Prospective Associations of Lifetime Post-traumatic Stress Disorder and Birth-Related Traumatization With Maternal and Infant Outcomes

Objective: Many women experience traumatic events already prior to or during pregnancy, and delivery of a child may also be perceived as a traumatic event, especially in women with prior post-traumatic stress disorder (PTSD). Birth-related PTSD might be unique in several ways, and it seems important to distinguish between lifetime PTSD and birth-related traumatization in order to examine specific consequences for mother and child. This post-hoc analysis aims to prospectively examine the relation of both, lifetime PTSD (with/without interpersonal trauma) and birth-related traumatization (with/without postpartum depression) with specific maternal and infant outcomes. Methods: In the prospective-longitudinal Maternal in Relation to Infants' Development (MARI) study, N = 306 women were repeatedly assessed across the peripartum period. Maternal lifetime PTSD and birth-related traumatization were assessed with the Composite International Diagnostic Interview for women. Maternal health during the peripartum period (incl. birth experience, breastfeeding, anxiety, and depression) and infant outcomes (e.g., gestational age, birth weight, neuropsychological development, and regulatory disorders) were assessed via standardized diagnostic interviews, questionnaires, medical records, and standardized observations. Results: A history of lifetime PTSD prior to or during pregnancy was reported by 25 women who indicated a less favorable psycho-social situation (lower educational level, less social support, a higher rate of nicotine consumption during pregnancy). Lifetime PTSD was associated with pregnancy-related anxieties, traumatic birth experience, and anxiety and depressive disorders after delivery (and in case of interpersonal trauma additionally associated with infant feeding disorder). Compared to the reference group, women with birth-related traumatization (N = 35) indicated numerous adverse maternal and infant outcomes (e.g., child-related fears, sexual problems, impaired bonding). Birth-related traumatization and postpartum depression was additionally associated with infant feeding and sleeping problems. Conclusion: Findings suggest that both lifetime PTSD and birth-related traumatization are important for maternal and infant health outcomes across the peripartum period. Larger prospective studies are warranted. Implications: Women with lifetime PTSD and/or birth related traumatization should be closely monitored and supported. They may benefit from early targeted interventions to prevent traumatic birth experience, an escalation of psychopathology during the peripartum period, and adverse infant outcomes, which in turn may prevent transgenerational transmission of trauma in the long term.Peer Reviewe

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU)

There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach.Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers.The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as 'strong' and plenary voting revealed 'strong agreement' for 99 (98%) recommendations.The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research

Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling

Objective The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment. Design We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny. Results Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids. Conclusions Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.This study was funded by the Deutsche Forschungsgemeinschaft (DFG, K.L. 2544/1-1 and 1-2), the Forschungskern SyStaR to AK, BIU (Böhringer Ingelheim Ulm to AK), the Fritz-Thyssen Foundation (Az. 10.15.2.040), the German Cancer Aid (111879) and the Else-Kröner-Fresenius-Stiftung (2011_A200). AK is indebted to the Baden-Württemberg Stiftung for the financial support of this research project by the Eliteprogramme for Postdocs. AK is also an Else-Kröner-Fresenius Memorial Fellow. LP is supported by a research fellowship of the Else-Kröner-Fresenius-Stiftung. MH was supported by the International Graduate School in Molecular Medicine and the Bausteinprogramme (L.SBN. 110), Ulm University. MM is supported by a grant of Ulm University (Baustein for Senior Clinician Scientists). IGC is funded by the Interdisciplinary Center for Clinical Research (IZKF Aachen) and Start Program, RWTH Aachen University Medical School, Aachen, German

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU)

Background:There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach. Methods: Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers. Results: The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as strong' and plenary voting revealed strong agreement' for 99 (98%) recommendations. Conclusions:The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research

Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

Background and aimsAutoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens.MethodsWe retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary endpoint was complete remission, defined as the absence of clinical symptoms and resolution of the index radiological pancreatic abnormalities attributed to AIP.ResultsWe included 735 individuals with AIP (69% male; median age 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, while 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower ( 2 weeks (OR 0.908; 95%CI 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (OR 0.639; 95%CI 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid tapering duration, induction treatment duration, and total cumulative dose.ConclusionPatients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens

A study of the involvement of non-selective cation channels in the transport of ammonia across the bovine ruminal epithelium

Landwirtschaftliche Nutztiere tragen in erheblichen Umfang zur weltweit wachsenden Stickstoffemission in die Umwelt bei. Insbesondere beim Wiederkäuer führen erhebliche Anteile des eingesetzten Futterproteins nicht wie erwünscht zu mehr Fleischansatz und erhöhter Milchproduktion, sondern werden nach fermentativer Aufspaltung zu Ammoniak über die Epithelien des Gastrointestinaltraktes resorbiert, in der Leber energieaufwendig zu Harnstoff entgiftet und nachfolgend über die Niere in die Umwelt ausgeschieden. Unzählige Versuche, durch ruminale Ansäuerung oder Synchronisation der Verfütterung von Kohlenhydraten und Proteinen eine Reduktion der Stickstoffemission zu erzielen, haben nicht zum Durchbruch geführt. In vitro Versuche am Schafspansen belegen, dass Ammoniak nicht alleine durch physikalische Diffusion der ungeladenen Form (NH3) aus dem Pansen entweicht, sondern dass zusätzlich ein Efflux des protonierten Ammonium-Ions (NH4+) erfolgt. Über die beteiligten Mechanismen ist bisher fast nichts bekannt. Ziel dieser Arbeit war es daher, die Resorptionsmechanismen für Ammoniak über das Pansenepithel des Rindes mittels der Patch-Clamp-Technik, Fluxmessungen in der Ussing-Kammer und Messungen mittels pH-selektiver Mikroelektroden näher zu charakterisieren. Im Einzelnen wurden die folgenden Ergebnisse erzielt: \- Ammoniak induzierte einen positiven Kurzschlussstrom über Pansenepithelien des Rindes in der Ussing-Kammer (10 mmol•l-1; *40 mmol•l-1; *p < 0,05, N/n = 8/40). \- Bei Bestimmung des Ammoniak-Fluxes über das intakte Epithel wurden nach einer Fluxdauer von 150 Minuten bei mukosalem Einsatz von 10 mmol•l-1 NH4+ serosal 3,08 ± 0,17 mmol•l-1 NH4+ nachgewiesen. Bei Einsatz von apikal 40 mmol•l-1 NH4+ erhöhte sich die serosal nachgewiesene Menge auf 8,72 ± 0,65 mmol•l-1 NH4+. Dabei kam es zu keiner Alkalinisierung des serosalen pH-Wertes, wie sie bei überwiegendem Efflux von NH3 in die nur gering gepufferte serosale Lösung zu erwarten gewesen wäre (p = 0,18; N/n = 8/40). \- Bei Mikroelektroden-Messungen führte der Ersatz von 40 mmol•l-1 NMDG+ durch eine äquimolare Menge NH4+ sowohl bei einem mukosalen pH-Wert von 6,4 als auch bei 7,4 zu einer signifikanten Steigerung des transepithelialen und apikalen Potentials (pH 6,4: ΔPDt 2,78 ± 0,37 mV; ΔPDa 2,13 ± 0,5 mV; pH 7,4: ΔPDt 2,53 ± 0,46 mV; ΔPDa 1,0 ± 1,8 mV; N/n = 6/12, p < 0,05). Gleichzeitig konnte unter beiden Versuchsbedingungen ein signifikanter Abfall des pHi gemessen werde (pH 6,4: ΔpHi -0,13 ± 0,02; pH 7,4: ΔpHi -0,16 ± 0,05; N/n = 6/12, p < 0,05). Dieses Ergebnis belegt einen transzellulären Effluxmechanismus und deutet weiterhin darauf hin, dass sowohl bei einem pH-Wert in Höhe von 6,4 als auch 7,4 die apikale elektrogene Aufnahme in Form von NH4+ leicht gegenüber der serosalen Abgabe in dieser Form überwiegt. \- Die Leitfähigkeit für NH4+ wurde durch extrazelluläre divalenten Kationen (Ca2+ und Mg2+) blockiert. Dies konnte sowohl in Patch-Clamp Messungen an isolierten Zellen, die mit einer Na- Glukonat oder K-Glukonat Pipettenlösung gefüllt waren (n = 8, p = 0,008 und n = 7, p = 0,016), als auch an intakten Epithelien (Mikroelektrodentechnik) (N/n = 3/4, p = 0,005) gezeigt werden. Verapamil hatte ebenfalls eine hemmende Wirkung (N/n = 3/7, p = 0,008). \- Verschiedene spezifische Modulatoren der TRP-Kanalfamilie hatten einen Einfluss auf den NH4+ induzierten Kurzschlussstrom. So konnte gezeigt werden, dass Menthol (200 μmol/l; 1 mmol/l) zu einer transienten Steigerung des Isc über das Epithel führte (ΔIsc 5,35 ± 0,97 μA•cm-2; N/n = 4/11, p = 0,02 bzw. ΔIsc 4,53 ± 0,94 μA.cm-2; N/n = 3/12, p = 0,022). Capsaicin (100 μmol•l-1) führte dagegen zu einer signifikanten Hemmung dieses Kurzschlussstroms (ΔIsc -3,25 ± 1,16 μA•cm-2; N/n = 4/6, p = 0,02). Die Applikation von Thymol (100 μmol•l-1 und 1 mmol•l-1) hatte ebenfalls einen deutlichen, wenn auch stark vom individuellen Epithel abhängigen Effekt auf den NH4+ induzierten Kurzschlussstrom (N/n = 2/4 und N/n = 6/9). Eine Applikation von Lösungsmittel ohne Agonist blieb hingegen ohne Effekt (N/n = 3/6). Auch an Epithelien von Schafen waren entsprechende Effekte nachweisbar. \- Da der apikale Ersatz von Chlorid durch Glukonat zu einer Hyperpolarisation des apikalen Potentials führte, dürften die in Zellen des Pansenepithels nachweißbaren Anionenkanäle basolateral exprimiert werden. Eine Beteiligung an den durch TRP-Modulatoren auslösbaren Stromantworten erscheint daher unwahrscheinlich. Zusammenfassend deuten die Ergebnisse auf die Beteiligung von nicht-selektiven Kationenkanälen der TRP-Familie am Efflux von Ammoniak aus dem Pansen hin. Eine mögliche Beteiligung dieser Kanäle am Efflux von Protonen aus dem Pansen im Sinne der intraruminalen pH-Homöostase wird diskutiert. Eine gezielte Beeinflussung des Ammoniumtransportes aus dem Pansen des Rindes durch Züchtung oder dem Einsatz entsprechender Modulatoren erscheint möglich.The impact of the livestock industry on the globally increasing emissions of nitrogen is profound. Particularly in ruminants, a large percentage of the protein that is fed does not lead to the desired increases in meat and milk production, but is microbially broken down into ammonia, absorbed across the epithelia of the gastro-intestinal tract, hepatically converted into urea in an energy-consuming process and finally emitted into the environment via the kidney. Countless studies attempting to reduce nitrogen emissions by ruminal acidification or synchronisation of the carbohydrate and protein content of the diet have not resolved this issue. In vitro studies on the sheep rumen show that epithelial efflux of ammonia does not only involve simple diffusion of the uncharged form (NH3), but also a transport of the protonated ammonium ion (NH4+). So far, there is very little information on the underlying mechanisms. The aim of the present study was to characterize the mechanisms for the absorption of ammonia across the bovine ruminal epithelium using the patch-clamp-technique, flux studies in the Ussing chamber and pH-selective microelectrodes. The experiments yielded the following results: \- The absorption of ammonia across the ruminal epithelium of cows induced a positive short-circuit current in the Ussing chamber (10 mmol·l-1; *40 mmol·l-1 *p < 0.05). \- A 2.5-hour incubation in the Ussing chamber exposing the mucosal side of the tissue to 10 mmol·l-1 NH4Cl led to a serosal concentration of 3.08 ± 0.17 mmol·l-1 NH4+. Increasing the mucosal concentration to 40 mmol·l-1 NH4Cl resulted in an increased serosal concentration of 8.72 ± 0.65 mmol·l-1 NH4+. No significant alkalinization of the only lightly buffered serosal solution was observed, as should have been the case if NH3 were the primary form transported (p = 0.18; N/ n = 8/40). \- In microelectrode measurements, the replacement of 40 mmol·l-1 NMDG+ by an equimolar amount of NH4+ (pH 6.4 and 7.4) resulted in a significant depolarization of the transepithelial and apical potential (pH 6.4: ΔPDt 2.78 ± 0.37 mV; ΔPDa 2.13 ± 0.5 mV; pH 7.4: ΔPDt 2.53 ± 0.46 mV; ΔPDa 1.0 ± 1.8 mV N/n = 6/12, p < 0.05). Simultaneously the intracellular pH dropped significantly at both values of pH (pH 6.4: (ΔpHi -0.13 ± 0.02; pH 7.4: (ΔpHi -0.16 ± 0.05; N/n = 6/12, p < 0.05). These results suggest a transcellular pathway. The acidification observed also implies that the apical influx of NH4+ slightly exceeded the basolateral efflux at pH 6.4 as well as 7.4. \- The NH4+ conductance of the ruminal epithelium was blocked by divalent cations (Ca2+ and Mg2+). This was shown in patch clamp measurements of isolated cells filled with Na-gluconate solution or K-gluconate solution (n = 8, p = 0.008 and n = 7, p = 0.016), as well as in intact epithelia measured in the Ussing Chamber (microelectrode-technique) (N/n = 3/4, p = 0.005). Verapamil (1 mmol·l-1) had an inhibitory effect (N/n = 3/7, p = 0.008). \- Various specific modulators of the TRP-channel-family had an effect on the NH4+ induced current. The mucosal application of menthol (200 μmol·l-1; 1 mmol·l-1) resulted in a clear but transient increase of Isc (ΔIsc 5.35 ± 0.97 μA•cm-2 (N/n = 4/11, p = 0.02) and ΔIsc 4.53 ± 0.94 μA•cm-2 (N/n = 3/12, p = 0.022), respectively). In contrast, the application of capsaicin (100 μmol·l-1) led to a significant decrease of the transepithelial current (ΔIsc -3.25 ± 1.16 μA•cm-2, N/n = 4/6, p = 0.02). Thymol (100 μmol·l-1 and 1 mmol·l-1) showed clearly visible effects on the NH4+ induced current, although with great variability depending on the tissue studied (N/n = 2/4 and N/n = 6/9). The application of the solvent alone had no effect (N/n = 3/6). Similar effects could be demonstrated on ovine ruminal epithelium. \- Apical replacement of chloride by gluconate led to a hyperpolarization of the apical potential, suggesting a basolateral localisation of the anion-channels expressed by ruminal epithelial cells. A participation of these channels in the currents induced by TRP-modulators appears unlikely. In summary, the results suggest an involvement of non-selective cation channels belonging to the TRP-family in the efflux of ammonia from the rumen. A participation of these channels in the efflux of protons across the ruminal epithelium to maintain pH-homeostasis is discussed. A targeted manipulation of ammonium transport across the ruminal epithelium of cows through breeding or the application of TRP-channel modulators appears possible

Sosiaalisen median markkinointisuunnitelma tilitoimistolle

Opinnäytetyön toimeksiantajana toimi keskikokoinen tilitoimisto, jonka toimipisteet ovat lähellä pääkaupunkiseutua. Tilitoimisto oli harkinnut sosiaaliseen mediaan siirtymistä, mutta se ei tarkalleen tiennyt, miten sitä voisi hyödyntää markkinoinnissa ja mitä siellä kannattaisi julkaista. Opinnäytetyön tavoitteena oli laatia sosiaalisen median markkinointisuunnitelma ja selvittää, miten tilitoimisto lisää näkyvyyttään, kuinka tilitoimisto voisi erottua kilpailijoistaan ja hankkia uusia asiakkaita sosiaalisesta mediasta. Opinnäytetyö koostuu teoriaosuudesta ja sosiaalisen median markkinointisuunnitelmasta. Työn teoreettiseen viitekehykseen kuuluivat asiakaskohderyhmän tunnistaminen ja sosiaalisen median kanavat. Asiakaskohderyhmien tunnistaminen valittiin toiseksi teoria-aiheeksi ajatellen tavoitetta saada uusia asiakkaita. Sosiaalisen median kanavien esittely keskittyi kolmeen tilitoimistolle sopivimpaan kanavaan, mutta myös sosiaalisen median muut kanavatyypit esiteltiin. Markkinointisuunnitelma koottiin toimitusjohtajan kyselyn, teoriaosuuden ja omien sosiaalisen median havaintojen pohjalta. Havaintoja tehtiin suomalaisista kilpailijoista ja ulkomaalaisista tilitoimistoista, joilla on toimivat sosiaalisen median sivut. Tulokset osoittivat, että sosiaalisessa mediassa ei pärjää suoralla markkinointiviestinnällä, vaan on käytävä dialogia asiakkaiden kanssa. Olemassa olevat asiakkaat ovat myös tärkeitä, koska heidän palautteensa leviää sosiaalisessa mediassa nopeammin ja suuremmalle yleisölle kuin perinteisissä medioissa tai kasvokkain. Suomessa tilitoimistojen sosiaalisen median sivut eivät ole menestyneet vielä.Social media marketing plan for the accounting firm Thesis was made for a middle-sized accounting firm which offices are near the metropolitan area. The accounting firm had considered joining social media but it didn’t know how marketing can be done there and what would be beneficial to publish there. Main goals for thesis were to create social media marketing plan for the firm and find ways to increase accounting firm’s visibility, stand out from competition and get new customers from social media. Thesis consists of theoretical part and social media marketing plan. Theoretical frame for thesis consisted of defining target group and social media channels. Defining target group was chosen as other theory part because of goal to get new customers. Introduction to social media channels concentrated on three most beneficial channels for the firm but also other channels were introduced. Practical part of the work was based on theory part, questionnaire to CEO, interview of former communication person and my observations on social media. Observations were made of Finnish accounting firm pages and foreign accounting firm pages that were functional. The results show that straight-forward marketing messages don’t work in social media. It’s more efficient to have dialog with customers. It is also important to take into account existing customers because word spreads fast and to more people than in traditional media or face-to-face. Finnish accounting firm pages haven’t succeeded yet