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Background: Gastrointestinal hormones (GIHs) are crucial for the regulation of a variety of physiological functions and have been linked to hunger, satiety, and appetite control. Thus, they might constitute meaningful biomarkers in longitudinal and interventional studies on eating behavior and body weight control. However, little is known about the physiological levels of GIHs, their intra-individual stability over time, and their interaction with other metabolic and lifestyle-related parameters. Therefore, the aim of this pilot study is to investigate the intra-individual stability of GIHs in normal-weight adults over time. Methods: Plasma concentrations of ghrelin, leptin, GLP-1 (glucagon-like-peptide), and PP (pancreatic polypeptide) were assessed by enzyme-linked immunosorbent assay (ELISA) in 17 normal-weight, healthy adults in a longitudinal design at baseline and at follow-up six months later. The reliability of the measurements was estimated using intra-class correlation (ICC). In a second step, we considered the stability of GIH levels after controlling for changes in blood glucose and hemoglobin A1 (HbA1c) as well as self-reported physical activity and dietary habits. Results: We found excellent reliability for ghrelin, good reliability for GLP1 and PP, and moderate reliability for leptin. After considering glucose, HbA1c, physical activity, and dietary habits as co-variates, the reliability of ghrelin, GLP1, and PP did not change significantly, the reliability of leptin changed to poor reliability. Conclusions: The GIHs ghrelin, GLP1, and PP demonstrated good to excellent test–retest reliability in healthy individuals, a finding that was not modified after adjusting for glucose control, physical activity, or dietary habits. Leptin showed only moderate to poor reliability, which might be linked to weight fluctuations, albeit small, between baseline and follow-up assessment in our study sample. Together, these findings support that ghrelin, GLP1, and PP might be further examined as biomarkers in studies on weight control, with GLP1 and PP serving as anorexic markers and ghrelin as an orexigenic marker. Additional reliability studies in obese individuals are necessary to verify or refute our findings for this cohort.

Introduction Precisely locating benign upper gastrointestinal tumors during laparoscopic-endoscopic surgery remains difficult and inaccurate. We describe reverse laser-supported diaphanoscopy (RLSD) for locating gastrointestinal tumors during laparoscopic surgery and present prospective evaluation results of the first cases. Materials and methods We studied 13 patients [women:men=7:6; mean age, 67 (range, 41 to 83) y] who underwent gastroscopic-laparoscopic rendezvous procedures during 2015 to 2018. Surgery duration, marking duration, and specimen resection size were recorded. The largest and smallest specimen resection margins were measured. Results After locating tumors using RLSD, patients underwent successful resections. Histopathologic examination confirmed 5 cases of gastrointestinal stromal tumor; 3, neuroendocrine tumors; 2, heterotopic pancreatic tissue; 1, leiomyoma; 1, adenoma; 1, hyperplastic polyp. We employed 4 to 6 marks, depending on tumor location and size. The average marking duration was 14 minute (1 to 21 min); the average surgery duration, 73 minute (37 to 143 min). The smallest resection median margin was 2.0 mm (1.0 to 5.0 mm); the largest, 7.0 mm (2.0 to 12.0 mm). Conclusions RLSD precisely locates gastric benign tumors during laparoscopic-endoscopic rendezvous procedures.

Introduction: Pancreatico-colonic fistula (PCF) is a rare adverse effect secondary to severe acute or chronic pancreatitis and potentially life-threatening because of abdominal sepsis. Ove...

Purpose: The implantation of a gastric balloon (also known as intragastric balloon) is an established and reversible endoscopic procedure for adiposity therapy. Structural changes of the stomach wall are expected to occur with gastric balloon implantation; however, until now these changes have rarely been investigated. Methods: We compared the histological structure of the stomach wall after gastric-sleeve resection in a group of patients following gastric balloon implantation and a group without previous gastric balloon implantation. Results: Following gastric balloon implantation, the tunica muscularis was found to be significantly thicker than without gastric balloon implantation. The enlarging of the tunica muscularis is not caused by hyperplasia of the leiomyocytes, but by hypertrophy of the leiomyocytes and an increase in collagen fibers (fibrosis). Conclusion: A longer-lasting hypertrophy of the tunica muscularis, particularly in the corpus, should be taken into account when surgical treatment follows gastric balloon implantation. The staple suture height should be adjusted to the altered tissue composition since reduced tissue elasticity must be expected due to fibrosis.

// Lars Ivo Partecke 1, * , Andre Kading 1, * , Dung Nguyen Trung 1 , Stephan Diedrich 1 , Matthias Sendler 2 , Frank Weiss 2 , Jens-Peter Kuhn 3 , Julia Mayerle 2 , Katharina Beyer 4 , Wolfram von Bernstorff 1 , Claus-Dieter Heidecke 1 , Wolfram Kesler 1 1 Department of General, Visceral, Thoracic and Vascular Surgery, University Medicine, Greifswald, Germany 2 Department of Internal Medicine A, University Medicine, Greifswald, Germany 3 Department of Experimental Radiology, University Medicine, Greifswald, Germany 4 Current address: Department of General, Visceral and Vascular Surgery, Charite–University Medicine, Campus Benjamin Franklin, Berlin, Germany * These authors contributed equally to this work and share first authorship Correspondence to: Andre Kading, email: andre.kaeding@uni-greifswald.de Keywords: vagus nerve, TNFα, pancreatic cancer, macrophages, murine cancer model Received: September 06, 2016 Accepted: January 23, 2017 Published: February 02, 2017 ABSTRACT This study analyses the effects of vagotomy on tumor growth and survival in a murine, pancreatic cancer model in wild-type and TNFα-knockout (–/–) mice. Throughout many operative procedures in the upper gastrointestinal tract the partial or complete transection of the vagus nerve or its local nerve fibers is unavoidable. Thereby its anti-inflammatory effects in residual tumor tissue may get lost. This effect may be mediated by tumor-associated macrophages (TAM) secreting TNFα. In an orthotopic murine pancreatic cancer model subdiaphragmatic vagotomy versus sham surgery was performed. The impact on tumor growth was monitored in wild type and TNFα –/– mice using MRI. TAMs as well as expression levels of TNFα were analyzed using immunohistochemistry. The role of TNFα on tumor growth and migration was examined in vitro . Vagotomised mice showed increased tumor growth with macroscopic features of invasive growth and had a shorter survival time. The loss of vagal modulation led to significantly increased TNFα levels in tumors and considerably elevated numbers of TAMs. In vitro TNFα significantly stimulated growth ( p 0.05). Vagotomy can increase tumor growth and worsen survival in a murine pancreatic cancer model mediated through TAMs and TNFα. Hence, the suppression of TAMs and the modulation of TNFα dependent pathways could offer new perspectives in immunotherapies of pancreatic cancer patients especially with remaining vital tumor cells and lost vagal modulation.

Chronic stress could promote tumour growth and reduce survival of pancreatic cancer patients via beta-adrenergic receptors of tumour cells. We have tested the impact of chronic acoustic and restraint stress on tumour development in an orthotopic syngeneic murine model of pancreatic cancer.Tumour-bearing C57BL/6 mice exposed to chronic stress had 45% (p = 0.0138) higher circulating steroid and 111% (p = 0.0052) higher adrenal tyrosine hydroxylase levels. Their immune response was significantly suppressed: The in vitro LPS response of splenocytes was significantly reduced regarding Th1- and Th2-cytokines including IFN-gamma, IL-6, IL-10 and MCP-1 (0.0011 p 0.043). Also, tumours of stressed mice showed a tendency towards fewer total CD4 cells, more regulatory T cells (Treg), less T cell/tumour cell contacts and a reduction of CTLA-4 in CD4 cells (p 0.05). TGF-beta in vitro was increased by 23.4% using catecholamines (p 0.012) and in vivo employing chronic stress (p 0.001). After 5 weeks tumour volumes were 130% (p = 0.0061) larger and median survival reduced by 13.5% (p = 0.0058). Tumours expressed more VEGF (p = 0.0334), had greater microvessel densities (p = 0.047), and an increased MMP-9 expression (p = 0.0456). Beta-catecholamines increased proliferation in tumour cells by 18% (p 0.0001) and migration by 78% (p = 0.0348) whereas the beta-blocker propranolol reduced these effects by 25% (p 0.0001) and 53% (p = 0.045), respectively. When stressed tumour-bearing animals were treated with propranolol tumour volumes were reduced by 69% (p = 0.0088) and survival improved by 14% (p 0.0058).The potential treatment with beta-blockers of patients with pancreatic cancer or other malignancies should be further evaluated as an adjuvant anti-neoplastic agent in clinical trials.

Despite intensive research efforts peritonitis leading to subsequent sepsis remains associated with a high mortality. The initial effector cells are the locally residing cells of the peritoneum, such as mesothelial cells, mast cells, macrophages and lymphocytes. Through the secretion of chemokines, an influx of neutrophils initially takes place followed by monocytes. The latter can differentiate into inflammatory macrophages. The non-directed activity of neutrophilic granulocytes is limited by the induction of apoptotic programs. Through the breaching of cytokines, bacteria and microbial products into the circulation, a systemic reaction in the sense of systemic inflammatory response syndrome (SIRS) or sepsis arises. This is viewed as a concomitant derailing of inflammatory as well as anti-inflammatory responses, which leads to extensive apoptosis of lymphocytes. The presentation of apoptotic cells leads to a strong immunosuppression. Due to the coexistence of hyperinflammation and immunosuppression, exact knowledge of the current immune status of the patient is a prerequisite in the development of immunotherapies for the treatment of sepsis.

Background: ‘Quality in medicine' is a term used in a broad sense. In this work the definition and dimensions of quality in medicine and the implementation of a measurement and reporting system in Germany are discussed. Existing applications are described and possible future effects are pointed out. Methods: The ongoing process of implementing a quality reporting system into the German healthcare system is studied by publicly available legal texts, published reactions of stakeholders and publications of G-BA and IQTIG. Definitions of quality, dimensions of quality and quality measurement in medicine are studied by using textbooks as well as the world wide web and PubMed search. Results: Donabedian‘s ‘dimensions of quality' are fundamental in dealing with quality in medicine. Existing measurement and reporting systems have immanent strengths and weaknesses, as the definition of quality is affected by one‘s point of view. The legislator will have to decide which ‘dimension of quality' is mandatory and how to measure it. Conclusion: Quality has become a control instrument with unforeseeable consequences. A clear definition of the used quality concept is as essential as the use of feasible measurement and reporting systems. The use of routine data could be an interesting option.

Hintergrund Die Empfehlungen zur Therapie perityphlitischer Abszesse werden kontrovers diskutiert. Die primar perkutane Drainage hat sich als effektive Therapie herausgestellt. Unklar ist bislang jedoch die Notwendigkeit einer nachfolgenden Appendektomie im Intervall.

Die operative Therapie der Appendizitis muss in Chirurgischen Kliniken routinemasig und jederzeit in hoher Qualitat gewahrleistet sein. Die laparoskopische Appendektomie setzt sich mehr und mehr als Standardverfahren durch. Dies begrundet den hohen Stellenwert der Aus- und Weiterbildung der Chirurgen in dieser Technik. Aufgrund der hohen Fallzahl hat die Appendektomie eine erhebliche sozio-okonomische Bedeutung. Entscheidender Schritt der laparoskopischen Appendektomie ist die Versorgung der Appendixbasis. Drei Verfahren des Appendixbasisverschlusses haben sich routinemasig im klinischen Alltag etabliert: Der Endoloop, der Clip und der Endostapler. Der Stapler kombiniert den Verschluss und die Durchtrennung der Appendix in einem Schritt und ermoglicht zudem auch eine partielle tangentiale Resektion des Zokums. Daher kann der Stapler auch bei einer entzundlich veranderten Appendixbasis sicher angewendet werden. Sein Nachteil spiegelt sich im Wesentlichen in den hohen Kosten wieder. Der Endoloop und der Clip sind demgegenuber kosteneffektiver. Der Clip erscheint einfacher in der Anwendung als der Loop und ermoglicht ebenso wie der Stapler den Verschluss der Appendixbasis vor der Dissektion der Mesoappendix. Dagegen ist beim Clip der zu versorgende Durchmesser der Appendixbasis mit 16 mm limitiert. Diesen Nachteil bietet der Endoloop nicht. In dieser Ubersicht diskutieren wir die Vor- und Nachteile der einzelnen Verfahren und geben eine Empfehlung zu deren stadiengerechtem Einsatz. Endoloop oder Clip sind bei der unkomplizierten Appendizitis das Verfahren der Wahl, wahrend der Endostapler bei fortgeschrittener Entzundung, insbesondere der Appendixbasis, zum Einsatz kommen sollte. So konnen die im Vergleich zur offenen Appendektomie hoheren Kosten des laparoskopischen Vorgehens kontrolliert werden.

A clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross-reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti-PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n = 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism.

Background: Postoperatively acquired immune dysfunction is associated with a higher mortality rate in case of septic complications. As details of this severe clinical problem are still unknown, animal models are essential to characterise the mechanisms involved. Methods: Mice were laparotomised and the small intestine was pressed smoothly in antegrade direction. For extension of trauma, the intestine was manipulated three times consecutively. Following this, the ex vivo cytokine release of splenocytes was determined. The degree of surgical trauma was analysed by detection of HMGB1 and IL-6 in serum and by neutrophil staining in the muscularis mucosae. Results: We adapted the previously described animal model of intestinal manipulation to provide a model of surgically induced immune dysfunction. Following intestinal manipulation, the mice showed elevated serum levels of HMGB1 and IL-6 and increased infiltration of granulocytes into the muscularis mucosae. Ex vivo cytokine release by splenocytes was suppressed in the postoperative period. The degree of suppression correlated with the extent of surgical trauma. Conclusions: In this study, we describe a surgically induced immune dysfunction animal model, in which a significant surgical trauma is followed by an immune dysfunction. This model may be ideal for the characterisation of the postoperative immune dysfunction syndrome.

The aim of this study was to evaluate the feasibility, morbidity, and cost-effectiveness of the closure of the appendicular stump with a single non-absorbable polymeric clip compared with the closure of the appendicular stump with a stapler.From January 2009 to December 2009, 82 patients, 31 males and 51 females (mean age of 35.4 years; range of 17 to 79 years), were included in this prospective, non-randomized trial. In 56 patients, the appendicular stump was closed by staplers, and in 26 patients, a single Hem-o-lok MLX polymeric clip was applied. The data collected included age, sex, time of surgery, costs, time of hospitalization, day-time of surgery, complications, and preoperative white blood count (WBC) and c-reactive protein (CRP).There were no differences between the two groups regarding age, sex, WBC, CRP, and time of hospitalization. Time of surgery was longer in the clip group due to the introductory phase. Morbidity did not differ significantly and was highly acceptable in both groups. The costs of one set of Hem-o-lock clips were negligible compared to staplers (19.94 euros versus 356.43 euros).The use of a single non-absorbable polymeric clip is easy to use even for surgical trainees; it is safe and cost-effective. We suggest the use of a single clip for the closure of the appendicular stump as the standard procedure in laparoscopic appendectomy whenever possible.

Major surgery can modulate the immune system and by this the clinical course of following complications. Effects of minor surgical treatments on the immune system and septic complications are poorly understood. We investigated the effect of a minor surgical procedure—the implantation of an osmotic pump—on the outcome of experimental polymicrobial sepsis (colon ascendens stent-induced peritonitis, CASP) in mice. Animals with pumps implanted 3 days prior to CASP showed an attenuated clinical course of sepsis and increased survival. While measured serum cytokine levels were not affected by the minor surgical stress of pump implantation, splenocyte secretion of IFN-gamma in response to lipopolysaccharide was increased. The early implantation of alloplastic material modulates the immune system and leads to an increased survival of a polymicrobial sepsis. Identifying the molecular nature of this effect might point the way to a new therapeutic approach to reduce sepsis mortality.

CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4−/−) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4−/−mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4−/−animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4−/−mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.

Abdominal surgery is regularly followed by immune dysfunction that can last for several days. In case of septic complications during this period, there is imminent danger of mortality due to reduced immune function. This fact leads to classification of sepsis in regard to its genesis: spontaneously acquired sepsis type A is distinguishable from sepsis type B, which is acquired postoperatively. The main difference between these types is the immunologic condition at the time point of sepsis development. Postoperative immune dysfunction can be described by several parameters, i.e. reduction of HLA-DR expression on monocytes and increased apoptosis of T lymphocytes. A direct correlation exists between magnitude of immune dysfunction and complexity of the previous surgical trauma. For the first time it is now possible to study this phenomenon of postoperative immune dysfunction by use of an adequate animal model. Intestinal manipulation in mice fulfils the necessary criteria to serve as a model of surgically induced immune dysfunction.

Cell migration is crucial for wound healing, immune defense, or formation of tumor metastases. In addition to the cytoskeleton, Ca2+ sensitive K+ channels (IK1) are also part of the cellular "migration machinery." We showed that Ca2+ sensitive K+ channels support the retraction of the rear part of migrating MDCK-F cells by inducing a localized shrinkage at this cell pole. So far the molecular nature and in particular the subcellular distribution of these channels in MDCK-F cells is unknown. We compared the effect of IK1 channel blockers and activators on the current of a cloned IK1 channel from MDCK-F cells (cIK1) and the migratory behavior of these cells. Using IK1 channels labeled with a HA-tag or the enhanced green fluorescent protein we studied the subcellular distribution of the canine (cIK1) and the human (hIK1) channel protein in different migrating cells. The functional impact of cIK1 channel activity at the front or rear part of MDCK-F cells was assessed with a local superfusion technique and a detailed morphometric analysis. We show that it is cIK1 whose activity is required for migration of MDCK-F cells. IK1 channels are found in the entire plasma membrane, but they are concentrated at the cell front. This is in part due to membrane ruffling at this cell pole. However, there appears to be only little cIK1 channel activity at the front of MDCK-F cells. In our view this apparent discrepancy can be explained by differential regulation of IK1 channels at the front and rear part of migrating cells.

Further investigations were carried out into the activation of the decomposition of organic peroxides. The rate of decomposition of di-tert-butyl peroxide, a standard initiator for the free radical high pressure polymerisation of ethylene, was measured in the presence of triethylaluminium using Raman spectroscopy. The results obtained at pressures of 10 to 1800 bar and temperatures of 85 to 200°C were used to determine the rate constant, the energy of activation and the activation volume as well as the decomposition half-life. In the same way, 2,2-bis(tert-butylperoxy)butane, a bifunctional initiator used only fairly recently in industrial-scale polymerisation, was investigated. The measurements show that not only the decomposition of peroxy esters but also that of dialkyl peroxides and perketals is accelerated by aluminium alkyls. Aluminium alkyls form complexes with the peroxides, radicals being formed during the decomposition of the complexes. These reactions have a substantially lower energy of activation than the decomposition of the pure peroxides. As a result, radical polymerisation reactions can be initiated by using a peroxide/aluminium alkyl system at lower temperatures.

Intraabdominelle Schwannome sind seltene Tumorentitaten und fallen haufig lediglich als Zufallsbefund auf. Dennoch ist bei dieser Tumorentitat – wie bei allen intramuralen intraabdominellen Tumoren – die Diagnostik und Operationsplanung nicht trivial. Ursachlich hierfur ist die Tatsache, dass die definitive Diagnose nur am Gesamtpraparat erbracht werden kann. Einer aussagekraftigen Probengewinnung sind diese Tumoren auch wegen einer inhomogenen Zusammensetzung mit Arealen unterschiedlicher Proliferationsrate schwer zuganglich. Im Folgenden wird das Vorgehen bei einem inzidentiellen Schwannom des Magens beschrieben. Leitsymptom war die Perforation eines peptischen Magenulkus.

The decomposition of tert-butyl peroxypivalate (TBPPI) in the presence of trialkylaluminium activators was examined in an optical cell using in-situ Raman spectroscopy. The measurements were carried out in the temperature range between 90 and 165°C at pressures between 1 and 1800 bar. The trialkylaluminium compounds used were triethyl, trihexyl, trioctyl and tridodecylaluminium which were employed in quantitative ratios of up to 1 mol trialkylaluminium per mol peroxide. From the graphs showing the peroxide concentration as a function of time, the rate constant, the energy of activation and the half-life time of the decomposition reaction were determined. A comparison of these data with the parameters of the decomposition of pure TBPPI in solution clearly illustrated the acceleration of the decomposition reaction as a result of the influence of the organoaluminium compound. By means of the NMR spectra of the individual components and their mixture it was possible to show that the activated decomposition takes place via trialkylaluminium/peroxide complexes. Der Zerfall von tert-Butylperoxypivalat (TBPPI) unter Zusatz von Trialkylaluminium-Aktivatoren wurde in einer optischen Zelle mittels in-situ Raman-Spektroskopie untersucht. Die Messungen wurden im Temperaturbereich von 90 bis 165°C unter Drucken von 1 bis 1800 bar durchgefuhrt. Als Trialkylaluminium-Verbindungen wurden Triethyl-, Trihexyl-, Trioctyl- und Tridodecylaluminium in Mengenverhaltnissen von bis zu 1 mol Trialkylaluminium pro mol Peroxid eingesetzt. Aus den Peroxid-Konzentration/Zeit-Verlaufen wurden die Geschwindigkeitskonstante, die Aktivierungsenergie sowie die Halbwertszeit der Zerfallsreaktion ermittelt. Aus dem Vergleich dieser Daten mit den Parametern des Zerfalls von reinem TBPPI in Losung wurde die Beschleunigung der Zerfallsreaktion unter dem Einflus der Organoaluminium-Verbindung deutlich. Anhand von NMR-Spektren der Einzelkomponenten und ihrer Mischung konnte gezeigt werden, das der aktivierte Zerfall uber Trialkylaluminium/Peroxid-Komplexe verlauft.

An optical high-pressure cell has been developed for spectroscopic investigations of rapid high-pressure reactions. It can be coupled with commercial Raman spectrometer. The measuring cell is suitable for use at pressures of up to 2000 bar and temperatures of up to 200°C. The advantages of in situ Raman spectroscopy are demonstrated in the course of an investigation of the decomposition of tertiary butyl peroxypivalate in solution. This organic peroxide is a standard initiator for the radical high-pressure polymerisation of olefins for which it is used at pressures of 1300 to 3000 bar and temperatures of 160 to 190°C. The rate of decomposition was measured within a wide pressure and temperature range. From the results the half-life, the frequency factor, the energy of activation and the activation volume of the peroxide decomposition reaction were determined. The data thus obtained were compared with data in the literature which had been obtained by other methods.

The term “neurogenic appendicopathy” has been used for patients operated on for acute appendicitis with their appendices lacking signs of acute inflammation. The aim of this retrospective study was to clarify the presence of potential neurogenic appendicopathies, analyzing patients’ clinical symptoms and their corresponding appendiceal specimens. One hundred twenty-one patients were identified showing a histological diagnosis of chronic appendicitis. Eventually, 40 patients qualified for the potential diagnosis “neurogenic appendicopathy.” Appendix specimens were immunohistochemically examined for the expression of S-100, vasoactive intestinal polypeptide (VIP), and substance P. Controls consisted of 110 patients with acute appendicitis and 120 patients following appendectomies operated on for other reasons. Eventually, 40 of 120 patients qualified for the potential diagnosis “neurogenic appendicopathy.” Compared to patients with acute appendicitis, there was only little difference in clinical symptoms. Histologically, neuromas, thought of being characteristic of neurogenic appendicopathy, were demonstrated significantly more often in the control group (p = 0.01). S-100 was significantly more expressed in the appendicopathy group (p = 0.0024), but nearly 50 % of control specimens showed an intense staining, too. S-100+ neurofibers were significantly (p = 0.00122) more often found in the mucosa of appendicopathy specimens, but this was true for only 25 % of specimens. VIP was more strongly expressed in control specimens (p = 0.0211). Substance P was of no diagnostic value. Our study could not confirm the neurogenic origin of appendicopathies. Yet, clinical data strongly suggest the existence of the entity “appendicopathy.” Therefore, we suggest removing a macroscopically unaffected appendix in patients with appendicitis-like symptoms if, on laparoscopy, no other cause can be found.

In view of the fact that appendectomy is the most common operation for an acute abdomen, laparoscopic appendectomy has evolved as the most frequently performed procedure. Hospitals, therefore, require at all times the expertise, technique, and staff to ensure a high quality of standard for appendectomies, which not only supports the requirements of the high caseload but also takes into consideration the socio-economical aspects. A critical step is the closure of the appendicular stump. The three most widely employed techniques are an endo-stapler, an endo-loop, or a clip. Although the endo-stapler is fairly expensive, it combines closing and transecting the appendix in one step, offers the possibility of a partial caecal resection, and can be used if the appendicular base is inflamed. Endo-loop and clip are equally cost-effective, but the clip appears to be simpler in handling than the endo-loop and, like the stapler, offers closing and cutting the appendix before dissecting the mesoappendix. However, only appendices up to 16 mm in diameter can be clipped, a disadvantage not shared with the loop.

Background: In postoperative sepsis, mortality is increased due to the surgically induced immune dysfunction. Further causes of this traumatic effect on the immune system include burn injuries and polytrauma, as well as endogenous traumata like stroke. Several animal models have been defined to analyse the characteristics of trauma-induced immune suppression. This article will correlate our results from animal studies and clinical observations with the recent literature on postoperative immune suppression. Methods: The previously described model of surgically induced immune dysfunction (SID) was performed in mice by laparotomy and manipulation of the small intestine in the antegrade direction. Blood samples were collected 6 and 72 h following SID to analyse the white blood cell count and corticosterone levels. To assess the postoperative immune status in humans, we analysed expression of HLA-DR on monocytes of 118 patients by flow cytometry prior to and 24, 48 and 72 h after surgery. Results: The postoperative immune suppression in our SID model is characterised by lymphocytopenia and significantly increased corticosterone levels in mice dependent on the degree of surgical trauma. This is comparable to the postoperative situation in humans: major and especially long-lasting surgery results in a significantly reduced expression of HLA-DR on circulating monocytes. Previous studies describe a similar situation following burn injury and endogenous trauma, i.e. stroke. Conclusions: We suggest the completion of our previously published sepsis classification due to the immune status at the onset of sepsis: type A as the spontaneously acquired sepsis and type B as sepsis in trauma-induced pre-existing immune suppression.

The particular importance of the vagus nerve for the pathophysiology of peritonitis becomes more and more apparent. In this work we provide evidence for the vagal modulation of inflammation in the murine model of colon ascendens stent peritonitis (CASP). Vagotomy significantly increases mortality in polymicrobial sepsis. This effect is not accounted for by the dilatation of gastric volume following vagotomy. As the stimulation of cholinergic receptors by nicotine has no therapeutic effect, the lack of nicotine is also not the reason for the reduced survival rate. In fact, increased septic mortality is a consequence of the absent modulating influence of the vagus nerve on the immune system: we detected significantly elevated serum corticosterone levels in vagotomised mice 24 h following CASP and a decreasedex vivoTNF-alpha secretion of Kupffer cells upon stimulation with LPS. In conclusion, the vagus nerve has a modulating influence in polymicrobial sepsis by attenuating the immune dysregulation.

Calcium-sensitive potassium channels (KCa3.1) are expressed in virtually all migrating cells. Their activity is required for optimal cell migration so that their blockade leads to slowing down. KCa3.1 channels must be inserted into the plasma membrane in order to elicit their physiological function. However, the plasma membrane of migrating cells is subject to rapid recycling by means of endo- and exocytosis. Here, we focussed on the endocytic internalization and the intracellular transport of the human isoform hKCa3.1. A hKCa3.1 channel construct with an HA-tag in the extracellularly located S3-S4 linker was transfected into migrating transformed renal epithelial MDCK-F cells. Channel internalization was visualized and quantified with immunofluorescence and a cell-based ELISA. Movement of hKCa3.1 channel containing vesicles as well as migration of MDCK-F cells were monitored by means of time lapse video microscopy. hKCa3.1 channels are endocytosed during migration. Most of the hKCa3.1 channel containing vesicles are moving at a speed of up to 2 µm/sec in a microtubule-dependent manner towards the front of MDCK-F cells. Our experiments indicate that endocytosis of hKCa3.1 channels is clathrin-dependent since they colocalize with clathrin adaptor proteins and since it is impaired when a C-terminal dileucine motif is mutated. The C-terminal dileucine motif is also important for the subcellular localization of hKCa3.1 channels in migrating cells. Mutated channels are no longer concentrated at the leading edge. We therefore propose that recycling of hKCa3.1 channels contributes to their characteristic subcellular distribution in migrating cells. J. Cell. Physiol. 227: 686–696, 2012. © 2011 Wiley Periodicals, Inc.

Sepsis remains a persistent problem on intensive care units all over the world. Understanding the complex mechanisms of sepsis is the precondition for establishing new therapeutic approaches in this field. Therefore, animal models are required that are able to closely mimic the human disease and also sufficiently deal with scientific questions. The Colon Ascendens Stent Peritonitis (CASP) is a highly standardized model for polymicrobial abdominal sepsis in rodents. In this model, a small stent is surgically inserted into the ascending colon of mice or rats leading to a continuous leakage of intestinal bacteria into the peritoneal cavity. The procedure results in peritonitis, systemic bacteraemia, organ infection by gut bacteria, and systemic but also local release of several pro- and anti-inflammatory cytokines. The lethality of CASP can be controlled by the diameter of the inserted stent. A variant of this model, the so-called CASP with intervention (CASPI), raises opportunity to remove the septic focus by a second operation according to common procedures in clinical practice. CASP is an easily learnable and highly reproducible model that closely mimics the clinical course of abdominal sepsis. It leads way to study on questions in several scientific fields e.g. immunology, infectiology, or surgery.

Background: Resident tissue macrophages exert important functions during severe systemic infection and contribute to changes in local as well as systemic immune responses. Alveolar macrophages (AM) play a crucial role in airway diseases and in the defense against microorganisms invading the body via the bronchopulmonary tract. It has been postulated that AM are involved in the development of acute local disorders as a consequence of extrapulmonary stimuli like pancreatitis, peritonitis, or trauma. Objective: The aim of this study was to analyze the local and systemic role of AM during sepsis using selective AM depletion in the murine colon ascendens stent peritonitis (CASP) model of polymicrobial sepsis. Methods: 48 h prior to CASP surgery, AM of female C57BL/6 mice were selectively depleted by intratracheal application of clodronate liposomes (Lipo-clod). For control purposes, phosphate-buffered saline (PBS) liposomes (Lipo-PBS) were used. Results: CASP led to significantly elevated levels of local and systemic cytokines independent of the presence of AM. In contrast, levels of gut-derived bacteria in bronchoalveolar lavage and lung of septic mice were significantly higher in Lipo-clod-treated animals compared to Lipo-PBS-treated animals. After CASP-induced sepsis, local barrier dysfunction in the lung was detected; AM depletion resulted in severely enhanced development of acute lung injury. Consequently, Lipo-clod-treated animals showed strongly reduced survival rates after CASP. Conclusions: Contrarily to other macrophage populations, AM do not significantly contribute to local and systemic cytokine release during polymicrobial abdominal sepsis. AM have important protective functions for local clearance of gut-derived bacteria and attenuation of lung injury.

Der Nervus vagus ist eine Schaltstelle zwischen Nervensystem und Immunsystem in der Sepsis. Der genaue Reaktionsmechanismus scheint hierbei jedoch noch nicht abschliesend geklart. Es wurde ein weiterer Hinweis auf eine antiinflammatorische Komponente des Nervus vagus erbracht. Eine Verletzung des Vagus scheint zumindest im von uns gewahlten Mausmodell eine deutliche Erhohung der Sepsissuszeptibilitat zu verursachen und muss im Zusammenhang von Operationen, bei denen zwangslaufig eine beidseitige Vagotomie erfolgt (Osophagektomie, Gastrektomie) als Risikofaktor fur den deletaren Verlauf einer abdominellen Sepsis diskutiert werden.

The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the “cholinergic inflammatory pathway.” Through stimulation of the acetylcholine receptors located upon the macrophages, the “unspecific” immune system can be directly influenced. The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model. After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis. The vagal nerve is therefore an important modulator of the immune system.

Cell migration is crucial for wound healing, immune defense, or formation of tumor metastases. In addition to the cytoskeleton, Ca2+ sensitive K+ channels (IK1) are also part of the cellular "migration machinery." We showed that Ca2+ sensitive K+ channels support the retraction of the rear part of migrating MDCK-F cells by inducing a localized shrinkage at this cell pole. So far the molecular nature and in particular the subcellular distribution of these channels in MDCK-F cells is unknown. We compared the effect of IK1 channel blockers and activators on the current of a cloned IK1 channel from MDCK-F cells (cIK1) and the migratory behavior of these cells. Using IK1 channels labeled with a HA-tag or the enhanced green fluorescent protein we studied the subcellular distribution of the canine (cIK1) and the human (hIK1) channel protein in different migrating cells. The functional impact of cIK1 channel activity at the front or rear part of MDCK-F cells was assessed with a local superfusion technique and a detailed morphometric analysis. We show that it is cIK1 whose activity is required for migration of MDCK-F cells. IK1 channels are found in the entire plasma membrane, but they are concentrated at the cell front. This is in part due to membrane ruffling at this cell pole. However, there appears to be only little cIK1 channel activity at the front of MDCK-F cells. In our view this apparent discrepancy can be explained by differential regulation of IK1 channels at the front and rear part of migrating cells.

Patients with sepsis are often immune suppressed, and experimental mouse models of sepsis also display this feature. However, acute sepsis in mice is also characterized by a generalized B cell activation and plasma cell differentiation, resulting in a marked increase in serum antibody concentration. Its effects on humoral memory are not clearly defined. We measured the effects of experimental sepsis on long-term immunological memory for a defined antigen: we induced colon ascendens stent peritonitis (CASP) 8 weeks after 2 rounds of immunization with ovalbumin. Four weeks later, the antigen-specific bone marrow plasma cell count had doubled in immunized non-septic animals, but remained unchanged in immunized septic animals. Sepsis also caused a decrease in antigen-specific serum antibody concentration. We conclude that sepsis weakens humoral memory by impeding the antigen-specific plasma cell pool's development, which is not complete 8 weeks after secondary immunization.