OPUS 4 | Medizin

Pancreatic resections for advanced M1-pancreatic carcinoma: the value of synchronous metastasectomy (2010)

Stefanie Katharina Seelig Björn Burkert Ansgar Michael Chromik Andrea Tannapfel Waldemar Uhl Mathias H. Seelig

Background. For M1 pancreatic adenocarcinomas pancreatic resection is usually not indicated. However, in highly selected patients synchronous metastasectomy may be appropriate together with pancreatic resection when operative morbidity is low. Materials and Methods. From January 1, 2004 to December, 2007 a total of 20 patients with pancreatic malignancies were retrospectively evaluated who underwent pancreatic surgery with synchronous resection of hepatic, adjacent organ, or peritoneal metastases for proven UICC stage IV periampullary cancer of the pancreas. Perioperative as well as clinicopathological parameters were evaluated. Results. There were 20 patients (9 men, 11 women; mean age 58 years) identified. The primary tumor was located in the pancreatic head (n=9, 45%), in pancreatic tail (n=9, 45%), and in the papilla Vateri (n=2, 10%). Metastases were located in the liver (n=14, 70%), peritoneum (n=5, 25%), and omentum majus (n=2, 10%). Lymphnode metastases were present in 16 patients (80%). All patients received resection of their tumors together with metastasectomy. Pylorus preserving duodenopancreatectomy was performed in 8 patients, distal pancreatectomy in 8, duodenopancreatectomy in 2, and total pancreatectomy in 2. Morbidity was 45% and there was no perioperative mortality. Median postoperative survival was 10.7 months (2.6–37.7 months) which was not significantly different from a matched-pair group of patients who underwent pancreatic resection for UICC adenocarcinoma of the pancreas (median survival 15.6 months; =.1). Conclusion. Pancreatic resection for M1 periampullary cancer of the pancreas can be performed safely in well-selected patients. However, indication for surgery has to be made on an individual basis.

Biological activities of aqueous and organic extracts from tropical marine sponges (2010)

Kristina Sepčić Silke Kauferstein Dietrich Mebs Tom Turk

We report on screening tests of 66 extracts obtained from 35 marine sponge species from the Caribbean Sea (Curaçao) and from eight species from the Great Barrier Reef (Lizard Island). Extracts were prepared in aqueous and organic solvents and were tested for hemolytic, hemagglutinating, antibacterial and anti-acetylcholinesterase (AChE) activities, as well as their ability to inhibit or activate cell protein phosphatase 1 (PP1). The most interesting activities were obtained from extracts of Ircinia felix, Pandaros acanthifolium, Topsentia ophiraphidites, Verongula rigida and Neofibularia nolitangere. Aqueous and organic extracts of I. felix and V. rigida showed strong antibacterial activity. Topsentia aqueous and some organic extracts were strongly hemolytic, as were all organic extracts from I. felix. The strongest hemolytic activity was observed in aqueous extracts from P. acanthifolium. Organic extracts of N. nolitangere and I. felix inhibited PP1. The aqueous extract from Myrmekioderma styx possessed the strongest hemagglutinating activity, whilst AChE inhibiting activity was found only in a few sponges and was generally weak, except in the methanolic extract of T. ophiraphidites.

Optimal management of Alzheimer’s disease patients: clinical guidelines and family advice (2010)

Julia Haberstroh Harald Hampel Johannes Pantel

Family members provide most of the patient care and administer most of the treatments to patients with Alzheimer’s disease (AD). Family caregivers have an important impact on clinical outcomes, such as quality of life (QoL). As a consequence of this service, family caregivers suffer high rates of psychological and physical illness as well as social and financial burdens. Hence, it is important to involve family caregivers in multimodal treatment settings and provide interventions that are both suitable and specifically tailored to their needs. In recent years, several clinical guidelines have been presented worldwide for evidence-based treatment of AD and other forms of dementia. Most of these guidelines have considered family advice as integral to the optimal clinical management of AD. This article reviews current and internationally relevant guidelines with emphasis on recommendations concerning family advice.

Das onkogene Transformationspotential durch die "Gatekeeper"-Mutation T315I in Philadelphia-Chromosom assoziierten BCR/ABL-Fusionsproteinen (2010)

Marion Schüll

Die Entwicklung Philadelphia Chromosom-positiver (Ph+) chronischer myeloischer und akuter lymphatischer Leukämie (CML und ALL) ist auf das Verschmelzen von ABL-und BCR-Gensequenzen zurückzuführen. Die Bildung dieses BCR/ABL-Fusionsprotein führt zu einer konstitutiv gesteigerten ABL-Tyrosinkinase-Aktivität mit der Folge einer Deregulierung vielfältiger intrazellulärer Signalwege und der Induktion des leukämischen Phänotyps. Eine zielgerichtete Inhibierung von BCR/ABL mit Hilfe von ABL-Kinase-Inhibitoren induziert Apoptose in BCR/ABL-transformierten Zellen und hat eine komplette hämatopoetische Remission in Ph+ Leukämie-Patienten in der chronischen Phase zur Folge. Eine große Zahl an Patienten mit fortgeschrittener Ph+ Leukämie erleidet allerdings einen Rückfall und entwickelt Resistenzen gegen die molekularen Therapeutika. Ein Hauptgrund für die Resistenzentwicklung sind Punktmutationen im Bereich der ABL-Tyrosinkinase. Die Punktmutation T315I ist als einzige Mutation gegen alle bisher entwickelten Medikamente resistent. Sie ist auf eine Punktmutation von Threonin zu Isoleucin an einer äußerst kritischen Stelle, der so genannten „Gatekeeper-Position“ zurückzuführen. Die T315I scheint nicht nur die Bindungsaffinität der Kinase- Inhibitoren zu verhindern, sondern erzeugt zusätzliche Eigenschaften, die das leukämogene Potential von BCR/ABL verstärken. Ziel dieser wissenschaftlichen Arbeit war es daher, den Einfluss der T315I auf das transformatorische Potential von BCR/ABL aufzuklären. Es konnte gezeigt werden, dass die T315I sowohl bei p185BCR/ABL, als auch bei p210BCR/ABL zu einem gesteigerten und Faktor-unabhängigen Wachstum führt. Zudem wurde im Rahmen einer Struktur- Funktionsanalyse verdeutlicht, dass die T315I unabhängig von BCR-Sequenzen in der Lage ist, Faktor-unabhängiges Zellwachstum in 32D- und Ba/F3-Zellen, aber nicht klassisches Transformationspotential in Fibroblasten zu vermitteln. 106 Ebenfalls war Gegenstand der experimentellen Arbeiten die Untersuchung, ob die durch die T315I-vermittelte Resistenz gegenüber der Hemmung der Oligomerisierung durch kompetitive Peptide von der Präsenz von BCR-Funktionsdomänen abhängt, welche für die Aktivierung der Ras-Signalwege unerlässlich sind. Es konnte nachgewiesen werden, dass die T315I-Punktmutation nur dann Resistenz gegenüber der Hemmung der Oligomerisierung induziert, wenn BCR-Sequenzen als Ausgangspunkt für den Ras-Signalweg (Tyr 177), in den verwendeten Konstrukten vorhanden sind. Fehlen BCR-Sequenzen, so hemmen die kompetitiven Peptide auch T315I-positive BCR/ABL-Deletionsmutanten. Darüber hinaus wurde im Rahmen dieser Arbeit versucht, neue Lösungsansätze in der Grundlagenforschung aufzuzeigen, indem ein neuartiges Zellkultursystem mit drei BALL- Patienten-abgeleiteten Langzeitkulturen (PDLTCs) angewendet wurde. Die CMPDLTC trägt unmutiertes BCR/ABL, während die KÖ-PDLTC BCR/ABL-T315I positiv ist. Als dritte PDLTC stand die CR als BCR/ABL-negative Zellkultur zur Verfügung. Zum ersten Mal war es mit Hilfe dieses relevanten Zellmodells möglich, die inhibitorische Wirkung des Helix-2-Peptids in primären ALL-PDLTCs zu überprüfen. Es konnten die bisherigen Ergebnisse aus den murinen Zelllinien zur Wirkung der Hemmung der Oligomerisierung bestätigt werden, da auch in diesem Modell die Zellen mit T315I-BCR/ABL resistent gegenüber den kompetitiven Peptiden waren. Zusammenfassend lassen die Daten dieser wissenschaftlichen Arbeit die Schlussfolgerung zu, dass die Punktmutation T315I nicht zum Schwerpunkt in der Erforschung weiterer molekularer Therapeutika erklärt werden sollte. Vielmehr scheint es in naher Zukunft von äußerster Bedeutung zu sein, besonders die Kaskade der aberranten Signaltransduktionswegen mit dem Ausgangspunkt in wesentlichen BCRFunktionsdomänen zu inhibieren. Außerdem stellen die primären Patienten-abgeleiteten Langzeitkulturen eine Möglichkeit dar, die Wirkung neuer molekularer Therapeutika effektiv zu überprüfen und die Pathogenese von Ph+ Leukämien noch besser zu verstehen.

The impact of shift work induced chronic circadian disruption on IL-6 and TNF-α immune responses (2010)

Anke van Mark Stephan W. Weiler Marcel Schröder Andreas Otto Kamila Jauch-Chara Jan David Alexander Groneberg Michael Spallek Richard Kessel Barbara Kalsdorf

AIM: Sleep disturbances induce proinflammatory immune responses, which might increase cardiovascular disease risk. So far the effects of acute sleep deprivation and chronic sleep illnesses on the immune system have been investigated. The particular impact of shift work induced chronic circadian disruption on specific immune responses has not been addressed so far. METHODS: Pittsburgh-Sleep-Quality-Index (PSQI) questionnaire and blood sampling was performed by 225 shift workers and 137 daytime workers. As possible markers the proinflammatory cytokines IL-6 and TNF-alpha and lymphocyte cell count were investigated. A medical examination was performed and biometrical data including age, gender, height, weight, waist and hip circumference and smoking habits were collected by a structured interview. RESULTS: Shift workers had a significantly higher mean PSQI score than day workers (6.73 vs. 4.66; p < 0.001). Day workers and shift workers had similar serum levels of IL-6 (2.30 vs. 2.67 resp.; p = 0.276), TNF-alpha (5.58 vs. 5.68, resp.; p = 0.841) or lymphocytes count (33.68 vs. 32.99, resp.; p = 0.404). Furthermore there were no differences in cytokine levels (IL-6 p = 0.761; TNF-alpha p = 0.759) or lymphocyte count (p = 0.593) comparing the sleep quality within the cohorts. When this calculation of sleep quality was stratified by shift and day workers irrespective of their sleep quality day workers and shift workers had similar serum levels of IL-6, TNF-alpha or lymphocytes count. Multiple linear regression analysis showed a significant correlation of lymphocytes count and smoking habits. CONCLUSION: Shift work induces chronic sleep debt. Our data reveals that chronic sleep debt might not always lead to an activation of the immune system, as we did not observe differences in lymphocyte count or level of IL-6 or TNF-alpha serum concentration between shift workers and day workers. Therefore chronic sleep restriction might be eased by a long-term compensating immune regulation which (in healthy) protects against an overstimulation of proinflammatory immune mechanisms and moderates metabolic changes, as they are known from short-term sleep deprivation or sleep related breathing disorders.

Berlin's medical students' smoking habits, knowledge about smoking and attitudes toward smoking cessation counseling (2010)

Bianca Kusma David Quarcoo Karin Vitzthum Tobias Welte Stefanie Mache Andreas Meyer-Falcke Jan David Alexander Groneberg Tobias Raupach

BACKGROUND: Diseases associated with smoking are a foremost cause of premature death in the world, both in developed and developing countries. Eliminating smoking can do more to improve health and prolong life than any other measure in the field of preventive medicine. Today's medical students will play a prominent role in future efforts to prevent and control tobacco use. METHODS: A cross-sectional, self-administered, anonymous survey of fifth-year medical students in Berlin, Germany was conducted in November 2007. The study explored the prevalence of smoking among medical students. We assessed their current knowledge regarding tobacco dependence and the effectiveness of smoking cessation methods. Students' perceived competence to counsel smokers and promote smoking cessation treatments was also explored. Analyses were based on responses from 258 students (86.6% response rate). RESULTS: One quarter of the medical students surveyed were current smokers. The smoking rate was 22.1% among women, 32.4% among men. Students underestimated smoking-related mortality and the negative effect of smoking on longevity. A considerable number of subjects erroneously assumed that nicotine causes coronary artery disease. Students' overall knowledge of the effectiveness of smoking cessation methods was inadequate. Only one third of the students indicated that they felt qualified to counsel patients about tobacco dependence. CONCLUSIONS: This study reveals serious deficiencies in knowledge and counseling skills among medical students in our sample. The curriculum of every medical school should include a tobacco module. Thus, by providing comprehensive training in nicotine dependence interventions to medical students, smokers will have access to the professional expertise they need to quit smoking.

Radiologische und funktionelle Resultate nach periprothetischer Frakturversorgung / von Susann Elisabeth Poßner (2010)

Susann Poßner

Die vorliegende Arbeit befasst sich mit periprothetischen Frakturen nach endoprotheti-schen Gelenkersatz von Schultergelenk, Hüftgelenk und Kniegelenk. Über einen Zeitraum von 6 Jahren konnten 64 operative Frakturversorgungen bei 59 Patienten identifiziert werden. Diese unterteilten sich in 8 Frakturen des Humerus, sowie 44 Frakturen des Femur nach Hüftgelenkersatz und 12 femorale Frakturen nach Kniegelenkersatz. Die epidemiologischen Daten unseres Kollektivs mit PPF nach Hüft- und Kniegelenker-satz decken sich mit denen der aktuellen Fachliteratur. So wiesen unsere Patienten einen Altersdurchschnitt von 77,7 +/- 11,0 Jahre auf. Ein Großteil (77% der Patienten) war weiblich. Das follow up erfolgte durchschnittlich nach 27,2 +/- 16,8 Monaten. Im Falle einer zementfreien primären Endoprothetik erfolgte die Fraktur früher, nach durchschnittlich 64,6 Monaten, gegenüber 103,4 Monate bei zementierter Prothese (p=0,11). Der Zeitpunkt der PPF lag bei Hüftendoprothesen nach durchschnittlich 96 Monaten und bei Kniegelenkendoprothesen nach durchschnittlich 56 Monaten. Hinsichtlich der Krankenhausliegezeit zeigten sich keine signifikanten Unterschiede. Ebenso war die Mobilisation gemessen am timed „up and go― Test in Abhängigkeit von der Prothesenlokalisation und Versorgungsart nicht signifikant unterschiedlich (Range 22-32 Sekunden). Bei der gezielten Nachuntersuchung von periprothetischen Femurfrakturen nach Hüft-gelenkersatz mit festem Prothesensitz zeigte sich bei der plattenosteosynthetischen Versorgung eine signifikant höhere verfahrensbezogene Komplikationsrate (66,7% gegenüber 18,8 %), p= 0,01. Die beiden Patientenkollektive unterschieden sich hin-sichtlich epidemiologischer Daten (Alter, Geschlecht, Rate an primär zementierten Pro-thesen, follow up) nicht. In der Gesamtzusammenschau bleiben PPF Verletzungen, die eine große Herausfor-derung an die behandelnden Chirurgen stellen. Aufgrund des multimorbiden Patientenkollektivs im hohen Lebensalter mit einer hohen lost to follow up Rate sind retrospektive Analysen meist von geringer Fallzahl. Die Effizienz der jeweiligen Versorgungsart in Abhängigkeit von Prothesentyp, Fraktur-klassifikation und Verwendung von Zement bei der Primärendoprothetik sollte in mulit-zentrischen, randomisiert kontrollierten Studien geprüft werden.

Autistic traits and autism spectrum disorders: the clinical validity of two measures presuming a continuum of social communication skills (2010)

Sven Bölte Eva Westerwald Martin Holtmann Christine M. Freitag Fritz Poustka

Research indicates that autism is the extreme end of a continuously distributed trait. The Social Responsiveness Scale (SRS) and the Social and Communication Disorders Checklist (SCDC) aim to assess autistic traits. The objective of this study was to compare their clinical validity. The SRS showed sensitivities of .74 to .80 and specificities of .69 to 1.00 for autism. Sensitivities were .85 to .90 and specificities .28 to.82 for the SCDC. Correlations with the ADI-R, ADOS and SCQ were higher for the SRS than for the SCDC. The SCDC seems superior to the SRS to screen for unspecific social and communicative deficits including autism. The SRS appears more suitable than the SCDC in clinical settings and for specific autism screening.

Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation (2010)

Selim Kuçi Eva Rettinger Bernhard Voß Gerrit Weber Miriam Stais Hermann Kreyenberg Andre Willasch Zyrafete Kuçi Ewa Koscielniak Stephan Klöss Dorothee von Laer Thomas Klingebiel Peter Bader

Background Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved. Design and Methods Peripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay. Results Cytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRαβ molecules on cytokine-induced killer cells or CD1d on rhabdomyosar-coma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential. Conclusions Our data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation.

Peer-victimization and mental health problems in adolescents: are parental and school support protective? (2010)

Christina Stadler Julia Feifel Sonja Rohrmann Robert Vermeiren Fritz Poustka

The aim of this study was to investigate the frequency and effects of peer-victimization on mental health problems among adolescents. Parental and school support were assumed as protective factors that might interact with one another in acting as buffers for adolescents against the risk of peer-victimization. Besides these protective factors, age and gender were additionally considered as moderating factors. The Social and Health Assessment survey was conducted among 986 students aged 11-18 years in order to assess peer-victimization, risk and protective factors and mental health problems. For mental health problems, the Strengths and Difficulties Questionnaire (SDQ) was used. Effects of peer-victimization on mental health problems were additionally compared with normative SDQ data in order to obtain information about clinically relevant psychopathology in our study sample. Results of this study show that peer-victimization carries a serious risk for mental health problems in adolescents. School support is effective in both male and female adolescents by acting as a buffer against the effect of victimization, and school support gains increasing importance in more senior students. Parental support seems to be protective against maladjustment, especially in peer-victimized girls entering secondary school. Since the effect of peer-victimization can be reduced by parental and school support, educational interventions are of great importance in cases of peer-victimization.

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