Regina Waldmann-Beushausen

Miniaturized HIA microdiagonal pump as left ventricular assist device in a sheep model.

We evaluated the newly developed miniaturized HIA microdiagonal blood pump (MDP) as a continuous flow left ventricular assist device. In a sheep model (n = 6), the MDP was implanted through left lateral thoracotomy and placed paracorporeally with inflow conduit to left atrium and outflow conduit to descending aorta. The sheep were pumped at a mean flow rate of 2.5 L/min for 7 days. Anticoagulation was applied by intravenous heparin administration. Postoperatively, activated clotting time was held stable with values of 200 seconds. During follow-up, blood samples (creatinine kinase, creatinine, glutamic-oxaloacetic transaminase (aspartate aminotransferase) (GOT), glutamate dehydrogenase (GLDH), gamma-GT, plasma-free hemoglobin, and hemoglobine) were taken daily. After 7 days, the sheep were killed for macroscopic examination. Systemic artery pressures remained stable during the whole test period. Because of operative reasons, the hemoglobin value (7.5 ± 0.61 g/dl) decreased perioperatively, but recovered within the test period, whereas creatinine kinase increased initially after thoracotomy, but decreased to normal within days. Renal and liver functions were slightly impaired perioperatively, indicated by temporarily enhanced values of GOT, gamma-GT, GLDH, and creatinine. The MDP did not produce significant hemolysis as measured by plasma-free hemoglobin levels. Wound infections did not occur. We conclude that the MDP ran successfully as an left ventricular assist device for 7 days in sheep has potential for long-term support, and may serve as an alternative to current technologies. Presented data were not obtained in a clinical trial; however, the results are promising enough to proceed with longer duration animal studies.

Intracellular ATP-Binding Cassette Transporter A3 is Expressed in Lung Cancer Cells and Modulates Susceptibility to Cisplatin and Paclitaxel

Patients with advanced-stage bronchial cancer benefit from systemic cytostatic therapy, in particular from regimens integrating cisplatin and taxanes. However, eventual disease progression leads to a fatal outcome in most cases, originating from tumor cells resisting chemotherapy. We here show that the intracellular ATP-binding cassette transporter A3 (ABCA3), previously recognized as critical for the secretion of surfactant components from type 2 pneumocytes, is expressed in non-small-cell lung cancer (NSCLC) cells. With some heterogeneity in a given specimen, expression levels detected immunohistochemically in primary cancer tissue were highest in adenocarcinomas and lowest in small cell lung cancers. Genetic silencing of ABCA3 in the NSCLC cell line models A549, NCI-H1650 and NCI-H1975 significantly increased tumor cell susceptibility to the cytostatic effects of both cisplatin (in all cell lines) and paclitaxel (in two of three cell lines). Taken together, ABCA3 emerges as a modulator of NSCLC cell susceptibility to cytostatic therapy.

Histological changes in neonatal kidneys after cardiopulmonary bypass and deep hypothermic circulatory arrest.

BACKGROUND Renal failure after open-heart surgery is a serious complication resulting in increased mortality and morbidity. The aim of the study was to find out whether different strategies for open-heart surgery would result in renal histological differences in a neonatal animal model. METHODS The renal tissue of newborn piglets was examined after mild hypothermic cardiopulmonary bypass (CPB group; n = 10), deep hypothermic circulatory arrest (DHCA group; n = 8), instrumentation without extracorporeal circulation (sham; n = 3), and the data were compared with those of normal porcine neonatal kidneys (control; n = 6). The severity of tissue damage was graded using a 4-point scoring system (0: normal morphology, 3: severe damage). Apoptotic cells and granulocytes were counted. RESULTS The histological score was higher in all groups compared with controls ( P < 0.05) and higher in the CPB group compared with the DHCA group ( P < 0.05). More apoptotic cells and granulocytes were found in the CPB group compared with controls and the DHCA group ( P < 0.05). CONCLUSIONS Although changes in the kidney tissue of newborn piglets are detectable after any cardiac procedure, changes are more profound after cardiopulmonary bypass with mild hypothermia.

The Effect of Cardiopulmonary Bypass and Hypothermic Circulatory Arrest on Hepatic Histology in Newborn Animals: An Experimental Study

Still little is known about the effect of cardiac surgery on neonatal hepatic tissue. We examined the effect of cardiopulmonary bypass (CPB) and the effect of deep hypothermic circulatory arrest (DHCA) on neonatal hepatic tissue. Liver biopsies of neonatal piglets were taken after CPB (n = 4), after DHCA (n = 5), and after surgery without CPB (non-CPB; n = 3). Additionally, findings were compared to those of control piglets (n = 9). The liver specimens were fixed, stained with hematoxylin and eosin, and scored regarding inflammatory reaction, hepatocellular edema, and apoptosis. Inflammation score of treated groups was higher than in control; CPB 2.5 ± 0.5, DHCA 1.6 ± 0.4, non-CPB 1.2 ± 0.6, control 0.4 ± 0.3 (P < 0.001 CPB and DHCA vs. control; P < 0.05 non-CPB vs. control). Hepatic cell edema was more evident after DHCA (score 2.0 ± 0.4 vs. 0.2 ± 0.3 in control and 0.6 ± 0.5 after CPB; P < 0.001 and P < 0.05, respectively). The highest apoptotic cell count was in the non-CPB group (22.3 ± 6.3 vs. 11.4 ± 3.6 in control and 8.9 ± 5.4 after CPB; P < 0.05). The present study showed that (i) surgical trauma induces hepatic cell apoptosis; (ii) CPB increases hepatic inflammatory reaction; and (iii) DHCA amplifies hepatic cell edema.

The effect of amifostine on lung ischaemia–reperfusion injury in rats

OBJECTIVES Lung ischaemia-reperfusion injury (LIRI) frequently occurs after lung transplantation or cardiac surgery with cardiopulmonary bypass, thus increasing postoperative morbidity and mortality. As LIRI is associated with the release of reactive oxygen species and a subsequent inflammatory reaction, we tested whether amifostine, a thiol and free radical scavenger, has a beneficial effect on LIRI. METHODS A total number of 72 Wistar rats were subjected to LIRI with or without a single or double dose of amifostine (100 mg/kg, intraperitoneally). Experimental induction of LIRI was performed by clamping either the left lung hilum or the pulmonary artery alone for 60 min, followed by 90 min of reperfusion. Control groups consisted of LIRI and NaCl, a sham group and a no intervention group (baseline). At the end of the experiments, the left lung was analysed by quantitative RT-PCR of inflammatory marker gene expression, western blot of activated nuclear factor-κB (NF-κB) and light and electron microscopy. RESULTS In placebo and amifostine groups, the expression levels of pro-inflammatory markers were increased significantly and to a similar extent independent of the type of ischaemia induction. In contrast, amifostine reduced the activation of NF-κB in comparison with placebo. This effect was present independent of the type of ischaemia or the application of a single or double dose of amifostine. However, oedema formation, blood-gas barrier damage and inflammatory reaction were similar in all amifostine or placebo LIRI groups. CONCLUSIONS Despite a significant reduction in NF-κB activation, amifostine failed to decrease the inflammatory response and structural changes induced by LIRI in this experimental setting.

Periodontal Bacterial DNA and Their Link to Human Cardiac Tissue: Findings of a Pilot Study.

Background The aim of this pilot study was to detect correlations of microbiological DNA, inflammatory proteins, and infection parameters in patients with periodontal disease (PD) and valvular heart disease (VHD). Methods A perioperative comprehensive dental examination for the investigation of periodontal status, including sampling of specific subgingival bacteria, was performed in 10 patients with indication for surgery of aortic valve stenosis with or without concomitant myocardial revascularization. Standard protocol biopsies were taken from right atrium (A), left septal myocardium (M), and aortic valve (V). Eleven periodontal pathogens DNA in oral and cardiac tissue samples (A/M/V) were analyzed using polymerase chain reaction. For cardiac tissue samples, Western blot analysis of LPS‐binding protein (LBP), immunohistochemical (IHC) detection of LBP‐big42, LPS‐binding protein receptor (CD14), and macrophages (CD68), as well as inflammation scoring measurement were performed. Results Periodontitis was present in all patients with severe intensity in 7, moderate in 2 and mild in one patient. Same bacterial DNA was detected in A, M, and V in different distribution, and detection was more often in atrium than in myocardium or valve tissue. Morphological investigation revealed increased extracellular inflammatory cell migration. In IHC markers of LBP, CD68 and CD14 showed positive findings for all patients in atrium and myocardium. Conclusion Our results demonstrate the presence of oral bacterial DNA in human cardiac tissue, as well as inflammatory markers potentially indicating connection of PD and VHD. Further investigation is necessary to confirm these preliminary data.

Apigenin Reduces NF-κB and Subsequent Cytokine Production as Protective Effect in a Rodent Animal Model of Lung Ischemia-Reperfusion Injury

ABSTRACT Purpose: Lung ischemia–reperfusion injury (LIRI) can complicate lung transplantation or cardiac surgery with cardiopulmonary bypass, increasing morbidity and mortality. In LIRI, pro-inflammatory cytokines are activated, reactive oxygen species are generated and nuclear factor-κB (NF-κB) is up-regulated, altering lung mechanics. We tested the effect of the flavonoid apigenin on a rodent model of LIRI. Methods: Thirty-seven Wistar rats were subjected to LIRI with or without a single or double dose of apigenin. Induction of LIRI involved sternotomy and clamping of either the left lung hilum or the pulmonary artery alone for 30 min, followed by 60 min of reperfusion. Control groups consisted of LIRI plus NaCl, a sham group and a baseline group. At the end of the experiments, both lungs were analyzed by RT-PCR, Western blot, and light microscopy. Results: In placebos, the expression levels of pro-inflammatory markers were increased in both lungs significantly, whereas NF-κB was markedly up-regulated. Administration of apigenin reduced the activation of NF-κB and the expression of TNFα, iNOS, and IL-6. These effects were observed in total lung ischemia. Histology showed greater hemorrhage and exudation in the pulmonary periphery of all groups, whereby damage was practically absent in the central lung regions of the apigenin animals. A second dose of apigenin did not outclass a single one. Conclusions: We conclude that apigenin given intraperitoneally can reduce activation of NF-κB and also attenuate the expression of TNFα, IL-6, and iNOS in a surgical model of LIRI. The surgical procedure itself can induce significant damage to the lungs.

ABCA3 Phenotype in Non-Small Cell Lung Cancer Indicates Poor Outcome

Background: ATP-binding cassette transport protein A3 (ABCA3) is expressed in non-small cell lung cancer (NSCLC). We hypothesize that high-level ABCA3 expression may have a negative prognostic impact in patients with NSCLC. Methods: In 89 patients with NSCLC and curative intended surgery, we analyzed postoperative immunohistochemistry staining of primary tumors (anti-ABCA3) and clinicopathological parameters. We used a unidimensional four point score (FPS) system for intensity assessment and, furthermore, a combined bidimensional scoring of intensity and quantity resulting in the positive index (PI). Results: Former or never-smokers were more likely to have intermediate or strong ABCA3 unidimensional expression (FPS) compared with current smokers (p < 0.01). Patients >65 years of age had a higher probability of intermediate/strong ABCA3 expression (FPS) than younger patients (p < 0.05). In PI measurement, there were no significant correlations between ABCA3 and clinicopathological parameters. Patients with high-level PI had a significantly worse disease-free survival as well as overall survival than patients with low-level PI (p < 0.05). Conclusions: High-level PI of ABCA3 in NSCLC showed poor disease-free and overall survival in this patient cohort, potentially indicating the relevance of ABCA3 in lung cancer. This observation needs to be validated in larger series.

Contents Vol. 84, 2013

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wisc. M. Dietel, Berlin M.S. Ernstoff , Lebanon, N.H. M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buff alo, N.Y. M.J. Kelley, Durham, N.C. P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buff alo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buff alo, N.Y. A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Lausanne M.S. Tallman, Chicago, Ill. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buff alo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief