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ZusammenfassungIn den letzten Dekaden wurden erhebliche Fortschritte bei der (frühzeitigen) Diagnostik und Therapie gastrointestinaler onkologischer Erkrankungen erzielt. Allerdings bleibt die Prognose für fortgeschrittene Stadien von gastrointestinalen Tumoren für viele Patienten limitiert, und ungefähr ein Drittel aller Tumorpatienten verstirbt an den Folgen eines gastrointestinalen Tumors. Der Prävention und Früherkennung gastrointestinaler Tumoren kommt somit eine große Bedeutung zu.Aus diesem Grund fassen wir im Folgenden den Wissensstand und Empfehlungen zur primären, sekundären und tertiären Prävention von Ösophagus-, Magen-, Pankreas-, Leberzell- und kolorektalem Karzinom zusammen.

A wide range of pollutants cannot be perceived with human senses, which is why theuse of gas sensors is indispensable for an objective assessment of air quality. Sincemany pollutants are both odorless and colorless, there is a lack of awareness, inparticular among high school students. The project SUSmobil (funded by DBU –Deutsche Bundesstiftung Umwelt) aims to change this. In three modules on the topic ofgas sensors and air quality, the students (1) are familiarized with the functionality of ametal oxide semiconductor (MOS) gas sensor, (2) perform a sensor calibration and (3)carry out environmental measurements with calibrated sensors. Based on theseintroductory experiments, the students are encouraged to develop their ownenvironmental questions. In this contribution, we focus on the experimental andmodeling approach which explains the function principle of a MOS gas sensor in a waysuitable for high school students. This includes a qualitative and quantitativedescription of a simplified sensor model explaining the main processes on the sensorsurface. In addition, an HTML-based self-learning course is presented in which thestudents investigate the sensor behavior in the presence of different substancesdepending on the sensor temperature.

Ultraviolet B (UVB) irradiation induces hyperalgesia in human and animal pain models. We investigated mechanical sensitization, increase in axonal excitability, and spontaneous activity in different C-nociceptor classes after UVB in pig skin. We focused on units with receptive fields covering both irradiated and nonirradiated skin allowing intraindividual comparisons. Thirty-five pigs were irradiated in a chessboard pattern, and extracellular single-fibre recordings were obtained 10 to 28 hours later (152 fibers). Units from the contralateral hind limb served as a control (n = 112). Irradiated and nonirradiated parts of the same innervation territory were compared in 36 neurons; low threshold C-touch fibers (n = 10) and sympathetic efferents (n = 2) were unchanged, but lower mechanical thresholds and higher discharge frequency at threshold were found in mechanosensitive nociceptors (n = 12). Half of them could be activated with nonnoxious brush stimuli in the sunburn. Four of 12 mechanoinsensitive nociceptors were found sensitized to mechanical stimulation in the irradiated part of the receptive field. Activity-dependent slowing of conduction was reduced in the irradiated and in the nonirradiated skin as compared with the control leg, whereas increased ability to follow high stimulation frequencies was restricted to the sunburn (108.5 ± 37 Hz UVB vs 6.3 ± 1 Hz control). Spontaneous activity was more frequent in the sunburn (72/152 vs 31/112). Mechanical sensitization of primary nociceptors and higher maximum after frequency are suggested to contribute to primary hyperalgesia, whereas the spontaneous activity of silent nociceptors might offer a mechanistic link contributing to ongoing pain and facilitated induction of spinal sensitization.

Background/Objectives: In chronic pancreatitis (CP), progressive fibrosis of the pancreas leads to exocrine and endocrine insufficiency and, finally, to pancreatic burnout. Alcohol consumption is associated with fibrosis in the pancreas and the liver, and the activation of stellate cells plays a central role in the induction of fibrosis in both organs. However, the relationship between pancreatic burnout and liver cirrhosis (LC) is still poorly understood in patients with alcoholic CP (ACP). Methods: We performed a single-center, retrospective, cross-sectional study with 537 CP patients. We analyzed the clinical presence of early and advanced pancreatic burnout and stated LC in cases of typical alterations in histology, liver stiffness measurement, cross-sectional imaging, or ultrasound. We analyzed further clinical parameters. Results: The frequency of advanced pancreatic burnout was 6.5% for ACP (20/306) and 4% for non-ACP (8/206; p = 0.20; χ2 test). Advanced pancreatic burnout was not associated with the amount of alcohol consumption (p = 0.34) but with the disease duration (p = 0.0470) and rate of calcification (p = 0.0056). Furthermore, advanced pancreatic burnout was associated with LC (p < 0.0001) but cannot be explained by the amount of alcohol consumption. In ACP with alcohol consumption >80 g/day, an isolated LC was significantly more frequently detectable (14%, without pancreatic burnout) than an isolated advanced pancreatic burnout (1%, without LC). These results were confirmed by multivariable analyses. Conclusions: We identified a close association between LC and pancreatic burnout. The disease duration positively correlates with the development of pancreatic burnout. The liver seems to be more vulnerable to alcohol than the pancreas.

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following.In den letzten Dekaden wurden erhebliche Fortschritte bei der (frühzeitigen) Diagnostik und Therapie gastrointestinaler onkologischer Erkrankungen erzielt. Allerdings bleibt die Prognose für fortgeschrittene Stadien von gastrointestinalen Tumoren für viele Patienten limitiert, und ungefähr ein Drittel aller Tumorpatienten verstirbt an den Folgen eines gastrointestinalen Tumors. Der Prävention und Früherkennung gastrointestinaler Tumoren kommt somit eine große Bedeutung zu.Aus diesem Grund fassen wir im Folgenden den Wissensstand und Empfehlungen zur primären, sekundären und tertiären Prävention von Ösophagus-, Magen-, Pankreas-, Leberzell- und kolorektalem Karzinom zusammen.

Background: Several guidelines recommend the risk-adapted monitoring of patients with chronic pancreatitis (CP). However, dedicated risk stratification is widely missing in CP. Elderly-CP (disease onset with 60 or more years of age) may represent a subgroup of CP subjects with a distinct course of disease. Aims: We aimed to investigate the clinical presentation of elderly-CP, and if elderly-CP requires an adapted monitoring. Methods: Seven hundred forty one patients with CP were analyzed in a multicenter (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104), cross-sectional, retrospective study and classified according to the M-ANNHEIM classification. Results: The frequency of elderly-CP was 20% (148/741). In comparison with non-elderly-CP, elderly-CP was less frequently caused by alcohol and nicotine dependency or genetic mutations. In contrast, the frequency of efferent duct abnormalities (p = 0.009, chi-square test) and idiopathic CP (p < 0.0001, chi-square test) increased significantly. The presence of multiple risk factors was found less frequently in elderly-CP than in non-elderly patients (p < 0.0001; chi-square test). Furthermore, elderly-CP was associated with increased rates of pseudocysts (p = 0.0002; chi-square test), endocrine insufficiency (p = 0.001; chi-square test), and the absence of pain (p = 0.04; chi-square test) in the first year of the disease. Conclusion: In elderly-CP, the course of disease significantly differs from non-elderly-CP. Therefore, individualized monitoring strategies for elderly-CP might be necessary.

Abdominal pain, diarrhea with weight loss, and endocrine insufficiency represent the dominant symptoms of chronic pancreatitis (CP). High intensity of pain and constant pain have been shown to reduce quality of life in CP and may result in disability and increased health resource utilization. Various basic challenges and unanswered questions still exist regarding the treatment of pain in CP. Recently, limited evidence has been gained that early surgery for painful disease might be associated with better treatment results. Thus, timing of pancreatic surgery in painful disease represents a major issue that needs to be clarified in future studies. In this context, surveillance of patients is necessary in clinical practice. It appears that a generally accepted classification of the disease represents a major requirement for inter-institutional comparison of data with future progress in clinical research. Among recently proposed classification systems, the M-ANNHEIM classification system of CP with its recently presented M-ANNHEIM Surgery Score might be a useful tool to picture the course of the disease and to monitor treatment results. Future research is required to clarify the possible role of this system in the management of pain in CP. In the present article, we provide an overview of current status, challenges, and unanswered questions in the treatment of pain in CP, and we demonstrate the potential benefits of the M-ANNHEIM classification system in the management of painful CP.

Key points C-nociceptors are generally assumed to have a low maximum discharge frequency of 10 - 30 Hz. However, only mechano-insensitive "silent" C-nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C-nociceptors in the pig follow even 100 Hz without conduction failure. Sensitization by nerve growth factor increases the maximum following frequency of "silent" nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation. A distinct class of C-nociceptors with mechanical thresholds >150 mN resembles "silent" nociceptors at low stimulation frequencies in pig and human, but is capable of 100 Hz discharge and thus, is suited to encode painfulness of noxious mechanical stimuli. Abstract Using extracellular single-fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5-100 Hz) in different classes of C-nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano-sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano-insensitive C-nociceptors (CMi) showed the highest ADS (34 % ± 8 %), followed only 66±27 % of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano-insensitive nociceptors (20 ±16 % to 38±23 % response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2±10.2 %) followed stimulation frequencies of 100 Hz without conduction failure (98.5±6 %). A distinct class of C-nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2 % ±7.6 %), but displayed almost no propagation failure even at 100 Hz stimulation (84.7±17 %). Also among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical for silent nociceptors. C-fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal condition when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit which possibly contributes to excruciating pain under inflammatory conditions. This article is protected by copyright. All rights reserved.

Background: Acid suppressing drugs (ASD) are generally used in acute pancreatitis (AP); however, large cohorts are not available to understand their efficiency and safety. Therefore, our aims were to evaluate the association between the administration of ASDs, the outcome of AP, the frequency of gastrointestinal (GI) bleeding and GI infection in patients with AP. Methods: We initiated an international survey and performed retrospective data analysis on AP patients hospitalized between January 2013 and December 2018. Results: Data of 17,422 adult patients with AP were collected from 59 centers of 23 countries. We found that 23.3% of patients received ASDs before and 86.6% during the course of AP. ASDs were prescribed to 57.6% of patients at discharge. ASD administration was associated with more severe AP and higher mortality. GI bleeding was reported in 4.7% of patients, and it was associated with pancreatitis severity, mortality and ASD therapy. Stool culture test was performed in 6.3% of the patients with 28.4% positive results. Clostridium difficile was the cause of GI infection in 60.5% of cases. Among the patients with GI infections, 28.9% received ASDs, whereas 24.1% were without any acid suppression treatment. GI infection was associated with more severe pancreatitis and higher mortality. Conclusions: Although ASD therapy is widely used, it is unlikely to have beneficial effects either on the outcome of AP or on the prevention of GI bleeding during AP. Therefore, ASD therapy should be substantially decreased in the therapeutic management of AP. (C) 2020 IAP and EPC. Published by Elsevier B.V.

Objectives Patients with inflammatory bowel disease (IBD) frequently reveal features of pancreatic inflammation. However, the prevalence of IBD in patients with alcoholic pancreatitis (AP) and nonalcoholic pancreatitis (NAP) has not yet been determined, and the prevalence of IBD in patients with autoimmune pancreatitis (AiP) from Germany is unknown. Aims Thus, we aimed, first, to determine the prevalence of IBD in AP, NAP, and AiP from a tertiary center in Germany and, second, to characterize patients with AiP and IBD. Methods We performed a retrospective cross-sectional study to determine the prevalence of IBD in patients with different forms of pancreatitis presenting to our clinic. Results Compared to the general population and to a control group with viral hepatitis from our clinic, we observed the most significant increase of IBD in patients with AiP (n = 3/28; p Conclusions Immune-mediated mechanisms related to IBD may participate in the development of AiP, especially AiP type 2, and may also increase the risk for the development of other forms of pancreatic inflammation.

Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest human malignancies and is associated with excruciating pain, which is a serious complication and severely impacts the quality of life in patients. In human patients, poor survival prognosis is linked to remarkable remodeling of intrapancreatic nerves, which, in turn, is correlated to increased pain intensity. Understanding mechanisms underlying pain associated with PDAC has been hampered by the lack of animal models which replicate all germane aspects of the disease and importantly, enable analyses of pain associated with PDAC. In this study, we describe an immunocompetent orthotopic mouse model of PDAC involving intrapancreatic growth of K8484 mouse PDAC cells, which reliably exhibits a large number of key characteristics of human PDAC, including its unique histopathology and neuroplastic changes. We observed that tumor-bearing mice demonstrated significant abdominal mechanical hypersensitivity to von Frey stimuli as well as on-going pain in the conditioned place preference paradigm. Moreover, a myriad of other behavioral tests revealed that indicators of overall well-being were significantly reduced in tumor-bearing mice as compared to sham mice. Morphological and immunohistochemical analyses revealed structural remodeling in several different types of sensory and autonomic nerve fibers. Finally, perineural invasion of tumor cells, a cardinal manifestation in human PDAC, was also observed in our orthotopic mouse model. Thus, we describe a validated tumor model for quantitatively testing hypersensitivity and pain in PDAC, which lays a crucial basis for interrogating tumor-nerve interactions and the molecular and cellular mechanisms underlying pain in PDAC.

Background/Aims: Autoimmune pancreatitis (AIP) has been associated with an increased risk of malignant diseases. We aimed to describe the incidence of malignant diseases in patients with AIP compared to the general population and to characterize the clinical presentation of these patients. Methods: We retrospectively analyzed data from 28 patients with AIP presenting to the clinic (periods 1998 until 2010, 2012 until September 2015). We retrieved the expected cancer incidence of the general population from the German cancer registry. We determined the ratio of patients with malignant disease, characterized the clinical presentation of these patients, and calculated standardized incidence ratios (SIR). Results: We observed 6 malignant diseases in 5 patients with AIP (non-Hodgkin lymphoma, colon cancer, breast cancer and ovarian carcinoma, breast cancer, bladder cancer, n = 5/28, 17.9%) during an overall observation period of 223 person-years (2,675 months). The overall SIR of cancer in patients with AIP was 17.3 (95% CI 5.9-35.8), and the overall incidence rate of malignant diseases in these patients was significantly increased compared to the expected incidence in the German population (Fisher's exact test, p < 0.001). Conclusion: The incidence of malignant diseases in patients with AIP is significantly increased compared to the general population. Careful clinical monitoring is required in individuals with AIP to exclude the occurrence of malignancy.

Background/Aims: The prevalence and incidence of autoimmune pancreatitis (AiP) in those living in western countries are largely unknown. We aimed to determine the prevalence of AiP among patients with pancreatitis presenting to our tertiary referral center in Mannheim, Germany; and to estimate the incidence of AiP in the Southwest of Germany. Methods: We performed a retrospective cross-sectional analysis and determined the prevalence of AiP in patients with acute pancreatitis (AP) or chronic pancreatitis (CP). Patients (n = 704; alcoholic pancreatitis n = 373, nonalcoholic pancreatitis n = 331) were stratified into the Retrospective-Pancreas-Cohort (RPC, period 1998-2008, n = 534) and the Pancreas-Clinic-Cohort (PCC, periods 2008-2010 and 2013-2014, n = 170, with detailed investigation for features of AiP). Diagnosis of AiP was established by International-Consensus-Diagnostic-Criteria and Unifying-Autoimmune-Pancreatitis-Criteria. Results: In the RPC, the prevalence of AiP was 5.9% (n = 13/221) among individuals with nonalcoholic pancreatitis (n = 1/61 with AP, 1.6%; n = 12/160 with CP, 7.5%). In the PCC, the prevalence of AiP was 9.1% (n = 10/110) among patients with nonalcoholic pancreatitis (n = 2/24 with AP, 8.3%; n = 8/86 with CP, 9.3%), and 1.7% (n = 1/60) among subjects with alcoholic pancreatitis. We estimated the incidence of AiP with 0.29 per 100,000 population each year. Conclusion: The prevalence rate of AiP may account for 9% of patients with nonalcoholic pancreatitis but is almost never observed in patients with alcoholic pancreatitis. The incidence of AiP in Germany appears lower than 1 per 100,000 population.

The M-ANNHEIM classification of chronic pancreatitis (CP) stratifies degrees of disease severity according to the M-ANNHEIM-Severity-Score. We aimed to demonstrate the clinical usefulness of the M-ANNHEIM-Severity-Score in quantifying and predicting the frequency of pancreatic surgery, and to establish the M-ANNHEIM-Surgery-Score as a simplified system for patient surveillance regarding the demand of pancreatic surgery. We performed a retrospective, cross-sectional study with 741 CP patients (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104) categorized according to the M-ANNHEIM classification. We observed a significantly higher M-ANNHEIM-Severity-Score in patients that were classified within 7 days preceding pancreatic surgery than in individuals that did not require surgery (p 0.001, Mann-Whitney-U-test). Using a logistic regression analysis with all variables of the M-ANNHEIM-Severity-Score, we established the M-ANNHEIM-Surgery-Score as a simplified new tool to identify patients that may require surgery. A receiver operating characteristic-analysis revealed a cut-off-value of 9 points within the M-ANNHEIM-Surgery-Score to identify these individuals (sensitivity 78.7 %, specificity 91 %). Based on the M-ANNHEIM-Surgery-Score, we defined three categories for demand of surgery with frequencies of pancreatic operations of 1.6 % (n = 7/440) in the "Baseline-Demand"-category, 7 % (n = 12/172) in the "Low-Demand"-category (p 0.0001, Chi-square-test, OR 4.6, Confidence Interval (CI) 1.8 - 12), and 54 % (n = 70/129) in the "High-Demand"-category (p 0.0001, OR 73, CI 32 - 167). Patients that were categorized for the "High-Demand"-category, but were not operated on, had a significantly increased ratio of clinical features that hamper performance of surgery (p 0.001, Chi-square-test). The M-ANNHEIM-Surgery-Score represents a useful tool to monitor patients with CP and to estimate the demand of surgery in CP. Die M-ANNHEIM-Klassifikation der chronischen Pankreatitis unterscheidet verschiedene Erkrankungsaktivitäten gemäß dem M-ANNHEIM-Severity-Score. Es war das Ziel unserer Arbeit, den klinischen Nutzen des M-ANNHEIM-Severity-Score bei der Quantifizierung des Bedarfs an Pankreasoperationen und bei der Vorhersage hinsichtlich einer Operationsnotwendigkeit bei Patienten mit chronischer Pankreatitis aufzuzeigen und den M-ANNHEIM-Surgery-Score als ein vereinfachtes System zur Patientenüberwachung hinsichtlich des Operationsbedarfs zu etablieren. Wir führten eine retrospektive Querschnittsstudie mit 741 Patienten mit chronischer Pankreatitis durch (Mannheim/Deutschland, n = 537; Gießen/Deutschland, n = 100; Donetsk/Ukraine, n = 104), die gemäß der M-ANNHEIM-Klassifikation kategorisiert waren. Wir beobachteten einen signifikant höheren M-ANNHEIM-Severity-Score bei Patienten, die innerhalb von 7 Tagen vor einer Pankreasoperation klassifiziert wurden, als bei Patienten, die nicht unmittelbar vor einer Operation standen (p 0,001, Mann–Whitney-U-Test). Wir konnten durch eine logistische Regressionsanalyse mit allen Variablen des M-ANNHEIM-Severity-Score den M-ANNHEIM-Surgery-Score als ein vereinfachtes und neues Werkzeug etablieren, das zur Identifikation von Patienten beiträgt, die möglicherweise eine Pankreasoperation benötigen. Eine Receiver-Operator-Characteristic-Analyse ergab einen Cut-Off-Wert von 9 Punkten im M-ANNHEIM-Surgery-Score, der diese Patienten identifiziert (Sensitivität 78,7 %, Spezifität 91 %). Mit dem M-ANNHEIM-Surgery-Score konnten 3 Kategorien des Bedarfs einer Pankreasoperation abgegrenzt werden: Die „Basisbedarfskategorie“ mit einer Häufigkeit von Pankreasoperationen von 1,6 % (n = 7/440), die „Niedrigbedarfskategorie“ mit einer Häufigkeit von Pankreasoperationen von 7 % (n = 12/172; p 0,0001, Chi-Square-Test, OR 4,6, Konfidenzintervall (CI) 1,8 – 12) und die „Hochbedarfskategorie“ mit einer Häufigkeit von Pankreasoperationen von 54 % (n = 70/129; p 0,0001, OR 73, CI 32 – 167). Patienten, die in der „Hochbedarfskategorie“ lagen, die aber nicht operiert wurden, hatten signifikant häufiger klinische Merkmale, die die Durchführung einer Pankreasoperation behinderten (p 0,001, Chi-Square-Test). Der M-ANNHEIM-Surgery-Score stellt ein nützliches Werkzeug zur Überwachung von Patienten mit chronischer Pankreatitis dar und unterstützt die Einschätzung des Bedarfs einer Pankreasoperation in diesem Patientenkollektiv.

Smart Glasses such as Google Glass are mobile computers combining classical Head-Mounted Displays (HMD) with several sensors. Therefore, contact-free, sensor-based experiments can be linked with relating, near-eye presented multiple representations. We will present a first approach on how Smart Glasses can be used as an experimental tool for head-centered, context-aware, wearable-technology-enhanced, and inquiry-based learning in physics education. Therefore, we developed an app that is based on the Google Glass platform and designed to perform educational physical experiments on the topic of acoustics. Its initial application is intended for high-school students whose task is to study the relationship between the frequency of the sound generated by hitting a glass of water and the amount of water in the glass. The core idea is to have Google Glass automatically measure both the water fill level with the camera and the sound frequency with the microphone, and incrementally generate a fill level/frequency graph in the HMD. We designed an educational setting and studied its effect on cognitive and affective variables with an intervention-control-group design. While the intervention group analyzed the fill level/frequency relationship with the Google Glass platform, control group 1 worked on the phenomenon using the same platform implemented on a tablet PC. Control group 2 analyzed the phenomenon using a tablet PC with a typical mobile-based education platform. We used a two-way ANCOVA to study learning outcome, wondering, curiosity, cognitive load, and experimentation time as dependent variables of 46 high-school eighth-graders together with group membership and gender influence as independent variables. While the positive effects of using Google Glass as a mobile lab on wondering and curiosity as well as a positive trend for experimentation time were detected, no differences were analyzed for learning achievement. Although students have a higher cognitive load when working with Google Glass compared to other devices, the cognitive load level is very low in general.

A variety of experiments with smartphones and tablet PCs allow a precise analysis of acoustic phenomena. For example, we recently described an experiment in which a noise signal simultaneously triggered harmonic acoustic resonances in the air column of a tube open at both ends and a tube closed at one end. The measured resonant frequencies were used to determine the speed of sound in air with an error less than 4%. The present article describes experiments for harmonic resonances in another type of one-dimensional wave carrier, viz. clamped metal rods. Resonances are generated by hitting one end face of the rod; the resonant frequencies can then be measured by an app on a smartphone or tablet PC. The experiments can be used to explore how the excitement of particular resonant frequencies depend on boundary conditions like the length of the rod, the number and specific positions of fixed points of the rod, and the rod's material. In addition the rod's longitudinal (the so-called extensional) speed of sound can be determined.

The checkpoint pathway consisting of programmed death ligand 1 (PD-L1) and its receptor, PD-1, modulates immune function in cancer and infection, but unexpectedly, it also silences pain signals in nerves.

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by excruciating pain, which has been associated with attraction of cancer cells and their invasion of intrapancreatic sensory nerves. Neutralization of the chemokine CCL2 reduced cancer-associated pain in a clinical trial, but there have been no systematic analyses of the highly diverse chemokine families and their receptors in PDAC. Methods We performed an open, unbiased RNA-interference screen of mammalian chemokines in co-cultures of mouse PDAC cells (K8484) and mouse peripheral sensory neurons, and confirmed findings in studies of DT8082 PDAC cells. We studied the effects of chemokines on migration of PDAC cell lines. Orthotopic tumors were grown from K8484 cells in mice, and mice were given injections of neutralizing antibodies against chemokines, antagonists, or control antibodies. We analyzed abdominal mechanical hypersensitivity and collected tumors and analyzed them by histology and immunohistochemistry to assess neural remodeling. We collected PDAC samples and information on pain levels from 74 patients undergoing resection and measured levels of CXCR3 and CCR7 by immunohistochemistry and immunoblotting. Results Knockdown of 9 chemokines in DRG neurons significantly reduced migration of PDAC cells towards sensory neurons. Sensory neuron–derived CCL21 and CXCL10 promoted migration of PDAC cells via their receptors CCR7 and CXCR3, respectively, which were expressed by cells in orthotopic tumors and PDAC specimens from patients. Neutralization of CCL21 or CXCL10, or their receptors, in mice with orthotopic tumors significantly reduced nociceptive hypersensitivity and nerve fiber hypertrophy and improved behavioral parameters without affecting tumor infiltration by T cells or neutrophils. Increased levels of CXCR3 and CCR7 in human PDAC specimens were associated with increased frequency of cancer-associated pain, determined from patient questionnaires. Conclusions In an unbiased screen of chemokines, we identified CCL21 and CXCL10 as proteins that promote migration of pancreatic cancer cells toward sensory neurons. Inhibition of these chemokines or their receptors reduce hypersensitivity in mice with orthotopic tumors, and patients with PDACs with high levels of the chemokine receptors of CXCR3 and CCR7 had increased frequency of cancer-associated pain.

Patients with inflammatory bowel disease (IBD) frequently reveal features of pancreatic inflammation. However, the prevalence of IBD in patients with alcoholic pancreatitis (AP) and nonalcoholic pancreatitis (NAP) has not yet been determined, and the prevalence of IBD in patients with autoimmune pancreatitis (AiP) from Germany is unknown.Thus, we aimed, first, to determine the prevalence of IBD in AP, NAP, and AiP from a tertiary center in Germany and, second, to characterize patients with AiP and IBD.We performed a retrospective cross-sectional study to determine the prevalence of IBD in patients with different forms of pancreatitis presenting to our clinic.Compared to the general population and to a control group with viral hepatitis from our clinic, we observed the most significant increase of IBD in patients with AiP (n = 3/28; p 0.0001 vs. general population, binomial proportion test; p = 0.0112 vs. hepatitis group, Fisher's exact test), followed by a significant increase in subjects with NAP (n = 11/278; p 0.0001 vs. general population, binomial proportion test; p = 0.0338 vs. hepatitis group, Fisher's exact test). A review of previous studies on the prevalence of IBD among patients with AiP revealed a combined prevalence of 12 % (n = 43/355). Type 2 AiP is significantly more often associated with IBD than type 1 AiP (n = 28/48, 58 % vs. n = 7/129, 5 %; combined patient cohort, p 10E - 12; Fisher's exact test).Immune-mediated mechanisms related to IBD may participate in the development of AiP, especially AiP type 2, and may also increase the risk for the development of other forms of pancreatic inflammation.Patienten mit chronisch entzündlicher Darmerkrankung (CED) entwickeln häufig morphologische Pankreasveränderungen. Die Prävalenz von CED bei Patienten mit alkoholischer Pankreatitis (AP) und nicht-alkoholischer Pankreatitis (NAP) wurde bislang nicht untersucht, und die Prävalenz von CED bei Patienten mit autoimmuner Pankreatitis (AiP) aus Deutschland ist ebenfalls unbekannt. ZIEL: Die Ziele der Arbeit waren, die Prävalenz von CED bei Patienten mit AP, NAP und AiP in einem tertiären Versorgungszentrum in Deutschland zu bestimmen, und die Patienten mit CED und AiP zu charakterisieren.Wir bestimmten in einer retrospektiven Querschnittsstudie die Prävalenz von CED bei Patienten mit verschiedenen Formen der Pankreatitis, die sich in unserer Klinik vorstellten.Wir beobachteten im Vergleich zur Allgemeinbevölkerung und zu einer Kontrollgruppe mit viraler Hepatitis unserer Klinik die deutlichste signifikante Häufung von CED bei Patienten mit AiP (n = 3/28; p 0.0001 versus Allgemeinbevölkerung, Binomial Proportion Test; p = 0.0112 versus Hepatitisgruppe, Fisher’s exact Test). Wir sahen ebenfalls eine signifikante Häufung von CED bei Patienten mit NAP (n = 11/278; p 0.0001 versus Allgemeinbevölkerung, Binomial Proportion Test; p = 0.0338 versus Hepatitisgruppe, Fisher’s exact Test). Ein Review unter Berücksichtigung aller vorangegangenen Studien ergab eine kombinierte Prävalenz der CED bei Patienten mit AiP von 12 % (n = 43/355). Die Typ 2 AiP war signifikant häufiger mit CED assoziiert als die Typ 1 AiP (n = 28/48, 58 % versus n = 7/129, 5 %; kombinierte Patientengruppe, p 10E - 12; Fisher’s exact Test).Mit CED assoziierte immunologische Mechanismen beteiligen sich möglicherweise bei der Entwicklung der AiP, insbesondere der Typ 2 AiP, und tragen eventuell auch zur Entstehung anderer entzündlicher Pankreaserkrankungen bei.

Autoimmune pancreatitis (AiP) is treated by immunosuppressive therapy. Exact description of disease activity of AiP is essential in clinical practice and research, but a score to describe the disease activity is missing. Thus, we aimed to establish an activity score of AiP.We retrospectively studied long-term disease courses of 29 patients with AiP (Mannheim, Germany), receiving corticosteroid treatment (CST) by analyzing 613 treatment appointments. Two assumptions were made: First, disease activity is higher at emergency treatments; second, disease activity drops under CST. In all patients, we evaluated established activity- and classification-systems of chronic pancreatitis (cP). Based on the most suitable system, we established an activity score of AiP by including AiP-specific parameters identified from our long-term disease courses and the literature. The new AiP-specific activity score was validated in an external cohort of 14 patients with AiP (Stockholm, Sweden).Within published activity indexes of cP, the M-ANNHEIM-classification most significantly correlated with emergency- and treatment-dependent disease activities (p 0.001 and p 0.01, conditional-logistic-regression-analysis). Significant correlations of disease activity were found for several clinical parameters (biliary involvement, extrapancreatic lesions, acute pancreatitis, focal pancreatic mass, pancreatic sausage/mass, focal enlargement, ascites; p 0.05, Wilcoxon-signed-rank-test). Based on these data and disease features from the literature, the M-ANNHEIM-AiP-Activity-Score (MAAS) was established. CST-induced reduction of MAAS disease activity of more than 60% was associated with lower relapse rates (p 0.05; Chi-Square-test). The results were validated in the external patient cohort.The MAAS might represent a useful tool to monitor AiP.

Smartphones and tablets are used as experimental tools and for quantitative measurements in two traditional laboratory experiments for undergraduate physics courses. The Doppler effect is analyzed and the speed of sound is determined with an accuracy of about 5% using ultrasonic frequency and two smartphones, which serve as rotating sound emitter and stationary sound detector. Emphasis is put on the investigation of measurement errors in order to judge experimentally derived results and to sensitize undergraduate students to the methods of error estimates. The distance dependence of the illuminance of a light bulb is investigated using an ambient light sensor of a mobile device. Satisfactory results indicate that the spectrum of possible smartphone experiments goes well beyond those already published for mechanics.

We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP.From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98).Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U-AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC.Unifying-Autoimmune-Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP.

Fur kaum eine andere Messgrose stehen mehr Smartphone-Applikationen zur Auswahl als fur den Schalldruckpegel. Die angebotenen Apps erfullen aber in der uberwaltigenden Mehrheit die in internationalen Normen festgelegten Qualitatsmerkmale (zum Beispiel fur Europa [1]) nicht [2]. Aus einer Reihe empfehlenswerter Anwendungen [2, 3] stellen wir die iOS-App Noise Immission Analyzer vor.

Nerve growth factor (NGF) induces acute sensitization of nociceptive sensory endings and long-lasting hyperalgesia. NGF modulation of sodium channel expression might contribute to neurotrophin-induced hyperalgesia. Here, we investigated NGF-evoked changes of the activity-dependent slowing of conduction in porcine C-fibers. Animals received intradermal injections of NGF (2 μg or 8 μg) or saline in both hind limbs. Extracellular recordings from the saphenous nerves were performed 1 week later. Based on sensory thresholds and electrically induced activity-dependent slowing (ADS) of axonal conduction, C-fibers were classified as mechano-sensitive afferents, mechano-insensitive afferents, cold nociceptors, and sympathetic efferents. NGF (2 μg) increased conduction velocity in C-fibers from 1.0 ± 0.05 m/s to 1.2 ± 0.07 m/s. In mechano-insensitive afferents, NGF (8 μg) reduced activity-dependent slowing of conduction, from 5.3 ± 0.2% to 3.2 ± 0.5% (0.125–0.5 Hz stimulation) and from 28.5 ± 1.3% to 20.9 ± 1.9% (2 Hz stimulation), such that ADS no longer differentiated between mechano-sensitive and mechano-insensitive fibers. Accordingly, the number of fibers with pronounced ADS decreased but more units with pronounced ADS were mechano-sensitive. Spontaneously active C-fibers were increased above the control level (1%) by NGF 8 μg (8%). The results demonstrate that NGF changes the functional axonal characteristics of mechano-insensitive C-fibers and enhances spontaneous activity thereby possibly contributing to hyperalgesia.

High-affinity receptors for nerve growth factor (NGF) are found on nociceptors and sympathetic efferents. NGF is known to sensitize nociceptors, increase innervation density, and fire frequency of sympathetic fibers. We explored axonal sensitization of afferent and efferent fibers following intracutaneous injection of NGF in human and pig skin. In humans, frequency-dependent (5, 20, 100 Hz) electrically induced pain was assessed 1, 3, 7, 21, and 49 days post injection. Sweat output was recorded in parallel using the quantitative sudomotor axon reflex test (QSART). Electrically induced pain ratings (7.5 mA for 30 s) significantly increased at the NGF sites for 5 Hz (numeric rating scale [NRS] 6 ± 0.5 vs 3.7 ± 0.4), 20 Hz (NRS 7.2 ± 0.4 vs 5 ± 0.5), and 100 Hz stimulation (NRS 6.9 ± 0.4 vs 5.4 ± 0.3) at day 21, and also for 5 Hz at day 49 (NRS 5.4 ± 0.4 vs 3.8 ± 0.3). Electrically evoked QSART increased frequency dependent, but was not altered by NGF throughout the entire observation period (average QSART at 5 Hz: 3 mL/h/m2, 20 Hz: 9 mL/h/m2, 100 Hz: 10 mL/h/m2). Similarly, NGF did not change the activity-dependent slowing of conduction of sympathetic efferents (6 ± 2% vs 5.1 ± 1.5%, for 3 minutes, 2 Hz) in pig single-fiber recordings. In parallel to the increased pain ratings recorded in humans, activity-dependent slowing of mechano-insensitive nociceptors was reduced by NGF (18.1 ± 2% vs 29 ± 1.4%). In summary, axonal sensitization of nociceptors by NGF could underlie the hyperalgesia to electrical stimulation. Enhanced responses were limited to nociceptors, as no sensitization was found in sympathetic efferent neurons.

We demonstrate how Smart Glasses can support high school science experiments. The vision is to (1) reduce the "technical" effort involved in conducting the experiments (measuring, generating plots etc.) and to (2) allow the students to interactively see/manipulate the theoretical representation of the relevant phenomena while at the same time interacting with them in the real world. As a use case, we have implemented a Google Glass app for a standard high school acoustics school experiment (determining the relationship between tone frequency that hitting a glass filled with water generates and the amount of water in the glass). We evaluated the system with a group of 36 high grade students split into a group using our application and a control group using an existing tablet based system. We show a statistically significant advantage in experiment execution speed, cognitive load, and curiosity.

When traveling by rail, you might have experienced the following phenomenon: The train enters a tunnel, and after some seconds a noticeable pressure change occurs, as perceived by your ears or even by a rapid wobbling of the train windows. The basic physics is that pressure waves created by the train travel down the tunnel, are reflected at its other end, and travel back until they meet the train again. Here we will show (i) how this effect can be well understood as a kind of large-scale outdoor case of a textbook paradigm, and (ii) how, e.g., a prediction of the tunnel length from the inside of a moving train on the basis of this model can be validated by means of a mobile phone measurement.

We present a fully functional application prototype gPhysics App based on the Google Glass platform which is designed to perform an educational physical experiment in the area of acoustics. The initial applications aims towards students whose task is to find the relationship between the frequency of the sound generated by hitting a water glass and the amount of water.