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High consumption of ultraprocessed foods (UPFs) continues to draw significant public health interest because of the associated negative health outcomes. Metabolomics can contribute to the understanding of the biological mechanisms through which UPFs may influence health.

Zusammenfassung: Jedes gesunde Gefäß wird luminal von einer endothelialen Glykokalyx ausgekleidet, die mit dem Blutstrom interagiert und Filterfunktionen an der Gefäßwand wahrnimmt. Obwohl diese Struktur bereits vor fast 70 Jahren entdeckt wurde, blieb ihre physiologische Bedeutung lange Zeit unterschätzt. Neueren Erkenntnissen zufolge ist die Glykokalyx, neben den Endothelzellen selbst, ein wesentlicher Bestandteil der vaskulären Barriere. Die unterschiedlichen kolloidosmotischen Gradienten inner- und unterhalb dieser Struktur haben mittlerweile zu einer Modifizierung der Starling-Gleichung geführt. Das Interstitium weist in vielen Abschnitten eine Proteinkonzentration auf, die mit derjenigen des Plasmas vergleichbar ist. Der einwärts gerichtete Gradient, der Wasser und Protein im Gefäßsystem zurückhält, entsteht unterhalb der Glykokalyx durch selektive Proteinfilterung über diese Struktur hinweg. Die endotheliale Glykokalyx besitzt damit als weitere kompetente vaskuläre Permeabilitätsbarriere eine Schlüsselfunktion nicht nur für perioperative Flüssigkeits- und Proteinverschiebungen ins Gewebe, sondern scheint darüber hinaus eine bedeutende Rolle in der Pathophysiologie von Diabetes, Arteriosklerose, Sepsis und Ischämie/Reperfusion (I/R) und den damit verbunden vaskulären Dysfunktionen zu spielen. Die fragile Glykokalyx kann durch chirurgische Eingriffe, Trauma, Ischämie/Reperfusion, Sepsis oder Entzündungsmediatoren wie Tumor-Nekrose-Faktor- (TNF-)α zerstört werden; dies kann zu Leukozytenadhäsion, Thrombozytenaggregation und Ödembildung führen. Neuere Studien konnten zeigen, dass eine Protektion dieser Schicht nicht nur einen Schutz der Gefäßbarriere darstellt, sondern ein wichtiger Bestandteil einer rationalen perioperativen Flüssigkeitstherapie sein kann.

Burnout among surgeons has been attributed to increased workload and decreased autonomy. Although prior studies have examined burnout among transplant surgeons, no studies have evaluated burnout in abdominal transplant surgery fellows. The objective of our study was to identify predictors of burnout and understand its impact on personal and patient care during fellowship. A survey was sent to all abdominal transplant surgery fellows in an American Society of Transplant Surgeons–accredited fellowship. The response rate was 59.2% (n = 77) and 22.7% (n = 17) of fellows met criteria for burnout. Fellows with lower grit scores were more likely to exhibit burnout compared with fellows with higher scores (3.6 vs 4.0, P= .026). Those with burnout were more likely to work >100 hours per week (58.8% vs 27.6%, P= .023), have severe work‐related stress (58.8% vs 22.4%, P= .010), consider quitting fellowship (94.1% vs 20.7%, P< .001), or make a medical error (35.3% vs 5.2%, P= .003). This national analysis of abdominal transplant fellows found that burnout rates are relatively low, but few fellows engage in self‐care. Personal and program‐related factors attribute to burnout and it has unacceptable effects on patient care. Transplant societies and fellowship programs should develop interventions to give fellows tools to prevent and combat burnout. A national survey of transplant surgery fellows shows that nearly 25% meet criteria for burnout and few engage in self‐care.

Imaging techniques can provide information about the tumor non-invasively and have been shown to provide information about the underlying genetic makeup. Correlating image-based phenotypes (radiomics) with genomic analyses is an emerging area of research commonly referred to as “radiogenomics” or “imaging-genomics”. The purpose of this study was to assess the potential for using an automated, quantitative radiomics platform on magnetic resonance (MR) breast imaging for inferring underlying activity of clinically relevant gene pathways derived from RNA sequencing of invasive breast cancers prior to therapy. We performed quantitative radiomic analysis on 47 invasive breast cancers based on dynamic contrast enhanced 3 Tesla MR images acquired before surgery and obtained gene expression data by performing total RNA sequencing on corresponding fresh frozen tissue samples. We used gene set enrichment analysis to identify significant associations between the 186 gene pathways and the 38 image-based features that have previously been validated. All radiomic size features were positively associated with multiple replication and proliferation pathways and were negatively associated with the apoptosis pathway. Gene pathways related to immune system regulation and extracellular signaling had the highest number of significant radiomic feature associations, with an average of 18.9 and 16 features per pathway, respectively. Tumors with upregulation of immune signaling pathways such as T-cell receptor signaling and chemokine signaling as well as extracellular signaling pathways such as cell adhesion molecule and cytokine-cytokine interactions were smaller, more spherical, and had a more heterogeneous texture upon contrast enhancement. Tumors with higher expression levels of JAK/STAT and VEGF pathways had more intratumor heterogeneity in image enhancement texture. Other pathways with robust associations to image-based features include metabolic and catabolic pathways. We provide further evidence that MR imaging of breast tumors can infer underlying gene expression by using RNA sequencing. Size and shape features were appropriately correlated with proliferative and apoptotic pathways. Given the high number of radiomic feature associations with immune pathways, our results raise the possibility of using MR imaging to distinguish tumors that are more immunologically active, although further studies are necessary to confirm this observation.

Vascular anastomoses are complex surgical procedures, performed in time-sensitive circumstances, making intraoperative teaching more challenging. We sought to evaluate whether a vascular anastomosis simulation was effective in developing resident skills.

BACKGROUND:Critical hypoperfusion and metabolic derangement are frequently encountered with refractory vasospasm. Endovascular rescue therapies (ERT) have proven beneficial in selected cases. However, angioplasty (AP) and intraarterial lysis (IAL) are measures of last resort and prospective, quantitative results regarding the efficacy (cerebral oxygenation, metabolism) are largely lacking.OBJECTIVE:To evaluate the efficacy of ERTs for medically refractory vasospasm using multimodal, continuous event neuromonitoring.METHODS:To detect cerebral compromise in a timely fashion, sedated patients with aneurysmal subarachnoid hemorrhage received continuous neuromonitoring (ptiO2measurement, intraparenchymal microdialysis). ERT (AP and/or IAL) was considered in cases of clinically relevant vasospasm refractory to conservative treatment measures. Oxygen saturation and cerebral and systemic metabolism before and after events of ERT was recorded.RESULTS:We prospectively included 13 consecutive patients and recorded a total of 25 ERT events: AP (n = 10), IAL (n = 11), or both (AP + IAL, n = 4). Average cerebral ptiO2was 10 ± 11 torr before and 49 ± 22 torr after ERT (P< .001), with a lactate-pyruvate ratio decreasing from 146.6 ± 119.0 to 27.9 ± 10.7 after ERT (P< .001). Comparable improvement was observed for each type of intervention (AP, IAL, or both). No significant alterations in systemic metabolism could be detected after ERTCONCLUSION:Multimodal event neuromonitoring is able to quantify treatment efficacy in subarachnoid hemorrhage-related vasospasm. In our small cohort of highly selected cases, ERT was associated with improvement in cerebral oxygenation and metabolism with reasonable outcome. Event neuromonitoring may facilitate individual and timely optimization of treatment modality according to the individual clinical course.

Wie ein Notentspannungssystem für Behälter von reaktiven Stoffen mit adiabatischer Reaktionskalorimetrie praktisch dimensioniert werden kann, beschreibt dieser Beitrag.

The era of living donor liver transplantation (LDLT) began in 1988 with the first successful case reported by Dr. Russell Strong in Australia and the first series published by Dr. Christoph Broelsch in 1991. Living donation was proposed as an option for pediatric patients with minimal access to appropriately sized deceased donor allografts. The first living donor transplants were performed using left lateral section grafts from adults to children. Early utilization of left lateral section grafts for adult recipients provided inadequate liver mass and resulted in poor outcomes.

The results from this study indicate that quantitative MR imaging radiomics shows promise as a means for image-based phenotyping in assessing the risk of cancer recurrence.

Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.

Whereas paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. In addition, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor antagonism by mifepristone treatment in primary human cells have never been described.

Despite new treatments for castrate-resistant prostate cancer (CRPC), the prognosis of patients with CRPC remains bleak due to acquired resistance to androgen receptor (AR)-directed therapy. The glucocorticoid receptor (GR) and AR share several transcriptional targets, including the anti-apoptotic genes serum and glucocorticoid-regulated kinase 1(SGK1) and Map kinase phosphatase 1(MKP1)/dual specificity phosphatase 1 (DUSP1). Because GR expression increases in a subset of primary prostate cancer (PC) following androgen deprivation therapy, we sought to determine whether GR activation can contribute to resistance to AR-directed therapy. We studied CWR-22Rv1 and LAPC4 AR/GR-expressing PC cell lines following treatment with combinations of the androgen R1881, AR antagonist MDV3100, GR agonist dexamethasone, GR antagonists mifepristone and CORT 122928, or the SGK1 inhibitor GSK650394. Cell lines stably expressing GR (NR3C1)-targeted shRNA or ectopic SGK1-Flag were also studied in vivo. GR activation diminished the effects of the AR antagonist MDV3100 on tumor cell viability. In addition, GR activation increased prostate-specific antigen (PSA) secretion and induced SGKIand MKP1/DUSPgene expression.Glucocorticoid-mediated cell viability was diminished by a GR antagonist or by co-treatment with the SGK1 inhibitor GSK650394. In vivo, GR depletion delayed castrate-resistant tumor formation, while SGK1-Flag-overexpressing PC xenografts displayed accelerated castrate-resistant tumor initiation, supporting a role for SGK1 in GR-mediated CRPC progression. We studied several PC models before and following treatment with androgen blockade and found that increased GR expression and activity contributed to tumor-promoting PC cell viability. Increased GR-regulated SGK1 expression appears, at least in part, to mediate enhanced PC cell survival. Therefore, GR and/or SGK1 inhibition may be useful adjuncts to AR blockade for treating CRPC.

Urban growth and transformation across the world are presenting great challenges for the comprehension and management of urban landscape change. Comparative urban morphology makes it possible to identify urban forms common to different geographical regions, while helping to distinguish unique historical characteristics and developments important for towns and cities in the hunt for place identity and prestige. The fringe-belt concept provides a frame of reference for depicting, explaining, and comparing the physical structure and historical development of urban landscapes. The walled cities of Pingyao, China and Como, Italy possess well-preserved historical urban environments that reflect the urban development traditions of their respective cultures. Newly available cartographic evidence and field work reveal critical differences between the embedded fringe belts of the two cities resulting from different historico-geographical dynamics. Pingyao's single composite fringe belt and Como's three distinct belts challenge current understanding of urban structural processes and argue for more focused urban landscape management.

Detailed knowledge on the dependence of material and component properties on the processing conditions during melt processing of carbon nanotube-polymer composites is of importance for product quality and economic efficiency. Combining of in-line process monitoring, laboratory tests, development of material models and implementation into process simulation can contribute to optimise the manufacturing process and the electrical and mechanical properties of the final plastic parts.

Since the detection of morphine by the pharmacologist Friedrich Sertürner in 1806, opioids have been used as potent centrally acting analgesics. In addition to the central site of action, peripheral endogenous opioid analgesic systems have been extensively studied, especially in the past two decades. This review is not only mentioned to give a brief summary in this well investigated field of peripheral opioid receptors, but also to highlight the role of peripheral opioid receptors in other physiological and pathophysiological conditions.

Adhesion of polymorphonuclear neutrophils (PMN) to coronary endothelium is a key event for cardiac ischemia/reperfusion injury. Adhesion molecules are normally harbored within the glycocalyx, clothing every healthy vascular endothelium, but shed by ischemia/reperfusion. Our aim was to show whether protection of the glycocalyx with either hydrocortisone or antithrombin can reduce postischemic leukocyte adhesion. Isolated guinea pig hearts, perfused with Krebs-Henseleit buffer, were subjected to 20 min of warm (37°C) no-flow ischemia and consecutive 10 min of reperfusion, either in the absence or presence of hydrocortisone (10 g/mL) or antithrombin (1 U/mL). An intracoronary bolus of 3 × 106PMN was applied at the end of reperfusion but without prior contact to the drugs. The sequestration of PMN was calculated from the difference between coronary input and output of cells. Expression of the integrin CD11b on PMN was measured before and after coronary passage. Ischemia/reperfusion induced severe degradation of the glycocalyx (coronary venous syndecan-1 release, 171 ± 15 ng/g heart vs. basal, 19 ± 2 ng/g; heparan sulfate, 5.27 ± 0.28 g/g vs. basal, 0.26 ± 0.06 g/g) and increased PMN adhesion (38.1% ± 3.5% vs. basal, 11.7% ± 3.1%). Hydrocortisone and antithrombin both not only reduced glycocalyx shedding (syndecan-1 release, 34 ± 6 ng/g and 26 ± 5 ng/g; heparan sulfate, 1.96 ± 0.24 g/g and 1.28 ± 0.2 g/g, respectively), but also PMN adhesion (17.3% ± 2.2% and 25.4% ± 3.3%, respectively) after ischemia/reperfusion. Electron microscopy revealed a mostly intact coronary glycocalyx after pretreatment with either drug. Activation of PMN upon coronary passage was not influenced. Preservation of the glycocalyx mitigates postischemic PMN adhesion. Preconditioning with either hydrocortisone or antithrombin should, thus, alleviate vascular leakage, tissue edema, and inflammation.

Because of the small size of in situmammary cancers in mouse models, high-resolution imaging techniques are required to effectively observe how lesions develop, grow and progress over time. The purpose of this study was to use magnetic resonance (MR) imaging to track in vivothe transition from in situneoplasia to invasive cancer in a transgenic mouse model of human cancer. MR images of 12 female C3(1) SV40 Tag mice that develop mammary intraepithelial neoplasia (MIN) were obtained. MIN is believed to be similar to human ductal carcinoma in situ(DCIS) and is considered a precursor of invasive tumors. Images were serially obtained from 10-21 weeks of age at 2-3 week intervals. MIN lesions were identified based on their morphology on MR images. Lesions were followed over time and several lesion features were measured including volume, growth rate and morphology. For those MIN lesions that progressed to invasive cancer the progression time was measured. Overall, 21 MIN lesions were initially detected at an average initial volume of 0.3 ± 0.2 mm3with an average growth rate of -0.15 ± 0.66 week-1. Even though all mice were inbred to express the SV40 Tag transgene in the mammary epithelium and expected to develop invasive carcinoma, the individual MIN lesions took vastly different progression paths: (i) 9 lesions progressed to invasive tumors with an average progression time of 4.6 ± 1.9 weeks; (ii) 2 lesions regressed, i.e., were not detected on future images; and (iii) 5 were stable for over 8 weeks, and were demonstrated by a statistical model to represent indolent disease. To our knowledge, the results reported here are the first measurements of the timescale and characteristics of progression from in situneoplasia to invasive carcinoma and provide image-based evidence that DCIS may be a non-obligate precursor lesion with highly variable outcomes. In addition, this study represents a first step towards developing methods of image acquisition for identifying radiological characteristics that might predict which in situneoplasias will become invasive cancers and which are unlikely to progress.

Major causes of death after heart transplantation are right ventricular pump failure and, chronically, cardiac allograft vasculopathy. Traditional preservation techniques focus on immediate cardioplegia, without particularly considering vascular demands. Recently, the endothelial surface layer, composed of the endothelial glycocalyx and plasma proteins, was discovered to play a major role in vascular barrier function, edema formation, and leukocyte-to-endothelial interaction. The impact of augmenting a traditional preservation solution with plasma colloid albumin was therefore investigated.

Orthotopic liver transplantation (OLT) continues to be the only remedy for end-stage liver disease. In an attempt to decrease the ever-widening gap between organ donor and recipient numbers, and ultimately make more livers amenable to transplantation, we characterized the healthy human liver’s response to ischemia and reperfusion-induced injury during transplantation. This was carried out by transcriptional profiling using cDNA microarray to identify genes whose expression was modulated at the 1-h postreperfusion time point. We observed that the map kinase phosphatase-1/dual-specificity phosphatase-1 (MKP-1/DUSP1) mRNA was strongly and significantly upregulated. Validation of this observation was carried out using reverse transcriptase-polymerase chain reaction (RT–PCR), immunoblotting and immunohistochemistry. In addition, we characterized the signaling pathways regulating MKP-1 expression using the human hepatoma cell line HepG2. Finally, by combining MKP-1 silencing with reperfusion-associated stresses, we reveal the preferential role of this protein in attenuating the activity of the JNK and p38MAPKpathways, and the resulting apoptosis, making MKP-1 a potential target for therapeutic intervention.

Orthotopic liver transplantation (OLT) continues to be the only remedy for end-stage liver disease. In an attempt to decrease the ever-widening gap between organ donor and recipient numbers, and ultimately make more livers amenable to transplantation, we characterized the healthy human liver's response to ischemia and reperfusion-induced injury during transplantation. This was carried out by transcriptional profiling using cDNA microarray to identify genes whose expression was modulated at the 1-h postreperfusion time point. We observed that the map kinase phosphatase-1dual-specificity phosphatase-1 (MKP-1DUSP1) mRNA was strongly and significantly upregulated. Validation of this observation was carried out using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting and immunohistochemistry. In addition, we characterized the signaling pathways regulating MKP-1 expression using the human hepatoma cell line HepG2. Finally, by combining MKP-1 silencing with reperfusion-associated stresses, we reveal the preferential role of this protein in attenuating the activity of the JNK and p38MAPKpathways, and the resulting apoptosis, making MKP-1 a potential target for therapeutic intervention.

AbstractRapid heating by x-rays and ions in Inertial Fusion Energy (IFE) chambers will produce stress waves in dry chamber walls, in some cases leading to damage that will ultimately fail the structure. These waves can affect the surface or propagate to the substrate and produce delamination. Hence, it is important that these waves be understood. Models exist for thermally induced stress waves resulting from surface heating, but models with volumetric heating have not been presented for IFE conditions. In this paper we develop models for elastic stresses caused by rapid volumetric heating in a half-space. The stress wave models are obtained analytically for heating distributions which are both uniform over a finite region and exponentially decaying over the entire depth. These two cases cover the relevant heating for a typical IFE threat. Results are given for both x-ray and ion heating using threats from a direct drive target developed for the High Average Power Laser (HAPL) target.

SGK-1 (serum- and glucocorticoid-regulated kinase-1) is a stress-induced serine/threonine kinase that is phosphorylated and activated downstream of PI3K (phosphoinositide 3-kinase). SGK-1 plays a critical role in insulin signalling, cation transport and cell survival. SGK-1 mRNA expression is transiently induced following cellular stress, and SGK-1 protein levels are tightly regulated by rapid proteasomal degradation. In the present study we report that SGK-1 forms a complex with the stress-associated E3 ligase CHIP [C-terminus of Hsc (heat-shock cognate protein) 70-interacting protein]; CHIP is required for both the ubiquitin modification and rapid proteasomal degradation of SGK-1. We also show that CHIP co-localizes with SGK-1 at or near the endoplasmic reticulum. CHIP-mediated regulation of SGK-1 steady-state levels alters SGK-1 kinase activity. These data suggest a model that integrates CHIP function with regulation of the PI3K/SGK-1 pathway in the stress response.

Glucocorticoid receptor (GR) activation has recently been implicated in the initiation of anti-apoptotic signaling pathways in epithelial cell lines grown in culture. However, the evidence that GR-mediated inhibition of tumor cell apoptosis is the mechanism that diminishes chemotherapy effectiveness in vivo is limited. We therefore initiated a breast cancer xenograft study to examine whether or not pretreatment with GCs decreases tumor response to chemotherapy by inhibiting tumor cell apoptosis. Here we report a significant decrease in paclitaxel-induced apoptosis in xenografts from mice pretreated with dexamethasone (Dex). A significant difference in apoptosis in xenografts from Dex/paclitaxel versus paclitaxel treated animals was seen eight days following initiation of chemotherapy. Nine days later, mice treated with Dex/paclitaxel had significantly larger tumors compared with those that received paclitaxel alone (p=0.032). Dex pretreatment did not significantly affect tumor cell proliferation rates. Taken together, these results demonstrate that systemic Dex administration results in significantly reduced breast cancer xenograft apoptosis in the context of chemotherapy treatment. We also found that systemic Dex treatment results in upregulation of the anti-apoptotic gene MKP-1 and downregulation of pro-apoptotic Bid and TRAIL genes in tumor cells six hours following Dex treatment. These in vivo gene expression changes correlated with significant inhibition of chemotherapy-induced apoptosis. Interestingly, the decreased chemotherapeutic response of Dex-pretreated tumors persisted for several weeks following treatment. These data suggest that GR-mediated transcriptional regulation of pro- and anti-apoptotic genes contributes to the mechanism through which GCs decrease paclitaxel-induced apoptosis.

Bronchopleural fistula is a complication of lung surgery or infectious or malignant lung disease. Management of these fistulas remains an unsolved problem in ventilated patients and no “gold standard” treatment has been established to date. Various nonsurgical and surgical techniques have been described, but there is no generally accepted or evidence based treatment strategy. We describe the case of a 74- year-old man, suffering from idiopathic kappa-cryoglobulinemia for more than 10 years. As a consequence of his underlying disease he developed lobar pneumonia, pneumothorax and a large bronchopleural fistula of the right middle lobe bronchus. Despite continuous intercostal chest drainage and a lung protective ventilation strategy we neither achieved control of the air leak nor closure of the fistula in the first two weeks of treatment. In order to identify the origin of the bronchopleural fistula, a 4F Fogarty embolectomy catheter was inserted into the right middle lobe bronchus under continuous radiological control and, in order to close the air leak, was blocked afterwards. In addition, a blood clot was administered through the embolectomy catheter to seal the large liquid-filled cavity distal to the bronchus block. Nevertheless, only partial occlusion of the fistula could be achieved. Complete and long-lasting occlusion of the fistula was possible after the right middle lobe bronchus was additionally occluded by oxidized regenerated cellulose proximal to the bronchus block via a flexible bronchoscope. We conclude that closure of large bronchopleural fistulas is achievable by a combination of three “geasy to use” techniques and discuss this case in context with previous publications. Das Auftreten einer bronchopleuralen Fistel stellt nach wie vor eine intensivmedizinische Problemsituation dar, für die bislang keine einheitlichen Behandlungsstandards entwickelt werden konnten. Dies wird durch die große Vielzahl der in der Literatur vorgeschlagenen problemlösenden Maßnahmen verdeutlicht. Mit einer Inzidenz von 0,8 bis 15% der Fälle treten bronchopleurale Fisteln als Komplikation in der Thoraxchirurgie auf. Ohne vorausgehendes OP-Trauma entwickeln sie sich meist im Zusammenhang mit pulmonalen bakteriellen Infektionen auf dem Boden unterschiedlicher Grunderkrankungen. Wir beschreiben den Fall eines Patienten mit plasmapherese-pflichtiger IgM/IgG-Kappakryoglobulinämie, bei dem es als Folge einer abszedierenden Staphylokokkenpneumonie zur Ausbildung eines Pneumothorax mit großer bronchopleuraler Fistel im Bereich des rechten Mittellappens kam. Trotz mehrfacher Drainage und Anwendung einer lungenprotektiven Beatmung konnte die Fistel, deren Leckagevolumen bis zu 50% des Tidalvolumens betrug, zunächst nicht geschlossen werden. In einem zweizeitigen Vorgehen wurde daher der zuführende Lappen- Bronchus mit Hilfe eines Fogarty-Ballon-Katheters geblockt, eine distal des Ballons gelegene Seromhöhle mit einem Eigenblutpatch gefüllt und letztlich der Bronchus proximal des Ballonkatheters mit oxidierter regenerierter Cellulose abgedichtet. Durch diese Kombination konservativer Maßnahmen konnte ein dauernder Fistelverschluss erreicht werden. Die beschriebene Behandlungsmethode wird im Zusammenhang mit einer ausführlichen Literaturdarstellung diskutiert.

Zusammenfassung Bereits vor rund 20 Jahren veröffentlichte Peter Stewart seine Abhandlung über eine moderne quantitative Analytik des Säure-Basen-Haushalts [88, 89]. Folgt man seinen Interpretationen, so wird die traditionelle Lehre vom Säure-Basen-Haushalt erheblich in Frage gestellt. Das wichtigste physikochemische Prinzip, das in Körperflüssigkeiten immer erfüllt sein muß, ist das Prinzip der Elektroneutralität. Es existieren dabei 3 verschiedene Komponenten in biologischen Flüssigkeiten, die diesem Prinzip unterliegen: a) Wasser, das nur in geringen Teilen in H + und OH − dissoziiert vorliegt, b) „starke“, d. h. vollständig dissoziierte und damit chemisch nicht mit anderen Substanzen reagierende, Elektrolyte und körpereigene Substanzen, wie Laktat und c) „schwache“, d. h. unvollständig dissoziierte, Substanzen. Peter Stewart unterschied nun strikt zwischen abhängigen und unabhängigen Variablen und beschrieb damit tatsächlich eine neue Ordnung des Säure-Basen-Haushalts. Die 3 abhängigen Variablen (die Bikarbonatkonzentration [Bic −], der pH und damit auch die Wasserstoffionenkonzentration [H +]) sind den unabhängigen Variablen vollständig untergeordnet, können sich also nur verändern, wenn die 3 unabhängigen Variablen dies zulassen. Zu den unabhängigen Variablen zählen: 1. der Kohlendioxidpartialdruck, 2. die Gesamtkonzentration aller schwachen Säuren ([A −] (Stewart nannte diese A TOT) und 3. die Differenz der starken Ionen (SID). [A −] erschließt sich aus der Albumin (Alb)- und der Phosphatkonzentration (Pi): [A −]=[Alb×(0,123×pH−0,631)]+[Pi×(0,309×pH−0,469)]. Mit Hilfe der messbaren Ionenkonzentrationen lässt sich eine apparente SID (oder „Bedside-SID“) berechnen: SID=[Na +]+[K +]−[Cl −]−Laktat. Betrachtet man die metabolischen Störungen des Säure-Basen-Haushalts, so sind nach der Terminologie von Stewart Veränderungen von pH, [H +] und [Bic −] nur möglich, wenn sich entweder die SID oder [A −] verändert. Nimmt z. B. die SID ab (etwa im Rahmen einer Hyperchloridämie), so bewirkt dieser Zuwachs an unabhängigen negativen Ladungen eine Abnahme der abhängigen negativen Ladungen in Form von [Bic −] mit dem entsprechenden Resultat einer Acidose (und vice versa). Damit wird aber beispielhaft bei der hyperchlorämen Acidose, die durch den Chloridanstieg bedingte Abnahme der SID als Ursache der Acidose identifiziert. Umgekehrt resultiert z. B. aus einer Abnahme von [A −] (etwa im Rahmen einer Hypoalbuminämie) ein Anstieg von [Bic −] und damit eine Alkalose (ebenfalls vice versa). Mit Hilfe dieser Analytik können also völlig neue Säure-Basen-Störungen, wie etwa die „hyperchloräme Acidose“ oder die „hypoalbuminäme Alkalose“ (die natürlich auch kombiniert vorliegen können), diagnostiziert werden, die der klassischen Säure-Basen-Analytik verschlossen waren. Damit kann diese Analytik zu einem vertieften Verständnis der Mechanismen, denen der Säure-Basen-Haushalt unterliegt, führen.

Zusammenfassung Auch heute ist die Suche nach dem idealen Inhalationsanästhetikum nicht abgeschlossen. Die Mitte der 90er-Jahre in Deutschland eingeführten Inhalationsanästhetika Desfluran und Sevofluran zeichnen sich durch niedrige Blut-Gas-Verteilungskoeffizienten aus. Dies spiegelt sich in günstigen pharmakokinetischen Eigenschaften wieder. Hohe hämodynamische Stabilität ist besonders für Sevofluran zu erwähnen. Als Nachteil einiger Substanzen ist eine potenzielle Organtoxizität zu nennen. Enfluran und Sevofluran zeigen hypothetisch nephrotoxische Eigenschaften. Abbauprodukte im Absorberkalk sind vor allem für Sevofluran (Compound-A-Bildung) sowie Desfluran (CO-Bildung) erwähnenswert. Gegenüber intravenösen Anästhetika zeichnen sich volatile Anästhetika durch kardio- und zerebroprotektive Eigenschaften aus.

The halogenated inhalational anaesthetics halothane, enflurane, isoflurane and desflurane can produce metabolic hepatocellular injury in humans to a variable extent. During metabolism of these anaesthetics, tissue acetylation occurs due to the formation of reactive intermediates. Proteins modified by acetylation may constitute neo-antigens with a potential for triggering an antibody-mediated immune response. The likelihood of suffering post-operative immune hepatitis depends on the amount of the anaesthetic metabolized and is thereby considerably less with enflurane, isoflurane or desflurane compared with halothane. Plasma inorganic fluoride concentrations are regularly increased after sevoflurane. Elevated inorganic fluoride concentrations have been associated with nephrotoxicity following methoxyflurane anaesthesiabut not after sevoflurane. Another source of concern is the products of degradation from reactions with carbon dioxide absorbents. Most important is compound A, which has been shown to exhibit nephrotoxicity in rodents. However, no significant changes in renal function parameters have been reported in surgical patients.

The serum and glucocorticoid-induced protein kinase gene (sgk-1) encodes a multifunctional kinase that can be phosphorylated and activated through a phosphatidylinositol 3-kinase-dependent signaling pathway. In many cell types, endogenous SGK-1 steady-state protein levels are very low but can be acutely up-regulated after glucocorticoid receptor-mediated transcriptional activation; in breast epithelial and cancer cell lines, this up-regulation is associated with promotion of cell survival. We and others have noted that ectopically introduced full-length SGK-1 is poorly expressed, although SGK-1 lacking the first 60 amino acids (delta60SGK-1) is expressed at much higher-fold protein levels than wild-type SGK-1 in both human embryonic kidney 293T and MCF10A mammary epithelial cells. In this report, we demonstrate for the first time that the low steady-state expression level of SGK-1 is due to polyubiquitination and subsequent degradation by the 26S proteasome. Deletion of the amino-terminal 60 amino acids of SGK-1 results in a mutant SGK-1 protein that is neither efficiently polyubiquitinated nor degraded by the 26S proteasome, accounting for the higher steady-state levels of the truncated protein. We also demonstrate that a subset of SGK-1 localizes to the plasma membrane and that the polyubiquitin-modified SGK-1 localizes to a membrane-associated fraction of the cell. Taken together, these data suggest that a significant fraction of SGK-1 is membrane-associated and ubiquitinated. These findings are consistent with the recently described role of SGK-1 in phosphorylating the membrane-associated protein Nedd4-2 and the integral membrane Na+/H+ exchanger isoform 3 (NHE3) and suggest a novel mechanism of regulation of SGK-1.

Erik Homburger Erikson was one of the most important representatives of psychoanalysis after the Second World War. This short article can afford no more than highlighting some fundamental positions of his complex oeuvre. With his open-mindedness, his creative spirit and his charming humor he was regarded as one of the last grand seigneurs in his field. He concentrated in his person fascinatingly the work as psychotherapeut and scientist and the roles of a writer, an expert in the field of cultural criticism and a public educator. His wide scope including psychodynamic approach, the commitment to social criticism and the public rejection of tyranny, rassism and war shaped the spirit of the whole epoch of the Sixties and Seventies of the last century. Erik Homburger Erikson war einer der bedeutendsten Vertreter der Psychoanalyse nach dem 2. Weltkrieg. Aus seinem komplexen Werk lassen sich auf wenigen Seiten gewiss nur einige Grundpositionen hervorheben. In seiner Weltoffenheit, seiner kreativen geistigen Energie und seinem liebenswürdigen Humor galt er als einer der letzten Grandseigneurs seines Fachgebiets, der in faszinierender Weise seine Arbeit als Psychotherapeut und Wissenschaftler mit der Rolle des Schriftstellers, Kulturhistorikers und Volkspädagogen verbinden konnte. Seine Mischung aus tiefenpsychologischer Betrachtung, gesellschaftskritischem Engagement und ethischer Besinnung, sein entschiedenes Eintreten gegen Gewaltherrschaft, Rassismus und Krieg prägte in den 60er- und 70er-Jahren des 20. Jahrhunderts das Denken einer ganzen Ära.

We previously demonstrated that activation of the glucocorticoid receptor (GR) initiates an antiapoptotic signal in the immortalized human mammary epithelial cell line MCF10A that is dependent on the GR's transcriptional activity. In this study, we show that the survival role of GR activation extends to protecting human breast cancer cells undergoing apoptosis after growth factor deprivation. Serum and glucocorticoid-regulated kinase-1 (sgk), a gene previously identified as a direct transcriptional target of the activated GR in a rat mammary tumor cell line, was rapidly induced after GR activation in human mammary epithelial cells. Furthermore, in the absence of all growth factors, ectopic sgkexpression inhibited apoptosis, suggesting that SGK is a survival kinase. Finally, kinase-dead SGK expression inhibited the protection from apoptosis usually seen after GR activation. These findings suggest that SGK is an important downstream target of GR-mediated survival signaling and that it is distinct from other survival kinases because it can be primarily regulated at the level of transcription.

Zusammenfassung: Nach bisherigem Kenntnisstand ist der Gehalt an Alkalimetallhydroxiden in Atemkalken wesentlich für die Bildung von Compound A (CpA) aus Sevofluran (Sevo) verantwortlich. Insbesondere das Kaliumhydroxid (KOH), weniger das Natriumhydroxid (NaOH), reagiert im Laborversuch stark mit Sevofluran. Mit dieser klinischen Studie sollte untersucht werden, ob die Verwendung eines KOH-freien Atemkalks während Niedrigflussnarkosen (0,8 l/min Frischgasfluss) mit Sevofluran bei laparoskopischen Cholezystektomien tatsächlich zu einer Verminderung der CpA-Exposition führt. In die Studie wurden 30 Patienten eingeschlossen. Bei jeweils 15 Patienten wurde entweder Sodasorb (SO) oder KOH-freier Soda Lime (SL) verwendet. Von der SO-Gruppe mussten 3 Patienten auf Grund von technischen Problemen bei der CpA-Messung ausgeschlossen werden. Neben demographischen Daten wurden Vital- und Beatmungsparameter sowie die Konzentrationen von Sevofluran und Kohlendioxid dokumentiert. Die durchschnittlichen endtidalen Sevoflurankonzentrationen betrugen 1,94±0,17 (SO) bzw. 1,97±0,15 (SL) Vol.-%, die Gesamtexposition gegenüber Sevofluran 1,52±0,36 (SO) und 1,64±0,47 (SL) MAC-h (n. s.). Die maximale inspiratorische CpA-Konzentration war in der SL-Gruppe signifikant höher (19,6±2,8 vs. 11,7±4,1 ppm, p<0,001). Der alleinige Verzicht auf KOH in NaOH-haltigen Atemkalken führt daher nicht zwangsläufig zu einer Verminderung von CpA.

ABSTRACTAnalysis of amino-terminus mutants of c-Myc has allowed a systematic study of the interrelationship between Myc's ability to regulate transcription and its apoptotic, proliferative, and transforming functions. First, we have found that c-Myc-accelerated apoptosis does not directly correlate with its ability to transactivate transcription using the endogenous ornithine decarboxylase (ODC) gene as readout for transactivation. Furthermore, deletion of the conserved c-Myc box I domain implicated in transactivation does not inhibit apoptosis. Second, the ability of c-Myc to repress transcription, using the gadd45 gene as a readout, correlates with its ability to accelerate apoptosis. A conserved region of c-Myc implicated in mediating transrepression is absolutely required for c-Myc-accelerated apoptosis. Third, a lymphoma-derived Thr58Ala mutation diminishes c-Myc-accelerated apoptosis through a decreased ability to induce the release of cytochrome cfrom mitochondria. This mutation in a potential phosphorylation site does not affect cell cycle progression, providing genetic evidence that induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc. Finally, we show that the increased ability of Thr58Ala mutant to elicit cellular transformation correlates with its diminished ability to accelerate apoptosis. Bcl-2 overexpression blocked and the lymphoma-associated Thr58Ala mutation decreased c-Myc-accelerated apoptosis, and both led to a significant increase in the ability of Rat1a cells to form colonies in soft agar. This enhanced transformation was greater in soft agar containing a low concentration of serum, suggesting that protection from apoptosis is a mechanism contributing to the increased ability of these cells to proliferate in suspension. Thus, we show here for the first time that, in addition to mutations in complementary antiapoptotic genes, c-Myc itself can acquire mutations that potentiate neoplastic transformation by affecting apoptosis independently of cell cycle progression.

Analysis of amino-terminus mutants of c-Myc has allowed a systematic study of the interrelationship between Myc's ability to regulate transcription and its apoptotic, proliferative, and transforming functions. First, we have found that c-Myc-accelerated apoptosis does not directly correlate with its ability to transactivate transcription using the endogenous ornithine decarboxylase (ODC) gene as readout for transactivation. Furthermore, deletion of the conserved c-Myc box I domain implicated in transactivation does not inhibit apoptosis. Second, the ability of c-Myc to repress transcription, using the gadd45 gene as a readout, correlates with its ability to accelerate apoptosis. A conserved region of c-Myc implicated in mediating transrepression is absolutely required for c-Myc-accelerated apoptosis. Third, a lymphoma-derived Thr58Ala mutation diminishes c-Myc-accelerated apoptosis through a decreased ability to induce the release of cytochrome cfrom mitochondria. This mutation in a potential phosphorylation site does not affect cell cycle progression, providing genetic evidence that induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc. Finally, we show that the increased ability of Thr58Ala mutant to elicit cellular transformation correlates with its diminished ability to accelerate apoptosis. Bcl-2 overexpression blocked and the lymphoma-associated Thr58Ala mutation decreased c-Myc-accelerated apoptosis, and both led to a significant increase in the ability of Rat1a cells to form colonies in soft agar. This enhanced transformation was greater in soft agar containing a low concentration of serum, suggesting that protection from apoptosis is a mechanism contributing to the increased ability of these cells to proliferate in suspension. Thus, we show here for the first time that, in addition to mutations in complementary antiapoptotic genes, c-Myc itself can acquire mutations that potentiate neoplastic transformation by affecting apoptosis independently of cell cycle progression.

Abstract: Adherent platelets in the coronary system can impair cardiac pump function. The volatile anesthetics sevoflurane, halothane, and isoflurane have been shown to reduce platelet adhesion. Additionally, an inhibitory effect on platelet cyclo-oxygenase-dependent formation of thromboxane A2 (TxA2) has been proposed for sevoflurane. Therefore, we analyzed the influence of sevoflurane on cardiac performance and TxA2 production after intracoronary application of platelets in isolated guinea pig hearts. Isolated guinea pig hearts perfused with Krebs-Henseleit buffer and performing pressure-volume work were employed. We compromised myocardial function by subjecting hearts to ischemia (20 min low-flow plus 10 min stopped-flow) and reperfusion. During low-flow perfusion the coronary endothelium was stimulated by thrombin prior to and during infusion of a bolus of 108 washed human platelets. Intervention groups contained either sevoflurane in a concentration being equivalent to 1 MAC in the platelet suspension or in the perfusate or 1 �M SQ29,548 (an isoprostane- and thromboxane-receptor antagonist) in the perfusate. The parameter external heart work (EHW), determined pre- and postischemically, served as criterion for loss of myocardial function. Additionally, formation of transudate and the production of TXA2 were measured during the reperfusion phase. Coronary perfusion pressure and myocardial production of lactate and consumption of pyruvate were also determined. Adherent platelets significantly enhanced loss of EHW after ischemia and reperfusion, but strongly attenuated coronary vascular leak. Sevoflurane reduced platelet adhesion when applied to the perfusate, but not when given only to the platelet suspension. However, platelets pretreated with sevoflurane lost their cardiodepressive effects, as did platelets in hearts treated with SQ29,548. Surprisingly, TXA2 formation in hearts was not different after platelet application in comparison to the ischemia control group, but was significantly reduced when sevoflurane was applied to the perfusate. Neither metabolic parameters, coronary perfusion pressure, vascular leak nor glycoprotein expression of platelets were influenced by sevoflurane. Conclusions: 1) Pretreatment of hearts with sevoflurane reduced intracoronary platelet adhesion, most likely via an endothelial mechanism. 2) Pretreatment of platelets with sevoflurane does not reduce platelet adhesion, but nevertheless averts cardiodepressive effects derived from or generated by adherent platelets. 3) Transudate formation of hearts during reperfusion was reduced after platelet application, independent of the adherence of platelets.

A case of thoracic diastematomyelia associated with acute disc herniation is reported. The female patient noted sensory and motor symptoms at 49 years of age, four months before hospitalization. Myelography, myelo-computerized tomography and nuclear resonance tomography of the thoracic spine and cord showed the region of diastematomyelia with an additional disc herniation at T 6/7. The bone spur and the disc was successfully excised. Post-operatively, the patient's deficits improved.