Abstract Acute pancreatitis is a common disease, Finland being among the countries with the highest incidence. The majority of patients have a mild, self-limiting disease. However, 20% of these patients develop severe necrotizing pancreatitis with a mortality rate of 7 to 25%. The mechanisms for developing the severe disease are not known, it is not possible to accurately forecast the severity of the disease and there is no curative treatment yet. This study was aimed at analyzing the early phase of acute experimental porcine oedematous and necrotizing pancreatitis. In Study I, the pancreatic microcirculatory changes were measured and the expression of tight junction proteins (claudins-2, -3, -4, -5 and -7) and the rate of apoptosis in the pancreas were all measured. In Study II, bacterial translocation to the blood in the portal vein blood or to the mesenteric lymph nodes was analyzed and the intestinal expression of tight junction proteins (claudins-2, -3, -4, -5 and -7) and the intestinal apoptosis/ proliferation rates were measured. The basic histology of the jejunum and colon were analyzed. Study III analyzed which cytokines are released from the pancreas to the portal venous blood. In Study IV, the ultrastructure of the epithelium of the jejunum and colon was analyzed and the expression of adherens junction proteins, E-cadherin and β-catenin, were measured from both jejunum and colon. The first study (I) showed that membranous immunoreactivity of claudin-2 in acinar cells appeared in the pancreas during acute oedematous and necrotizing pancreatitis. The expressions of claudins -3, - 4, - 5 and 7 were unaffected. The second study (II) showed that bacterial translocation from the gut was not present at the beginning of acute porcine pancreatitis. The expressions of claudins-2 and -5 do not become altered; however, there might be some decrease in claudin-3 expression in the colon and decrease in the expression of claudins-4 and -7 in the jejunum in necrotizing pancreatitis. Performing the laparotomy itself caused increased apoptosis in the colon and the jejunum. In the third study (III), the initial inflammatory process was diverse in oedematous and necrotizing pancreatitis. Increased monocyte count in combination with elevated PDGF and IL-6 are characteristic of necrotizing pancreatitis in our model. The fourth study (IV) indicated that necrotizing pancreatitis caused damage to the epithelial and endothelial cells of the colon in the early stages of the disease. The expression of E-cadherin immunoreactivity showed a decreasing trend in the colon in both oedematous and necrotizing pancreatitis. The results of this study suggest that claudin-2 increases in acinar cells during acute porcine pancreatitis. Bacterial translocation is not present during the early phase of acute porcine pancreatitis. Increased monocyte count and elevated PDGF and IL-6 are characteristic of early phase necrotizing porcine pancreatitis and necrotizing porcine pancreatitis causes damage to the epithelial and endothelial cells of the colon. / Tiivistelmä Akuutti haimatulehdus on yleinen sairaus, jonka ilmaantuvuus Suomessa on verrattain suuri. Suurimmalla osalla potilaista tauti on lievä ja itsestään paraneva. Kuitenkin 20 %:lle potilaista kehittyy vaikea haimatulehdus, johon liittyy 7–25 %:n kuolleisuus. On epäselvää, miksi toisinaan kehittyy vaikea tautimuoto. Taudin vaikeusastetta ei voida etukäteen tarkasti ennustaa, eikä tautiin ole parantavaa hoitoa. Väitöskirjatyön tarkoituksena oli tutkia lievän ja vaikean haimatulehduksen varhaisvaihetta kokeellisessa sikamallissa. Työssä I mitattiin haiman mikroverenkierron muutoksia, tutkittiin tiivisliitosproteiinien klaudiini-2:n, -3:n, -4:n, -5:n ja -7:n ilmenemistä sekä apoptoosin määrää haimassa. Toisessa työssä tutkittiin mahdollista bakteeritranslokaatiota porttilaskimovereen ja vatsaontelon imusolmukkeisiin, mitattiin suoliston tiivis liitos-proteiinien klaudiinien-2, -3, -4, -5 ja -7 ilmenemistä ja suoliston apoptoosin ja soluproliferaation määrää. Mahdollisia muutoksia ohut- ja paksusuolen perushistologiassa analysoitiin. Kolmannessa työssä mitattiin sytokiinipitoisuuksia porttilaskimoverestä. Neljännessä työssä analysoitiin ohut- ja paksusuolen mikrorakennetta elektronimikroskopian avulla ja mitattiin vyöliitosproteiinien E-cadherin ja β-catenin määrää. I työssä todettiin klaudiini-2:n ilmaantuvan haiman asinaarisolujen solukalvoille lievässä ja vaikeassa kokeellisessa haimatulehduksessa. Klaudiinien 3,- 4,- 5 ja 7 esiintyminen haimassa ei muuttunut. II työssä todettiin, että bakteeritranslokaatiota ei tapahtunut seuranta-aikana. Suolistossa klaudiinien-2 ja -5 ilmenemisessä ei tapahtunut muutoksia. Klaudiini-3:n ilmenemisessä paksusuolessa ja klaudiinien -4 ja -7 ilmenemisessä ohutsuolessa saattaa tapahtua vähenemistä vaikeassa haimatulehduksessa. Tutkimustoimenpide itsessään aiheutti ohut- ja paksusuolen apoptoosin lisääntymistä. III työn mukaan tulehdusvaste oli erilainen akuutissa lievässä ja vaikeassa kokeellisessa haimatulehduksessa. Monosyyttimäärän sekä PDGF:n ja IL-6:n pitoisuuksien lisääntyminen, olivat tyypillisiä vaikealle haimatulehdukselle tässä mallissa. IV työssä todettiin, että vaikea haimatulehdus vaurioittaa paksusuolen epiteeli- ja endoteelisoluja. E-cadherin: n määrässä todettiin jonkin verran vähentymistä sekä lievässä että vaikeassa haimatulehduksessa. Näiden tulosten mukaan klaudiini-2 lisääntyy sian haiman asinaarisoluissa akuutissa haimatulehduksessa. Sialla ei tapahdu bakteerien translokaatiota haimatulehduksen varhaisvaiheessa. Sian vaikeaan haimatulehdukseen liittyy monosyyttien, PDGF:n ja IL-6:n lisääntyminen. Kokeellisessa vaikeassa haimatulehduksessa paksusuolen epiteeli- ja endoteelisolut vaurioituvat jo varhaisvaiheessa.

Severe Acute Pancreatitis (SAP) is the rapid onset of inflammation within the pancreatic organ. Unlike the milder form of this illness, SAP is associated with a high mortality and morbidity. No significant reduction in the outcomes of this disease has been made since the implementation of organ supportive management over two decades ago. This is due to difficulties in distinguishing between the milder form of the disease in the early period of the onset of symptoms when clinical intervention is most likely to prevent complications and death. Clinical equipoise exists in the management of one of these complications, namely Abdominal Compartment Syndrome (ACS) as the conventional management of surgery runs contrary to published evidence showing early abdominal surgery deteriorates clinical outcomes. Aims: Validation of the potential use of the Early Warning Score (EWS) as a predictor of SAP. Evaluation of the evidence for recombinant human protein C (Xigris™) in the early treatment of SAP. Determination of the safety profile of Xigris™ when given early in SAP. To determine if surgical management of ACS in SAP is of significant benefit compared to conventional management alone. Methods: Four studies were performed: A prospective observational study assessing the median EWS of patients admitted with acute pancreatitis; a systematic review of published evidence reporting the use of Xigris™ in SAP; a prospective cohort study using a 24 hour infusion of Xigris™ early in patients diagnosed with SAP and a pilot randomized controlled trial of targeted decompression in patients with ACS complicating SAP. Results: The highest EWS values for 130 patients with acute pancreatitis within the first 3 days of admission were not shown to have significant sensitivity and specificity in predicting an unfavourable outcome. A review of the published literature between from January 1985 to January 2011 supported the further investigation of Xigris™ as a treatment for SAP. No significant adverse events or differences in outcomes were evident in 19 patients who received a 24-hour infusion of Xigris™ early in SAP compared to matched historical controls. 22 patients were screened for the development of ACS. No patient developed ACS and consequently no randomization to either treatment arm was possible. Conclusion: With the recent advent of an updated classification system for the severity of acute pancreatitis, further prospective evaluation of the use of EWS in clinical practice is warranted. The results of the Phase 1 clinical trial of Xigris™ didnot reveal significant safety issues that might preclude the further investigation of Xigris™ as a specific therapy early in the onset of SAP. The absence of ACS inpatients with SAP lends support to a theory that ACS may be an epiphenomenon in the course of SAP.

Effective management of acute pancreatitis has for centuries eluded mankind. The disease has a wide spectrum of presentation; the milder form is usually a self limiting condition, whereas the severe form presents as a highly morbid and frequently lethal attack. The ability to predict disease progression on admission would aid in the comprehensive and multidisciplinary management of patients. The perfect predictor of disease progression has been an elusive factor hindering the management of the disease. On systematically reviewing literature and identifying appropriate biochemical markers in predicting progression of acute pancreatitis, the ideal predictor would be a combination of biochemical, clinical and contemporary organ dysfunction scoring systems. Early prediction of disease progression however, is important in the better management of the disease. The pathophysiological changes of acinar cell injury and death are the earliest events that occur in acute pancreatitis. Identification of potential pharmacological interventions offered through valuable insight in to experimental and clinical acute pancreatitis may lead on to the development of various natural and synthetic potential disease modifiers. Green Tea Extracts (GTE) consumed in many parts of the world has been examined as a potential therapeutic medication. Experimental results have demonstrated the effect of GTE on the oxidative pathway significantly ameliorating the effects of pancreatic injury. The various green tea catechins especially Epigallocatechin-3- gallate (EGCG) can perhaps be useful lead compounds for new drug discovery. With no specific targeted therapy for severe acute pancreatitis at present, various medications have been tested. The possibility of targeting initial acinar cell injury may not be a feasible option as patient presentation and management would usually be after this phase. As the disease progresses, severe acute pancreatitis is characterised by inflammation and necrosis. The hypothesis of preserving pancreatic parenchymal microvascular patency and thus ameliorating pancreatic injury through the early administration of recombinant human Activated Protein C (rhAPC) has identified a potential treatment for acute pancreatitis. rhAPC converted from its inactive precursor, protein C, by thrombin acts through fibrinolysis and inhibition of thrombosis. Studies on rhAPC in experimental acute pancreatitis examined the modulation of rhAPC on inflammatory markers, morphology, microvascular thrombosis and apoptosis. The encouraging results from initial experimental work helped set up the Phase 2 clinical trial of administering rhAPC early on in severe acute pancreatitis. Prior to taking this significant step from bench to bed side, the variation in functional protein C levels with the severity of the disease was examined as a precursor to the Phase 2 trial.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22351号 / 医博第4592号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 溝脇 尚志, 教授 戸井 雅和 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13363号 / 論医博第2205号 / 新制||医||1045(附属図書館) / (主査)教授 妹尾 浩, 教授 今中 雄一, 教授 川上 浩司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introducción y objetivos: la colangiopancreatografía retrógrada endoscópica (CPRE) actualmente tiene una finalidad eminentemente terapéutica. Su complicación más frecuente es la pancreatitis aguda con una incidencia entre 1.8% y 7.2%. El objetivo del estudio fue determinar la frecuencia de pancreatitis aguda post CPRE y sus características clínico - laboratoriales en pacientes del hospital Regional de Lambayeque. Métodos: Estudio descriptivo transversal en pacientes sometidos a CPRE durante el año 2017. Resultados: De 267 intervenciones CPRE se obtuvo una muestra de 156 pacientes. La edad promedio fue de 54.5 años (RIC: 69 - 32), el 68.5% fueron mujeres, el 76.2% de intervenciones fueron electivas y 23.8% emergencias, y la etiología más frecuente para su realización fue la causa litiásica (95.5%). La frecuencia de pancreatitis aguda post CPRE fue de 6.9%, esta población tuvo una mediana de edad fue de 46 años (RIC: 72 - 34), tuvieron una mediana de hospitalización de 4 días (RIC: 6 -3). Se registraron 9 casos leves y 2 moderados de pancreatitis aguda post CPRE. No se reportaron defunciones.

El documento digital no refieres asesor. / Compara el índice neutrófilo/linfocito con el APACHE II y BISAP como predictores de severidad en pacientes con pancreatitis aguda. El presente estudio fue realizado en el Hospital Nacional Daniel Alcides Carrión- Callao durante el periodo de enero del 2011 a diciembre del 2013, donde se recolectaron los datos de todos los pacientes hospitalizados en el Servicio de Gastroenterología, UCIN y UCI con diagnóstico de pancreatitis aguda. Se trató de un estudio observacional, retrospectivo y analítico. Se evaluaron un total de 201 pacientes, la edad promedio fue 42,09 ± 16.87, el sexo predominante fue el femenino 143 (71.14 %) y la etiología más frecuente fue la biliar 178 (88.55 %). Con respecto a la severidad 178 (88.5 %) fueron leves y 23 (11.5 %) fueron severas; 19 (9.45 %) pacientes presentaron falla orgánica y solamente 10 (4.97 %) presentaron necrosis pancreática. El score de BISAP tuvo una sensibilidad de 13,2%, especificidad de 93,6%, VPP de 27,7% y VPN de 86,6%. El score de APACHE una sensibilidad de 19,7%, especificidad de 85,1%, VPP de 17,2% y VPN de 86,9% y el índice neutrófilo/linfocito una sensibilidad de 34,5%, especificidad de 60,6%, VPP de 10,3% y VPN de 86,4%. Las áreas bajo la curva ROC fueron 81.4 % para BISAP, 55% para APACHE II y 49% para el índice neutrófilo/linfocito. Se concluye que el índice neutrófilo/linfocito no es mejor predictor de severidad que el APACHE II y BISAP en los pacientes con pancreatitis aguda, además de no tener una adecuada capacidad discriminatoria diagnóstica. / Trabajo de investigación

MOTIVATING PATIENTS TO CHANGE THEIR LIFESTYLE AFTER HOSPITALIZATION AT INTENSIVE CARE UNIT FOR PANCREATITIS ATTACK Introduction: This diploma thesis focuses on the motivation of patiens to change their lifestyle choices and habits after they suffered an acute pancreatitis. The aim: The aim of this thesis was to analyse the barriers and motivators to change their lifestyle patiens after they suffer an acute pancreatitis. Methods: The research group of this qualitative study consisted of twenty probands (seven male and thirteen female) aged 45,15 - 12,41. The analysis of aspects motivating them to change their lifestyle after an acute pancreatitis was conducted right before they were released from intensive care in a faculty hospital in Prague into aftercare at their homes. The analysis was conducted trough semi-structured interviews. The interviews were recorded with the patient's permission in order to be transcribed and analyzed later on. Results: The main barriers to lifestyle change after pancreatitis attack are fear of the future, feeling guilty, seducing guilt on others, feeling sick, loneliness and separation, emotional interia towards love dones; feel overworked, constant rush, lack of time for yourself and for other family members, fear of reintegration into society; bad eating habits lack...

MOTIVATING PATIENTS TO CHANGE THEIR LIFESTYLE AFTER HOSPITALIZATION AT INTENSIVE CARE UNIT FOR PANCREATITIS ATTACK Introduction: This diploma thesis focuses on the motivation of patients to change their lifestyle choices and habits after they suffered an acute pancreatitis. The aim: The aim of this thesis was to analyse the barriers and motivators to change their lifesyle patients after they suffer an acute pancreatitis. Methods: The research group of this qualitative study consisted of twenty probands (seven male and thirteen female) aged 45,15 ± 12,41. The analysis of ascpects motivating them to change their lifestyle after an acute pancreatitis was conducted right before they were released from intensive care in a faculty hospital in Prague into aftercare at their homes. The analysis was conducted through semi-structured interviews. The interviews were recorded with the patient's permission in order to be transcribed and analyzed later on. Results: The main barriers to lifestyle change after pancreatitis attack are fear of the future, feeling guilty, seducing guilt on others, feeling sick, loneliness and separation, emotional inertia towards loved ones; feel overworked, constant rush, lack of time for yourself and for other family members, fear of reintegration into society; bad eating habits...

Chirurgische Eingriffe werden bei 10% der Patienten mit Komplikationen der chronischen Pankreatitis erforderlich. Neben Ableitungsoperationen kommt bei fokaler Akzentuierung der Erkrankung die Resektion von Teilen der Bauchspeicheldrüse zum Einsatz. Entzündliche Tumoren des Korpus und des Schwanzbereichs werden durch linksseitige Resektion, wenn möglich Milz erhaltend, entfernt. Zu den klassischen Resektionsverfahren von Pankreaskopfprozessen gehören die Duodenopankreatektomie (DPE) nach Kausch- Whipple und die Pylorus erhaltende Kopfresektion (PPPD). Im eigenen Krankengut wurden von Oktober 1993 bis Mai 2001 373 Patienten mit chronischer Pankreatitis behandelt. 104 Patienten wurden reseziert (27,9%). Neben 13 Linksresektionen, davon 5 Milz erhaltend, wurden 91 DPE durchgeführt (54 Kausch-Whipple, 37 PPPD). Von den 91 Patienten, die einer DPE unterzogen wurden, hatten 25,2% der Patienten einen Diabetes mellitus. Konservativ unbeeinflussbare Schmerzen bestanden in 93% der Fälle, ein Verschlussikterus war bei einem Drittel der Patienten aufgetreten. Der Gewichtsverlust in dieser Gruppe betrug median 14 (3–30) kg. Nach der Operation traten bei 28 Patienten (30,8%) Komplikationen auf. Fünf Patienten aus dieser Gruppe mussten reoperiert werden, keiner verstarb im postoperativen Verlauf. Für die Langzeitergebnisse konnten in einem Beobachtungszeitraum von median 20 Monaten bisher 49 Patienten nachuntersucht werden. Vier Patienten (8,2%) waren nach einer medianen Überlebenszeit von 22 Monaten verstorben. Von den verbleibenden 45 Patienten nach DPE hatten 51,1% im Median 7 (1–27) kg an Gewicht zugenommen. Postoperativ ist ein De-novo-Diabetes in 5 Fällen (11,1%) aufgetreten. Dreimal (6,1%) war nach DPE kein Diabetes mehr nachweisbar, 61,5% der Patienten wurden wieder arbeitsfähig. Wenn auch die untersuchte Patientengruppe noch klein ist, Spätergebnisse bisher nur an einem Teil der Behandelten erhoben werden konnten und der Vergleich verschiedener Serien nicht zulässig ist, scheint die klassische DPE bei der Kopfpankreatitis nach wie vor ein vertretbares Operationsverfahren zu sein. / Classic Resection Procedures in Patients with Chronic Pancreatitis Surgery is needed in 10% of patients with chronic pancreatitis. In cases with focal inflammation of the pancreatic head or tail, bypass procedures or partial resections are performed. If possible, the left part of the pancreas is resected, with preservation of the spleen. Duodenopancreatectomy (DPE) according to Kausch-Whipple and the pylorus-preserving resection of the pancreatic head (PPPD) belong to the classic resections. Between October 1993 and May 2001, 373 patients with chronic pancreatitis were admitted to our department. Resection was necessary in 104 patients (27.9%). 13 left-sided resections, with splenic preservation in 5 cases, and 91 DPE were performed, 54 of them as Kausch- Whipple operations and 37 as PPPD. In the group of 91 DPE, 25.2% of the patients were diabetic and 93% suffered from conservatively uncontrollable pain. One third of the patients presented with obstructive jaundice and median weight loss of 14 (3–30) kg. Early postoperative complications were observed in 28 cases (30.8%); no patient died. Up to now longterm results could be achieved in 49 patients, with a median follow-up of 20 months. Four patients (8.2%) died after a median survival time of 22 months. 51.1% of the 45 survivors after DPE gained 7 (1–27) kg of weight. De novo diabetes occurred postoperatively in 5 patients (11.1%). In 3 patients (6.1%) diabetes disappeared postoperatively, 61.5% returned to work. Although this group is small, long-term results are still incomplete and the comparison of different series does not allow to draw any significant conclusions, the classic DPE for chronic pancreatitis still seems to lead to quite remarkable results. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.