Determinants of Weight Loss following Laparoscopic Sleeve Gastrectomy: The Role of Psychological Burden, Coping Style, and Motivation to Undergo Surgery

Background. The amount of excess weight loss (%EWL) among obese patients after bariatric surgery varies greatly. However, reliable predictors have not been established yet. The present study evaluated the preoperative psychological burden, coping style, and motivation to lose weight as factors determining postoperative treatment success. Methods. The sample included 64 morbidly obese patients with a preoperative BMI of 51±8 kg/m2 who had undergone laparoscopic sleeve gastrectomy (LSG). Well-established questionnaires were applied before surgery to assess the psychological burden in terms of “perceived stress” (PSQ-20), “depression” (PHQ-9), “anxiety” (GAD-7), and “mental impairment” (ISR) as well as coping style (Brief COPE) and motivation to lose weight. %EWL as an indicator for treatment success was assessed on average 20 months after surgery. Results. Based on the %EWL distribution, patients were classified into three %EWL groups: low (14–39%), moderate (40–59%), and high (60–115%). LSG patients with high %EWL reported significantly more “active coping” behavior prior to surgery than patients with moderate and low %EWL. Patients’ preoperative psychological burden and motivation to lose weight were not associated with %EWL. Conclusion. An “active coping” style might be of predictive value for better weight loss outcomes in patients following LSG intervention

An in-vitro and in-vivo trail with molecular and scanning electron microscopic investigation

Titel, Inhaltsverzeichnis 1. Einleitung und Problemstellung 5 1.1 Stand der Forschung - Laparoskopie und Tumorwachstum 5 2. Fragestellung und Ziel der Arbeit 16 3. Methodik 19 3.1 Rasterelektronenmikroskopie 19 3.2 Adhäsionsmolekülexpression auf HT-29-Zellen 27 3.3 Intrazelluläre Kalzium-Messung 34 4. Ergebnisse 37 4.1 Rasterelektronenmikroskopie 37 4.2 Adhäsionsmoleküle auf HT-29-Zellen 49 4.3 Intrazelluläre Kalziumkonzentrationen in HT-29-Zellen 79 5. Diskussion 84 5.1 Einfluß des Pneumoperitoneums auf die rasterelektronenmikroskopische Struktur des Peritoneums 88 5.2 Einfluß von Gas, Druck und pH-Wert auf die Expression von Adhäsionsmolekülen auf Kolonkarzinomzellen (HT-29) 93 5.3 Einfluß von Gas und Druck auf den intrazellulären Kalziumgehalt von Kolonkarzinomzellen (HT-29) 108 6. Zusammenfassung 113 7. Literatur 116 8. Tabellenverzeichnis 130 9. Abbildungsverzeichnis 131 10. Abkürzungsverzeichnis 133 Eidesstattliche VersicherungDie laparoskopische Behandlung intraabdomineller Malignome ist immer noch überschattet von der potentiellen Gefahr, die durch eine Tumorzellverschleppung in die Inzisionen droht. Dabei gibt es Hinweise, dass das für die Laparoskopie benötigte Pneumoperitoneum Konditionen schafft, die für das Tumorwachstum und die Tumormetastasierung vorteilhaft erscheinen. Umfangreiche Berichte von größeren klinischen Serien weisen jedoch darauf hin, dass die Inzidenz an Trokarmetastasen in der laparoskopischen Chirurgie sehr wahrscheinlich weniger als 1% beträgt. Diese Beobachtungen decken sich mit einer erst kürzlich veröffentlichten prospektiv, randomisierten Studie, die zeigen konnte, dass im Vergleich zur konventionellen Kolonchirurgie die laparoskopische Chirurgie zu keinem verstärktem Tumorwachstum führt. Trotz dieser ermutigenden Daten bleiben grundlegende Fragen bezüglich einer möglichen Stimulierung des Tumorwachstums in der Laparoskopie weiterhin unbeantwortet. Deshalb sollen in dieser Arbeit drei tumorphysiologische Fragen beantwortet werden, die eine wichtige Rolle im Bereich der Tumorbiologie haben könnten. Zunächst wird in einem in-vivo Modell untersucht, ob durch die Laparoskopie das Peritoneum von Ratten geschädigt wird. In einem in-vitro Experiment wird untersucht, ob Kohlendioxid, Helium und Druck die Expression von Adhäsionsmoleküle auf Tumorzellen soweit verändern, dass das metastatische Verhalten bzw. das Tumorwachstum der Zellen modifiziert wird. In einem zweiten in-vitro Experiment wird untersucht, ob durch das Pneumoperitoneum das intrazelluläre Kalzium in Tumorzellen soweit verändert wird, daß auch hier eine Veränderung des Zellwachstums hervorgerufen werden könnte. Interessanterweise zeigt unsere in-vivo Studie, dass das Pneumoperitoneum mit den Insufflationsgasen CO2 oder Helium und einem intraabdominellen Druck von 15 mmHg keine Veränderung der morphologischen Struktur des Peritoneums verursacht. Die Adhäsionsmoleküluntersuchungen zeigen kein einheitliches Bild. Es fällt jedoch auf, dass Kohlendioxid einen größeren Einfluss auf die Expression der einzelnen Adhäsionsmoleküle im Vergleich zu Helium hat. Helium bewirkt weder auf E-Cadherin, noch auf CD44-v6 und ICAM-1 einen signifikanten Einfluß. Im Gegensatz dazu scheint Kohlendioxid die Expression der einzelnen Moleküle stärker zu modifizieren. In allen Fällen kommt es eher zu einer Reduktion der Expression von Adhäsionsmolekülen. In unserer letzten Versuchsreihe zeigt sich, dass Kohlendioxid zu einem signifikanten Anstieg des intrazellulären Kalziums in der Tumorzelle führt. Helium dagegen hat keinen Einfluss auf den intrazellulären Kalziumgehalt. Auch hier deutet sich an, dass Kohlendioxid einen stärkeren Einflußs auf die Zellen hat als Helium und somit möglicherweise spezifische Zellmechanismen durch den intrazellulären Kalziumeinstrom beeinflusst. Insgesamt schlussfolgern wir, dass das Pneumoperitoneum mit Kohlendioxid zwar den strukturellen Aufbau des Peritoneums nicht verändert, molekularbiologisch und physiologisch doch in die Funktion der Tumorzelle eingreift. Ob dies allerdings auf die klinische Realität einen Einfluß hat, lässt sich zur Zeit noch nicht eindeutig evaluieren.Laparoscopic treatment of intraabdominal malignancies has always been shadowed by the potential risk of tumor metastasis in the trocar sites. According to previous reports, the pneumoperitoneum which is necessary for laparoscopy could create the right environment promoting tumor growth and metastasis. Yet other reports based on large clinical studies give an incidence of trocar metastasis in laparoscopy lower than 1%. These reports are consistent with the results of a lately published prospective randomised study, which showed that laparoscopic colon surgery does not lead to a higher tumor growth compared to conventional surgery. Despite these reports basic questions concerning the potential stimulation of the tumor growth after laparoscopic surgery remain unclear. In these terms the current study tried to answer three questions about the tumor physiology, which could play a significant role in tumor biology. In an animal model it was initially evaluated whether laparoscopy harms the peritoneal structure in rats. In an in-vitro experiment we additionally analysed whether CO2 or Helium influence the expression of adhesion molecules on tumor cells in a way promoting the metastatic behaviour or growth of tumors. In a second in-vitro experiment the effects of pneumoperitoneum on intracellular Calcium were determined in tumor cells. Interestingly our in-vivo study showed that the pneumoperitoneum with CO2 or Helium up to an intraabdominal pressure of 15 mmHg does not affect the morphological structure of peritoneum. Studies of adhesion molecules show conflicting results. It is impressing though, that CO2 affects the expression of adhesion molecules stronger than Helium. Helium has no significant influence either on E-Cadherin, or on CD44-v6 and ICAM-1, while CO2 seems to modify the expression of several molecules. In all cases a reduction in the expression of adhesion molecules was observed. In our last experiment we observed a CO2 mediated strong increase of the intracellular calcium concentration in the tumor cells. Again no influence was observed with the use of Helium. Therefore CO2 affects cells more strongly than Helium possibly stimulating several intracellular mechanisms related to the intracellular calcium stream. In summary, CO2 pneumoperitoneum does not affect the structural morphology of the peritoneum but does modify molecular and physiological functions of tumor cells. At the moment it remains unclear, whether these observations could have any clinical implications. This has to be further examined with additional clinical studies

The COP9 signalosome, cullin 3 and Keap1 supercomplex regulates CHOP stability and adipogenesis

Summary Obesity is one of the most serious health problems of the 21st century. It is associated with highly increased risk of type 2 diabetes, high blood pressure, cardiovascular disease as well as several cancers. The expansion of the fat tissue needs the differentiation of preadipocytes to adipocytes, a process called adipogenesis. Dysfunction of adipogenesis is a hallmark of obesity and delineation of underlying mechanisms has high priority for identifying targets for pharmacological intervention. Here we investigate the impact of the COP9 signalosome (CSN), a regulator of cullin-RING ubiquitin ligases (CRLs), and of C/EBP homologous protein (CHOP) on the differentiation of LiSa-2 preadipocytes. CHOP induced by piceatannol or by permanent overexpression in LiSa-2 cells blocks adipocyte differentiation as characterized by inhibited fat droplet formation and vascular endothelial growth factor (VEGF) production. Knockdown of the CSN by permanent downregulation of CSN1 in LiSa-2 cells elevates CHOP and retards adipogenesis. The effect of the CSN knockdown on CHOP stability can be explained by the protection of the CRL component Keap1 by the CSN associated ubiquitin-specific protease 15 (USP15). Pulldowns and glycerol gradients reveal that CHOP interacts with a supercomplex consisting of the CSN, cullin 3 and Keap1. Transient knockdown of Keap1 increases CHOP steady state level and retards its degradation. We conclude that CHOP stability is controlled by a CSN-CRL3Keap1 complex, which is crucial for adipogenesis. Our data show that CHOP is a distinguished target for pharmacological intervention of obesity

Weight loss reduces head motion: Revisiting a major confound in neuroimaging

Abstract Head motion during magnetic resonance imaging (MRI) induces image artifacts that affect virtually every brain measure. In parallel, cross‐sectional observations indicate a correlation of head motion with age, psychiatric disease status and obesity, raising the possibility of a systematic artifact‐induced bias in neuroimaging outcomes in these conditions, due to the differences in head motion. Yet, a causal link between obesity and head motion has not been tested in an experimental design. Here, we show that a change in body mass index (BMI) (i.e., weight loss after bariatric surgery) systematically decreases head motion during MRI. In this setting, reduced imaging artifacts due to lower head motion might result in biased estimates of neural differences induced by changes in BMI. Overall, our finding urges the need to rigorously control for head motion during MRI to enable valid results of neuroimaging outcomes in populations that differ in head motion due to obesity or other conditions

Weight loss reduces head motion: Revisiting a major confound in neuroimaging

Abstract Head motion during magnetic resonance imaging (MRI) induces image artifacts that affect virtually every brain measure. In parallel, cross‐sectional observations indicate a correlation of head motion with age, psychiatric disease status and obesity, raising the possibility of a systematic artifact‐induced bias in neuroimaging outcomes in these conditions, due to the differences in head motion. Yet, a causal link between obesity and head motion has not been tested in an experimental design. Here, we show that a change in body mass index (BMI) (i.e., weight loss after bariatric surgery) systematically decreases head motion during MRI. In this setting, reduced imaging artifacts due to lower head motion might result in biased estimates of neural differences induced by changes in BMI. Overall, our finding urges the need to rigorously control for head motion during MRI to enable valid results of neuroimaging outcomes in populations that differ in head motion due to obesity or other conditions

A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro

Background and aims: Helicobacter pylori is the causative agent of gastric diseases and the main risk factor in the development of gastric adenocarcinoma. In vitro studies with this bacterial pathogen largely rely on the use of transformed cell lines as infection model. However, this approach is intrinsically artificial and especially inappropriate when it comes to investigating the mechanisms of cancerogenesis. Moreover, common cell lines are often defective in crucial signalling pathways relevant to infection and cancer. A long-lived primary cell system would be preferable in order to better approximate the human in vivo situation. Methods: Gastric glands were isolated from healthy human stomach tissue and grown in Matrigel containing media supplemented with various growth factors, developmental regulators and apoptosis inhibitors to generate long-lasting normal epithelial cell cultures. Results: Culture conditions were developed which support the formation and quasi-indefinite growth of three dimensional (3D) spheroids derived from various sites of the human stomach. Spheroids could be differentiated to gastric organoids after withdrawal of Wnt3A and Rspondin1 from the medium. The 3D cultures exhibit typical morphological features of human stomach tissue. Transfer of sheared spheroids into 2D culture led to the formation of dense planar cultures of polarised epithelial cells serving as a suitable in vitro model of H. pylori infection. Conclusions: A robust and quasi-immortal 3D organoid model has been established, which is considered instrumental for future research aimed to understand the underlying mechanisms of infection, mucosal immunity and cancer of the human stomach

Erratum : Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

This corrects the article DOI: 10.1038/nm.4484