The influence of positive end-expiratory pressure on stroke volume variation and central blood volume during open and closed chest conditions.

OBJECTIVE: Intermittent positive pressure ventilation and positive end-expiratory pressure (PEEP) affect cardiac preload. Their effect is dependent on chest wall compliance. This study compares the effects of intermittent positive pressure ventilation and PEEP on stroke volume variation and central blood volume during open and closed chest conditions. MATERIALS AND METHODS: Fourteen anesthetized and mechanically ventilated pigs (25-40 kg) were studied. Central blood volume was assessed using global end-diastolic volume and right ventricular end-diastolic volume measured by thermodilution. Further, left and right ventricular stroke volume variations were determined with ultrasonic flow probes placed around the pulmonary artery and ascending aorta, respectively. Measurements were performed during mechanical ventilation without and with PEEP (15 cmH(2)O) in open and closed chest conditions. RESULTS: With the chest closed mean arterial pressure, cardiac output, stroke volume, global end-diastolic volume, and right ventricular end-diastolic volume were significantly lower when compared to open chest conditions. Concomitantly, right ventricular, but not left ventricular stroke volume variation increased significantly. Applying PEEP led to a significant reduction of cardiac output, stroke volume and right ventricular end-diastolic volume, with a concomitant increase in left and right ventricular stroke volume variation both during open and closed chest conditions (all P-values<0.05). CONCLUSIONS: We conclude that PEEP increases right and left ventricular stroke volume variation both during open and closed chest conditions. The concomitant reduction of right ventricular end-diastolic volume further indicates that PEEP has a preload reductive effect during open chest conditions, too.     

Hemodilution and intravenous perflubron emulsion as an alternative to blood transfusion: effects on tissue oxygenation during profound hemodilution in anesthetized dogs

BACKGROUND: Intravenously administered perfluorocarbon (PFC) emulsions increase oxygen solubility in plasma. PFC might therefore temporarily replace red cells (RBCs) lost during intraoperative hemorrhage. In patients who have undergone hemodilution, the return of autologous blood may be delayed by the administration of PFC, and autologous RBCs may be saved for transfusion after surgical bleeding is stopped and PFC is cleared by the reticuloendothelial system. STUDY DESIGN AND METHODS: In 22 anesthetized, hemodiluted dogs (hemoglobin [Hb] 7 g/dL) breathing 100-percent O2, an intraoperative volume-compensated blood loss was simulated. The efficacy of three therapeutic regimens in maintaining tissue oxygenation was compared: 1) RBC group (n = 7): maintenance of a Hb > 7 g per dL by transfusion of autologous RBCs; 2) PFC group (n = 7): bolus application of a second-generation PFC emulsion (60% wt/vol perflubron) and further acute normovolemic hemodilution (ANH) to a Hb of 3 g per dL; and 3) control group (n = 7): further ANH alone to a Hb of 3 g per dL. Systemic and myocardial oxygenation status and tissue oxygenation were assessed. RESULTS: Autologous RBCs transfused to maintain a Hb of 7 g per dL preserved hemodynamics and tissue oxygenation during blood loss. In the PFC and control groups, heart rate and cardiac index increased significantly in response to further ANH. Tissue oxygenation was not different in the PFC and the RBC groups. Direct comparison of the PFC and control groups revealed better tissue oxygenation in the PFC group, as reflected by significantly higher mixed venous, coronary venous, and local tissue pO2 on liver and skeletal muscle. CONCLUSION: Bolus intravenous administration of 60- percent (wt/vol) perflubron emulsion and further hemodilution from a Hb of 7 g per dL to one of 3 g per dL were as effective as autologous RBC transfusion in maintaining tissue oxygenation during volume-compensated blood loss designed to mimic surgical bleeding.     

Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients

Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.     

MMP7 is a target of the tumour-associated antigen EpCAM

Epithelial cell adhesion molecule (EpCAM) is a single-transmembrane protein, which is involved in numerous cellular processes including cell adhesion, proliferation, maintenance of stemness of embryonic cells and progenitors, migration and invasion. Activation of signal transduction by EpCAM is warranted by regulated intramembrane proteolysis and nuclear translocation of the intracellular domain EpICD. Here, we describe matrix metalloproteinase 7 (MMP7) as a target gene of EpCAM signalling viaEpICD nuclear translocation. EpCAM and MMP7 expression pattern and levels positively correlated in vitro and in vivo, and were strongly elevated in primary carcinomas of the head and neck area. Hence, MMP7 is a novel target of EpCAM signalling.     

Hyperoxic ventilation reduces six-hour mortality after partial fluid resuscitation from hemorrhagic shock

Ventilation with 100% oxygen (Fio(2) 1.0; hyperoxic ventilation; HV) as an alternative to red blood cell transfusion enables survival in otherwise lethal normovolemic anemia. The aim of the present study was to investigate whether HV as a supplement to fluid infusion therapy could also restore adequate tissue oxygenation and prevent death in otherwise lethal hemorrhagic shock. In 14 anesthetized pigs ventilated on room air (Fio(2) 0.21), hemorrhagic shock was induced by controlled withdrawal of blood (target mean arterial pressure 35-40 mmHg) and maintained for 1 h. Subsequently, the animals were partially fluid-resuscitated (i.e., replacement of lost plasma volume) either with hydroxyethyl starch (6% HES, 200/0.5) alone (G 0.21) or with HES supplemented by HV (G 1.0). After completion of partial fluid resuscitation, all animals were followed up for the next 6 h. Five of seven animals of G 0.21 died within the 6-h observation period (i.e., 6-h mortality 71%). Death was preceded by a continuous increase of the serum concentrations of arterial lactate and persistent tissue hypoxia. In contrast to that, all animals of G 1.0 survived the 6-h observation period without lactic acidosis and with improved tissue oxygenation (i.e., 6-h mortality 0%; G 0.21 versus G 1.0 P < 0.05). In anesthetized pigs submitted to lethal hemorrhagic shock, the supplementation of partial fluid resuscitation with HV improved tissue oxygenation and enabled survival for 6 h.     

Relevance of PTEN loss in brain metastasis formation in breast cancer patients

Introduction

With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Therefore, our aim was to identify molecular markers associated with the development of brain metastases in breast cancer.

Methods

Patterns of chromosomal aberrations in primary breast tumors and brain metastases were compared with array-comparative genetic hybridization (CGH). The most significant region was further characterized in more detail by microsatellite and gene-expression analysis, and finally, the possible target gene was screened for mutations.

Results

The array CGH results showed that brain metastases, in general, display similar chromosomal aberrations as do primary tumors, but with a notably higher frequency. Statistically significant differences were found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (P < 0.01; false discovery rate (fdr) < 0.04). Allelic imbalance (AI) patterns at 10q were further verified in 77 unmatched primary tumors and 21 brain metastases. AI at PTEN loci was found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared with primary tumors from patients without relapse (18%; P = 0.003) or relapse other than brain tumors (12%; P = 0.006). Loss of PTEN was especially frequent in HER2-negative brain metastases (64%). Furthermore, PTEN mRNA expression was significantly downregulated in brain metastases compared with primary tumors, and PTEN mutations were frequently found in brain metastases.

Conclusions

These results demonstrate that brain metastases often show very complex genomic-aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation.     

Akute normovol?mische H?modilution (ANH) Effekte der ANH auf die diastolische Funktion des linken Ventrikels Effekte der ANH auf die diastolische Funktion des linken Ventrikels

Isch?miebedingte Ver?nderungen der linksventrikul?ren (LV) Relaxationseigenschaften gehen h?ufig entsprechenden EKG-Ver?nderungen voraus. Im Rahmen der vorliegenden tierexperimentellen Untersuchung sollte gekl?rt werden, ob eine durch akute normovol?mische H?modilution (ANH) induzierte Verdünnungsan?mie (H?matokrit, HKT, 20%) mit Ver?nderungen der diastolischen LV-Funktion einhergeht.