronchial circulation by microvascular anastomosis.

The effects of direct revascularization of the bronchial artery after bronchoplasty were estimated by laser Doppler velocimetry and india ink injection in dogs. Bronchoplastic surgery at the right main bronchus was performed in all dogs, and the bronchial artery was reconstructed using the internal thoracic artery in the reconstruction group. The mucosal blood flow was measured at the distal side of the anastomosis. India ink was injected into the aorta in the nonreconstruction group and into the internal thoracic artery in the reconstruction group. The peripheral blood flow had diminished immediately after surgeries to 59% of the baseline value and took 14 days to recover to the baseline value in the nonreconstruction group. However, in the reconstruction group, the blood flow recovered at once to 78% of the baseline value and had returned to that value in 5 days. Statistically significant differences were noted between the groups from just after operation to day 7. India ink data confirmed these findings. In the nonreconstruction group, no ink was observed in the peripheral bronchial vessels on day 3; it was noted in part of the vessels on day 7 and in most on day 14. On the other hand, a relatively large number of vessels were stained just after operation in the reconstruction group. Thus reconstruction of the bronchial artery by means of the anastomosis with the internal thoracic artery can be said to be a useful and effective method for preventing airway ischemia.

Nicorandil, a potent adenosine triphosphate-sensitive potassium-channel opener, ameliorates lung allograft reperfusion injury.

BACKGROUND: Lung allograft ischemia-reperfusion injury, characterized by increased pulmonary vascular resistance, pulmonary edema, and hypoxia, is the most frequent cause of early graft failure. Exogenous nitric oxide has been shown to reduce lung allograft reperfusion injury. During hypoxia, the adenosine triphosphate-sensitive potassium channel is an important ionic channel that links the bioenergetic metabolism to membrane excitability. It has been shown to play a critical role in vascular permeability and in activation of neutrophils and their subsequent interaction with vessel wall cellular components. The purpose of this study was to investigate whether nicorandil, a novel nitric oxide generator and adenosine triphosphate-sensitive potassium-channel opener, might enhance lung preservation and prevent allograft reperfusion injury. MATERIALS AND METHODS: Fourteen dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1 degree C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (inspired oxygen fraction 1.0) were assessed for 6 hours before the dogs were put to death. After the assessment, activity of allograft myeloperoxidase and protein levels of bronchoalveolar lavage fluid were measured. Control animals (group I, n = 5) received no nicorandil. In group II (n = 5), the donor lung received nicorandil (24 mg/L) in the flush solution. In addition, recipient animals received nicorandil (0.5 mg/kg, intravenously) just before reperfusion, as well as a continuous infusion (0.74 +/- 0.03 mg/kg per hour) during the 6-hour assessment period. In group III (n = 4), glibenclamide, a selective adenosine triphosphate-sensitive potassium-channel blocker, was administered 15 minutes before nicorandil administration to both donor and recipient. The animals in group III received nicorandil in the same regimen as group II. RESULT: Superior gas exchange and hemodynamics were observed in lungs receiving only nicorandil. Allograft myeloperoxidase activity and protein levels in bronchoalveolar lavage fluid were significantly reduced in group II. Glibenclamide eliminated the beneficial effects of nicorandil. CONCLUSIONS: Nicorandil administration in the flush solution and during the reperfusion period ameliorates lung allograft dysfunction, improves blood flow, and reduces pulmonary vascular resistance and myeloperoxidase activity in the transplanted lung. The present study suggests that nicorandil reduces lung allograft reperfusion injury. The beneficial effects of nicorandil may be attributed to its properties as an adenosine triphosphate-sensitive potassium-channel opener.

Physical development of surgically treated patients with primary spontaneous pneumothorax.

STUDY OBJECTIVES: There have been many studies on the physical characteristics at the time of contraction of a primary spontaneous pneumothorax (PSP), but it has not been shown when and how such physical characteristics develop. These issues were investigated. PATIENTS AND DESIGN: Physical development of 27 male patients with PSP were examined. Their physical records were collected with the patients' permission, and standard curves, estimated from the Japanese nationwide records in the year corresponding to the ages of the patients, were plotted as control values. RESULTS: The height of patients was already greater at 6 years of age. It showed a marked increase from 11 to 14 years. The body weight was more than the standard until 9 years, but it became less after age 11, and this difference increased after age 15. Rohrer's index was significantly lower than the standard at all ages, and the difference was particularly large from 11 to 15 years. In the standard group, there was a balance between the annual height and weight gain. In the patient group, annual weight gain was similar to that in the standard group whereas height began to increase 2 years earlier, and as a result, ectomorphy, which was also observed before this age, became marked at this age. CONCLUSIONS: The rapid increase in the vertical dimension of the thorax compared with the horizontal dimension during the period of rapid physical development is considered to affect intrathoracic pressure at the apex of lung, which would have some influence on enhancing cyst formation.

Well-differentiated fetal adenocarcinoma of lung.

Well-differentiated fetal adenocarcinoma (WDFA) histologically resembles pulmonary blastoma, and is thought to be a subtype of pulmonary blastoma which has differentiated epithelial features resembling the fetal lung among its epithelial features and sarcomatous features. We recently encountered one patient who underwent surgery for WDFA. This case is reported with a discussion of the literature. A 33-year-old woman had a tumor shadow in the lower lobe of the right lung. The tumor was diagnosed as pulmonary blastoma as a result of echographic biopsy, and right total pneumonectomy was performed. No sarcomatous features were observed on postoperative histological assessment, and the patient was diagnosed as having WDFA. Its prognosis is believed to tend to be better than that of biphasic blastoma, in which sarcomatous features are mingled with epithelial features. However, it is reported that chemotherapy or radiotherapy has seldom been effective. Complete surgical resection is essential for long-term survival.

Vasoactive intestinal peptide ameliorates reperfusion injury in rat lung transplantation.

BACKGROUND: Vasoactive intestinal peptide (VIP) has been reported to have some properties that provide protection from lung injury. Furthermore, its protective effect in cold storage of donor lungs has been confirmed. We examined its effect and the timing of administration in an in vivo rat lung transplantation model. METHODS: All lungs were flushed with low-potassium dextran-1% glucose solution, and orthotopic left lung transplantations were performed. Rats were divided into four groups (n = 6). Group I received no preservation or storage. Groups II, III, and IV grafts were stored for 18 hours at 4 degrees C. Group II received no VIP. Group III received VIP (0.1 g/ml) via the flush solution. Group IV recipients received VIP (3 microg/kg) intravenously just after reperfusion. Twenty-four hours after transplantation, the right main pulmonary artery and right main bronchus were ligated, and the rats were ventilated with 100% O2 for 5 minutes. Mean pulmonary arterial pressure, peak airway pressure, blood gas analysis, serum lipid peroxide level, tissue myeloperoxidase activity, and wet-dry weight ratio were measured. RESULTS: The partial O2 tension values of groups III and IV were better than group II (groups II, III, and IV: 147.4 +/- 71.4, 402.1 +/- 64.8, 373.4 +/- 81.0 mm Hg; p < 0.05). Peak airway pressure was lower in groups III and IV than in group II (groups II, III, and IV: 19.7 +/- 0.8, 16.7 +/- 0.9. and 16.3 +/- 1.0 mm Hg; p < 0.05). Mean pulmonary arterial pressure in group III was lower than group II (groups II and III: 36.3 +/- 3.0 and 22.1 +/- 2.2 mm Hg; p < 0.01). Wet-dry weight ratio in group III was lower than in groups II and IV (group II, III, and IV: 5.2 +/- 0.2, 4.4 +/- 0.2, and 5.2 +/- 0.3; II vs III; p < 0.05, III vs IV; p < 0.01). Serum lipid peroxide levels in groups III and IV were significantly lower (groups II, III, and IV: 2.643 +/- 0.913, 0.455 +/- 0.147, and 0.325 +/- 0.124 nmol/ml; p < 0.01). CONCLUSION: VIP ameliorates reperfusion injury in an in vivo rat lung transplantation model. Either administration of VIP via the flush solution or systemically just after reperfusion was associated with improved pulmonary function.

Delayed administration of low-dose NPC18915 ameliorates lung ischemia-reperfusion injury.

BACKGROUND: NPC18915, a member of new antiinflammatory agent called nactins (neutrophil activation inhibitors), has been shown to reduce reperfusion injury in rat lung transplantation at high dosage. In vitro studies have demonstrated effectiveness of this compound even at low dosage. We hypothesized that this compound ameliorates lung ischemia reperfusion injury even at low dosage levels if administration is optimally timed. The aim of this study was to determine the efficacy and the best timing for administration of low-dose NPC18915. METHODS: Forty syngeneic rat left lung transplantations were performed. All isografts were flushed with low-potassium dextran-1% glucose solution 20 ml and preserved for 18 hours at 4 degrees C. Animals were divided into four groups. Group I animals (n = 10) served as control subjects. In groups II (n = 10), III (n = 10), and IV (n = 10), NPC18915 (0.04 mg) was added to the flush solution and was administered intravenously (0.4 mg/kg) immediately before reperfusion (group II) and 60 minutes (group III) and 120 minutes (group IV) after reperfusion. Pulmonary function was assessed 24 hours after reperfusion. RESULTS: In group III, oxygenation improved in comparison to group I (247.2 +/- 59.8 versus 76.6 +/- 16.0 mm Hg, p < 0.002). Wet-to-dry weight ratio and graft myeloperoxidase activity were significantly improved (group III versus group I, 6.02 +/- 0.21 versus 7.19 +/- 0.41, p = 0.013) (group III versus group I, 0.093 +/- 0.019 versus 0.207 +/- 0.023 delta optical density/min/mg, p < 0.002). There were no significant differences in CD11b expression. CONCLUSION: These data suggest that delayed administration of NPC18915, 60 minutes after reperfusion, dramatically improves pulmonary graft function.

Carbohydrate selectin inhibitor CY-1503 reduces neutrophil migration and reperfusion injury in canine pulmonary allografts.

BACKGROUND: Neutrophil adhesion is initiated by the interaction of rapidly expressed endothelial selectins with oligosaccharide structures (sialyl Lewis(x) on polymorphonuclear neutrophils (PMN). The carbohydrate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration. METHODS: We evaluated the inhibitory effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs were flushed with modified Euro-Collins solution (1500 ml, 4 degrees C) and preserved for 21 hours at 1 degree C. Left lung allotransplantation was subsequently performed in 14 mongrel dogs. Immediately after transplantation and allograft reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (FIO2 = 1.0). Allograft gas exchange (q 15 minutes) and hemodynamics (q 60 minutes) were assessed. After sacrifice, allograft bronchoalveolar lavage fluid (BALF) PMN count and allograft tissue myeloperoxidase (MPO) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung flush (20 mg/L) and given to the recipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour assessment period. Group II animals (n = 7) received no CY-1503. RESULTS: Gas exchange in group I was superior throughout the assessment period (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 +/- 0.3 x 10(6) PMN/ml compared with 3.9 +/- 1.3 x 10(6) PMN/ml in group II (p < 0.05). Group I allograft MPO activity was 0.21 +/- 0.06 compared with 0.40 +/- 0.02 delta OD/mg/ min in controls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis. CONCLUSIONS: Our observations indicate that selectin inhibition effectively reduces PMN adhesion, migration, and subsequent reperfusion injury in preserved canine lung allografts.