The influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome.

OBJECTIVE: The aim of this study was to investigate the influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome. PATIENTS AND METHODS: Endonasal swabs from the olfactory groove of 22 patients with moderate and severe obstructive sleep apnea (OSA) and a control group of 17 healthy controls were obtained at the Department of Otorhinolaryngology of the Friedrich-Alexander-Universität Erlangen-Nürnberg. 16S rRNA gene sequencing was performed to further evaluate the endonasal microbiome. In a second step, the longitudinal influence of continuous positive airway pressure (CPAP) therapy on the nasal microbiome was investigated (3-6 and 6-9 months). RESULTS: Analysis of the bacterial load and ß-diversity showed no significant differences between the groups, although patients with severe OSA showed increased α-diversity compared to the control group, while those with moderate OSA showed decreased α-diversity. The evaluation of longitudinal changes in the nasal microbiota during CPAP treatment showed no significant difference in α- or ß-diversity. However, the number of bacteria for which a significant difference between moderate and severe OSA was found in the linear discriminant analysis decreased during CPAP treatment. CONCLUSIONS: Long-term CPAP treatment showed an alignment of the composition of the nasal microbiome in patients with moderate and severe OSA as well as an alignment of biodiversity with that of the healthy control group. This change in the composition of the microbiome could be both part of the therapeutic effect in CPAP therapy and a promoting factor of the adverse side effects of the therapy. Further studies are needed to investigate whether the endonasal microbiome is related to CPAP compliance and whether CPAP compliance can be positively influenced in the future by therapeutic modification of the microbiome.

[Emergency physician training-survey of course participants regarding training conditions and motivation]. / Notarztweiterbildung ­ Befragung von Kursteilnehmern zu Weiterbildungsbedingungen und Motivation.

INTRODUCTION: Qualification is the basis to prevent a shortage of emergency medicine service (EMS) physicians. To find out more about the motivation and training conditions young doctors attending EMS medicine courses were questioned. MATERIALS AND METHODS: 33 planned courses were identified and participants from 19 courses were asked to fill out the questionnaires. The questionnaires contained 22 questions on person, motivation, support by the employer and individual aims of course attendance. RESULTS: 2,050 questionnaires were distributed, 970 (47.3%) were returned. Participants were 31.8 ± 5.2 years old (mean) and attended the course after 3.7 ± 4.3 years of clinical experience. 907 were in specialist training (237 surgery, 320 internal medicine, 269 anaesthesia). 751 participants planned to work as emergency physician in the future (196 possibly), 213 in urgent care centres. For 309 participants attendance was an employer requirement. Attendance was on educational leave (489), paid leave (258), annual leave (112) or free time (85). The course was fully (493) or partially (177) paid by the employer. Accommodation was paid for by physicians (525) or employers (287). Practical training on the ambulance was planned in free time or during annual leave (582), on paid leave (204) or during regular shifts (119). 682 participants hoped to gain more safety with in-hospital emergencies, 560 planned shifts on the ambulance of the own hospital and 511 planned to work on a free-lance basis. 388 physicians planned to use the services of an agency for free-lance work. CONCLUSION: While employers supported course attendance in more than 50%, the majority of the participants had to organise the practical training on the ambulance during free time. Only 58% planned to work on the ambulance as part of their regular job or 53% on a free-lance basis. Other participants attended in preparation for work in urgent-care or to gain competence in handling in-hospital emergencies.

Participation of the intestinal microbiota in the mechanism of beneficial effect of treatment with synbiotic Syngut on experimental colitis under stress conditions.

Gut-brain axis plays a central role in the regulation of stress related diseases such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). It is increasingly recognized that stress modulates gut microbiota community structure and activity and represents an important causal factor in dysbiosis. This study was designed to determine the effect of daily treatment with synbiotic (Syngut) containing inulin, Lactobacillus acidophilus, Bifidobacterium lactis W51, Lactobacillus plantarum W21 and Lactococcus lactis applied i.g. at a dose of 50 mg/kg i.g. on the colonic damage and colonic mucosal blood flow in rats with experimentally induced TNBS-colitis that were additionally exposed or not to acute stress (episodes of cold restraint stress every other day before colitis induction). Control rats received daily treatment with vehicle (saline, i.g.) or mesalazine (50 mg/kg-d i.g.), the standard drug recommended in therapy of IBD. At the termination of TNBS colitis, the histologic evaluation of colonic mucosa, mucosal malonyldialdehyde (MDA) level and plasma concentrations of proinflammatory cytokines (TNF-α, IL-1ß) and adipokine adiponectin were assessed. the samples of colonic mucosa not involving colonic lesions and surrounding the flared mucosa were excised for the determination of mRNA expression for proinflammatory biomarkers TNF-α, IL-1ß, IL-10 and COX-2 as well as antioxidazing factors SOD-1 and SOD-2. Finally, the gut microbial profiles were analyzed by 16S rRNA sequencing at phylum, family and genus level. Episodes of cold stress significantly aggravated the course of TNBS colitis, and significantly increased the release of proinflammatory cytokines as well as the significant increase in the MDA concentration has been observed as compared with non-stressed TNBS rats. These changes were followed by the significant fall in the CBF and plasma adiponectin levels and by the overexpression of mRNA of proinflammatory biomarkers. Synbiotic treatment with Syngut significantly reduced the area of colonic lesions observed macroscopically and microscopically in rats with TNBS colitis with or without exposure to cold stress, significantly increased the CBF, normalized plasma adiponectin levels and significantly attenuated the release and colonic expression of proinflammatory cytokines and biomarkers. the analysis of the gut microbiota showed a significant reduction of microbial diversity (Shannon index) in rats with TNBS colitis with or without exposure to stress. The therapy with Syngut failed to significantly affect the alpha diversity. At the phylum level, the significant rise in Proteobacteria has been observed in stressed rats with TNBS colitis and this effects was attenuated by treatment with Syngut. At family level, TNBS colitis alone or in combination with stress led to a significant decrease of SCFA producing bacterial taxa such as Ruminococaceae and Lachnospiraceae and Syngut counteracted this effect. We conclude that: 1) cold stress exacerbates the gastrointestinal inflammation in experimental colitis; 2) the synbiotic therapy with Syngut ameliorates the gut inflammation in rats with TNBS colitis combined with cold stress; 3) the beneficial effect of Syngut is accompanied by increase of anti-inflammatory taxa such as Ruminococaceae and Lachnospiraceae, and 4) the modulation of gut microbiota with Syngut alleviates stress-related intestinal inflammation suggesting a potential usefulness of synbiotic therapy in intestinal disorders accompanied by stress in patients with IBD.

Microbial patterns in patients with histamine intolerance.

Histamine intolerance represents a controversially discussed disorder. Besides an impaired degradation of orally supplied histamine due to diamine oxidase (DAO) deficiency, a deranged gut flora may also contribute to elevated histamine levels. Our aim was to determine the intestinal bacterial composition in patients with proven histamine intolerance in comparison to other food intolerances and healthy controls. A total of 64 participants were included in the study, encompassing 8 patients with histamine intolerance (HIT), 25 with food hypersensitivity (FH), 21 with food allergy and 10 healthy controls (HC). All participants underwent blood testing for total and food-specific immunoglobulin E, plasma histamine and DAO serum activity. Stool samples were used to analyze stool histamine and zonulin levels and bacterial composition by 16s rRNA sequencing. No significant differences in stool histamine levels were observed, but HIT patients showed elevated levels of stool zonulin. Microbiota analysis revealed increased levels of Proteobacteria (5.4%) and a significantly reduced alpha-diversity in the HIT group (P = 0.019). On family level, HC showed a significantly higher abundance of Bifidobacteriaceae compared to other study groups (P = 0.005), with lowest levels in the HIT group (P = 0.036). Also significantly reduced abundances of the genera Butyricimonas (P = 0.026) and Hespellia (P = 0.025) were observed in the HIT patients, whereas Roseburia were significantly elevated (P = 0.021). We concluded that the altered occurrence of Proteobacteria and Bifidobacteriaceae, reduced alpha-diversity as well as elevated stool zonulin levels suggest a dysbiosis and intestinal barrier dysfunction in histamine intolerant patients, which in turn may play an important role in driving disease pathogenesis.

[Use of cognitive aids in pediatric emergency care : Interdisciplinary consensus statement]. / Anwendung kognitiver Hilfsmittel im Kindernotfall : Interdisziplinär konsentierte Stellungnahme.

Preclinical pediatric emergencies are rare events and are therefore often associated with stress and uncertainty for emergency medical service personnel. To ensure adequate treatment of pediatric patients a variety of different cognitive aids exist (e.g. books, apps, rulers, weight-adapted bag systems). Especially the size specifications of the medical equipment and the dosage of emergency medication are individually very different in children and are dependent on parameters, such as body height and weight. Therefore, cognitive aids often enable length measurement whereby it is possible to draw conclusions on body weight for calculating the child's medication dosage. These aids may help to avoid the wrong medication dose or the wrong therapy of children but uncritical and untrained usage of these aids carries a potential risk of mistakes. This recommendation gives an overview of the general requirements and different problems of cognitive aids and should help improve the general framework and the rational basis for the use and further development of cognitive aids in emergency medicine.

IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells.

Group 2 innate lymphoid cells (ILC2) were recently characterized by their ability to produce significant amounts of type-2 signature cytokines and drive central beneficial and pathological features of type-2 immune responses. Although factors such as IL-33 and IL-25 were shown to have ILC2 activating capacity, it is not well understood, how ILC2 responses are regulated in vivo. Here we provide compelling evidence that IL-27-signalling directly inhibits ILC2 responses and reveal a novel mechanism for negative regulation of the innate arm of type-2 immunity. We demonstrate that IL-27-deficiency is linked to increased mucosal presence of ILC2 in a model of inflammatory lung disease. Moreover, IL-27-treatment inhibited ILC2 proliferation and cytokine production and significantly reduced their accumulation in vivo. During helminth infection, regulation of ILC2 by IL-27 directly impacted anti-parasitic immunity. Thus, therapeutic modulation of the IL-27/IL-27R axis may be relevant in a number of inflammatory conditions associated with dysregulated type-2 responses.

Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production.

The transient receptor potential (TRP) ion channel family is well characterized in sensory neurons; however, little is known about its role in the immune system. Here we show that the cold-sensing TRPM8 has an unexpected role in innate immunity. TRPM8 expression and function in macrophages were demonstrated in vitro using molecular techniques and calcium imaging. In addition, adoptive macrophage transfer and systemic interleukin (IL)-10 overexpression were performed in experimental colitis. TRPM8 activation induced calcium-transients in murine peritoneal macrophages (PM) and bone marrow-derived macrophages of wild-type (WT) but not TRPM8-deficient mice. TRPM8-deficient PM exhibited defective phagocytosis and increased motility compared with those in WT, whereas the opposite effects of TRPM8 activation were induced in WT PM. TRPM8 activation or blockage/genetic deletion induced a anti- or pro-inflammatory macrophage cytokine profile, respectively. WT mice treated with repeated menthol (TRPM8 agonist) enemas were consistently protected from experimental colitis, whereas TRPM8-deficient mice showed increased colitis susceptibility. Adoptive transfer of TRPM8-deficient macrophages aggravated colitis, whereas systemic IL-10 overexpression rescued this phenotype. TRPM8 activation in peptidergic sensory neurons did not affect neuropeptide release from the inflamed colon. TRPM8 in macrophages determines pro- or anti-inflammatory actions by regulating tumor necrosis factor-α and interleukin-10 production. These findings suggest novel TRPM8-based options for immunomodulatory intervention.

Successful therapy of Clostridium difficile infection with fecal microbiota transplantation.

Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea and represents an important burden for healthcare worldwide. Symptoms of severe CDI include watery, foul-smelling diarrhea, peripheral leucocytosis, increased C-reactive protein (CRP), acute renal failure, hypotension and pseudomembranous colitis. Recent studies indicate that the main cause of CDI is dysbiosis, an imbalance in the normal gut microbiota. The restoration of a healthy gut microbiota composition via fecal microbiota transplantation (FMT) recently became more popular. The aim of the present study was to assess the effect of FMT on the healing of CDI and to analyze the changes in the level of pro-inflammatory markers (C-reactive protein, fecal calprotectin) and pro-inflammatory cytokines. Eighteen patients with CDI were included in our study (6 males and 12 females) with recurrent and/or severe CDI. The FMT was performed in 17 patients using colonoscopy, including 16 patients receiving a one-time FMT and 1 patient who needed 2 additional FMTs. One patient was treated with a single round of FMT using push-and-pull enteroscopy. In all CDI patients, before and 3 weeks after FMT, the following parameters were analyzed: C-reactive protein, fecal calprotectin, and plasma interleukin (IL)-6, IL-8 and IL-12, and tumor necrosis factor-alpha (TNF-α). In addition, the plasma level of LL-37, a cathelicidine peptide was assessed by fluorescence-activated cell sorting (FACS) before and 3 months after FMT. Finally, in 7 patients a microbiome analysis was performed by sequencing of 16SrRNA in stool probes obtained before and 3 weeks after FMT. The healing rate of CDI was 94%. In all successfully treated patients no recurrent CDI was observed during follow-up (16 months). The serum level of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-8 and IL-12) significantly decreased after FMT. Similarly, CRP and fecal calprotectin normalized after FMT. 3 months after FMT a significant increase of LL-37 in the plasma of successfully treated patients was monitored. The sequencing analysis demonstrated an elevated abundance of beneficial bacterial species such as Lactobacillaceae, Ruminococcaceae, Desulfovibrionaceae, Sutterellaceae and Porphyromonodacea after FMT. No serious side effects were observed. We concluded that FMT represented a very effective and safe treatment of recurrent and/or severe CDI and led to favorable shifts in the composition of gut microbiome.

Separation of harmful impurities from refuse derived fuels (RDF) by a fluidized bed.

In firing systems of cement production plants and coal-fired power plants, regular fossil fuels are increasingly substituted by alternative fuels. Rising energy prices and ambitious CO2-reduction goals promote the use of alternative fuels as a significant contribution to efficient energy recovery. One possibility to protect energy resources are refuse-derived fuels (RDF), which are produced during the treatment of municipal solid, commercial and industrial waste. The waste fractions suitable for RDF have a high calorific value and are often not suitable for material recycling. With current treatment processes, RDF still contains components which impede the utilization in firing systems or limit the degree of substitution. The content of these undesired components may amount to 4 wt%. These, in most cases incombustible particles which consist of mineral, ceramic and metallic materials can cause damages in the conveying systems (e. g. rotary feeder) or result in contaminations of the products (e. g. cement, chalk). Up-to-date separation processes (sieve machine, magnet separator or air classifier) have individual weaknesses that could hamper a secure separation of these particles. This article describes a new technology for the separation of impurities from refuse derived fuels based on a rotating fluidized bed. In this concept a rotating motion of the particle bed is obtained by the tangential injection of the fluidization gas in a static geometry. The RDF-particles experience a centrifugal force which fluidized the bed radially. The technical principle allows tearing up of particle clusters to single particles. Radially inwards the vertical velocity is much lower thus particles of every description can fall down there. For the subsequent separation of the particles by form and density an additionally cone shaped plate was installed in the centre. Impurities have a higher density and a compact form compared to combustible particles and can be separated with a high efficiency. The new technology was experimentally investigated and proven using model-RDF, actual-RDF and impurities of different densities. In addition, numerical simulations were also done. The fluidization chamber was operated in batch mode. The article describes experiences and difficulties in using rotating fluidized bed systems.

[Relevance of parents as source for contamination of neonates with multiresistant Gram-negative pathogens (MRGN)]. / Bedeutung der Eltern als Quelle bei der Besiedlung von Neonaten mit multiresistenten gramnegativen Erregern (MRGN).

BACKGROUND: There is an increase in nosocomial contamination and infection with multi-resistant bacteria among NICU patients. In 2011 we had to deal with an outbreak from multi-resistant Klebsiella pneumoniae in our NICU. Analysing the situation, we found 3 different clonal tribes. We presume that there are different sources for the contamination with multiresistant Gram-negative pathogens (MRGN) and we suspect that parents of NICU children may be of some importance. We studied in a one-year setting whether the incidence of nosocomial contaminations and infections may be prevented in a setting of barrier nursing and surveillance of the NICU patients and their parents. Our study was prospective and justified by a vote of support from the ethics committee of the 'Hamburger Ärztekammer' as well as additional funding from the Asklepios-Hamburg Pro-Research for the laboratory expenses. MATERIAL AND METHODS: In a one-year study we undertook a programme of barrier nursing for all children admitted to our NICU with bacteriological surveillance on their entry into the NICU for children and their parents with anal and pharyngeal-nasal swabs. As long as there were no results, barrier-nursing for the children, their parents and staff was maintained. Where negative results were found, barrier-nursing was interrupted and children were nursed under normal hygienic conditions. Surveillance cultures from the children were taken once a week until being released. In cases of detection of MRGN bacteria, barrier-nursing was implemented together with room isolation. RESULTS: We detected 23 families carrying MRGN bacteria pre-existent before hospitalisation. In cases of MRGN findings, barrier-nursing and room isolation were maintained. Under these circumstances, there were 6 cases of contamination of NICU children, 4 after vaginal delivery and secondary admittance in the NICU. The circumstances for the 2 others are discussed. CONCLUSION: Parents are an important source for MRGN bacteria in the NICU. The early detection of those carriers is important for the avoidance of outbreaks in an NICU. In most cases, contamination and infection can be prevented.

[Mass maritime casualty incidents in German waters: structures and resources]. / Massenanfall von Verletzten auf See in deutschen Gewässern : Strukturen und Ressourcen.

The Central Command for Maritime Emergencies was founded in Germany in 2003 triggered by the fire on board of the cargo ship "Pallas" in 1998. Its mission is to coordinate and direct measures at or above state level in maritime emergency situations in the North Sea and the Baltic Sea. A special task in this case is to provide firefighting and medical care. To face these challenges at sea emergency doctors and firemen have been specially trained. This form of organization provides a concept to counter mass casualty incidents and peril situations at sea. Since the foundation of the Central Command for Maritime Emergencies there have been 5 operations for firefighting units and 4 for medical response teams. Assignments and structure of the Central Command for Maritime Emergencies are unique in Europe.

[How often is bronchopneumonia overlooked as the cause of death in intensive care unit patients?]. / Wie häufig wird die Bronchopneumonie als Todesursache bei Intensivpatienten übersehen?

BACKGROUND: This study addresses the issue of analyzing the relationship between pre-mortem diagnoses and post-mortem findings in an intensive care unit (ICU). MATERIALS AND METHODS: Investigating a total of 1,205 autopsy cases, pre-mortem and post-mortem diagnoses were retrospectively evaluated and compared statistically by means of established categories (i.e."complete, partial, or lacking concordance" and"clinically suspected diagnosis"). RESULTS: When comparing clinical diagnoses and autopsy findings in terms of bronchopneumonia, concordance was recorded in only 21.15% of the cases investigated. CONCLUSION: In multimorbid ICU patients, bronchopneumonia frequently fails to be clinically recognized since clinical parameters commonly used for monitoring appear to be modified due to therapeutical interventions, and thus are inappropriate to reflect the complete histomorphological equivalent of the disease. This study also emphasizes the importance of autopsy which represents a sensitive means for professional medical quality assurance, and again establishes the necessity for strengthening the request for autopsy, which is currently characterized by an unfavourable decline.

Three-dimensional cytoarchitectonic analysis of the posterior bank of the human precentral sulcus.

Studies employing functional magnetic resonance imaging have identified the human frontal eye field as being in the anterior and partly in the posterior wall, as well as at the base of the precentral sulcus. Moreover, it is known that the frontal eye field extends rostrally to the superior frontal sulcus. According to Brodmann's cytoarchitectonic map, this region belongs to the dysgranular Brodmann area 6 of the premotor cortex. However, the frontal eye field in non-human primates has been located within the arcuate sulcus in Brodmann area 8, generating considerable debate about where to locate exactly the frontal eye field in humans. Functional studies of the primate frontal eye field have revealed a principal homology of voluntary saccadic control systems in human and old-world monkeys, especially the macaque. But these homologies seem to be contradicted by the reported topographic localization at the cytoarchitectonic level. Therefore, we studied the cytoarchitectonic structure of the posterior bank of the precentral sulcus of a human brain, employing newly developed spatial mapping techniques to provide data about whether or not this region should be considered cytoarchitecturally homogeneous or heterogeneous. We used functional magnetic resonance imaging results, as an initial guide in localizing a region which is activated by saccadic tasks. A maximum of activation was detected around the junction of the superior frontal sulcus and the precentral sulcus extending 1.5 cm along the precentral sulcus in direction of the lateral sulcus. Here, one human brain has been analyzed to obtain preliminary data about the cytoarchitectonical changes of a part of area 6. Statistical analysis of the three-dimensional architectonic data from this region allowed us to identify a zone at the posterior bank, which in other studies has been associated with a functional region that controls pursuit eye movements and performs sensory-to-motor transformations. We found two significant sectors along the ventral part of the posterior bank of the precentral sulcus. The caudal transition region coincides partly with a region that integrates retinal and eye position signals for target location, arm, and axial movements. The second more ventrally located region is attributed to process oral-facial movements. The caudal transition region coincides with our functional magnetic resonance imaging investigation. It was revealed that this region lies at the inferior frontal eye field, where a pronounced activation over a larger region can be stimulated. Currently, more studies are needed to combine functional magnetic resonance imaging data of maximal activation with data from whole histologic brain sections of more individuals and to quantify the variability of this region and its sub-regions by means of a standardized brain atlas.

Comparison of electrical velocimetry and transoesophageal Doppler echocardiography for measuring stroke volume and cardiac output.

BACKGROUND: Impedance cardiography (ICG) has been used extensively to estimate stroke volume (SV) and cardiac output (CO) from changes of thoracic electrical bioimpedance (TEB). However, studies comparing ICG with reference methods have questioned the reliability of this approach. Electrical velocimetry (EV) provides a new algorithm to calculate CO from variations in TEB. As the transoesophageal Doppler echocardiographic quantification of CO (TOE-CO) has emerged as a reliable method, the purpose of this study was to determine the limits of agreement between CO estimations using EV (EV-CO) and TOE-CO. METHODS: Standard ECG electrodes were used for non-invasive EV-CO measurements. These were placed on 37 patients scheduled for coronary artery surgery necessitating transoesophageal echocardiography monitoring. Simultaneous EV-CO and TOE-CO measurements were recorded after induction of anaesthesia. EV-CO was calculated using the Bernstein-Osypka equation. TOE-CO was measured across the aortic valve using continuous-wave Doppler echocardiography and a triangular orifice model. RESULTS: A significant high correlation was found between the TOE-CO and the EV-CO measurements (r2=0.86). Data were related linearly. The slope of the line (1.10 (se 0.07)) was not significantly different from unity, and the point at which it intersected the ordinate (-0.46 (0.32) litre min(-1)) was not significantly different from zero. Bland-Altman analysis revealed a bias of 0.18 litre min(-1) with narrow limits of agreement (-0.99 to 1.36 litre min(-1)). CONCLUSIONS: The agreement between EV-CO and TOE-CO is clinically acceptable, and these two techniques can be used interchangeably.

Effective systolic orifice area of the aortic valve: implications for Doppler echocardiographic cardiac output determinations.

BACKGROUND: Substantial research using echocardiography has established that stroke volume (SV) or cardiac output (CO) can be measured non-invasively at the level of the aortic valve (AV) with high accuracy. Stroke volume is the product of the velocity time integral occurring at the sampling site and the effective systolic AV orifice area (AVOAeff). Nevertheless, a generally accepted method for the determination of AVOAeff is still lacking. METHODS: Aortic valve OAeff was measured in 228 consecutive patients scheduled for coronary artery surgery. Two widely adopted methods were applied to approximate the constantly changing orifice area of the AV: (1) the circular orifice model (AVOA-CM), and (2) the triangular orifice model (AVOA-TM). Aortic valve OA-CM assumes the shape of a circle as an appropriately time averaged geometrical model, and AVOA-TM takes the shape of an equilateral triangle for granted. RESULTS: The AV was easily imaged by echocardiography in both short- and long-axis views in all patients. Relying on AVOA-CM, AVOAeff was 3.49+/-0.77 cm2. AVOA-TM estimates were 2.80+/-0.55 cm2 (mean+/-SD). The results did not agree (bias analysis). CONCLUSIONS: The echocardiographic measurement of SV or CO at the level of the AV has to be reconsidered.

In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy.

BACKGROUND: Mouse models of colitis and cancer are indispensable for our understanding of the pathogenesis of these diseases. In the past, mice had to be sacrificed in order to analyse colitis activity and tumour development. We have developed a safe method for high resolution endoscopic monitoring of living mice. METHODS: Mice developing colitis or colonic tumours were anaesthetised using avertine and repeatedly examined by endoscopy. A novel miniendoscope (1.9 mm outer diameter), denoted Coloview, was introduced via the anus and the colon was carefully insufflated with an air pump before analysis of the colonic mucosa. An extra working channel allowed the introduction of biopsy forceps or injection needles as well as surface staining with methylene blue in order to visualise the surface of the crypts and the pit pattern architecture. RESULTS: Endoscopic pictures obtained were of high quality and allowed monitoring and grading of disease. Scoring of colitis activity as well as tumour size and growth was possible. In addition, pit pattern analysis using chromoendoscopy permitted discrimination between inflammatory and neoplastic changes. Biopsies yielded enough tissue for molecular and histopathological analyses. CONCLUSIONS: In summary, chromoendoscopy in mice allows monitoring of the development of colitis and colon cancer with high resolution. Manipulations such as local injection of reagents or taking biopsies can be performed easily.

IL-6 signaling promotes tumor growth in colorectal cancer.

Recent investigations support an important role for TGF-beta in the development of colorectal cancer. However, the molecular consequences of TGF-beta signaling in the colon remains incompletely understood. In a recent study in Immunity, we analyzed the role of TGF-beta in a murine model of colon cancer. Using transgenic mice overexpressing TGF-beta or a dominant negative TGF-beta receptor II under control of the CD2 minigene, we show that TGF-beta signaling in tumor infiltrating T lymphocytes regulates the growth of dysplastic colon epithelial cells, as determined by histology and a novel system for high resolution chromoendoscopy in vivo. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Similar to these observations in mice, here we show that human colon cancer tissue expressed only low amounts of membrane bound IL-6R. In contrast, expression and activity of the matrix metalloproteinase TACE were increased. In summary, our data provide novel insights into the role of TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on an inhibition of TGF-beta-dependent IL-6 trans-signaling.

Severe hepatic injury in interleukin 18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo.

BACKGROUND: Interleukin 18 (IL-18) is a cytokine with pleiotropic activity that augments T helper 1 responses and cytotoxic activity of natural killer cells. METHODS: To assess the function of IL-18 in vivo, we generated IL-18 transgenic (IL-18 Tg) mice under the control of a CD2 promoter/enhancer construct. RESULTS: Macroscopically, IL-18 Tg mice showed reduced relative liver weight compared with wild-type littermates. TUNEL assays demonstrated increased hepatocyte apoptosis, and primary hepatocytes isolated from IL-18 Tg mice exhibited an increased spontaneous apoptosis rate. Furthermore, cross linking of Fas increased significantly the apoptosis rate in hepatocytes isolated from wild- type mice but to a much lesser extent in IL-18 Tg mice, suggesting spontaneous activation of the Fas pathway in the latter mice. In fact, in vivo blockade of Fas signal transduction by an adenovirus overexpressing the dominant negative form of the Fas associated death domain rescued hepatocytes from undergoing apoptosis. Finally, adoptive transfer of CD4(+) T cells from IL-18 Tg mice but not from wild-type littermates in SCID mice resulted in severe liver failure with massive periportal fibrosis due to hepatocyte apoptosis. CONCLUSION: IL-18 plays a fundamental role in regulating hepatocyte apoptosis. Furthermore, our transgenic model provides a novel tool to study the mechanisms of IL-18 dependent liver injury in vivo.