Einleitung: Der Verdacht, dass Hunde mit einem Bandscheibenvorfall eine Prädisposition für die Entstehung einer Pankreatitis haben könnten, wurde in der Veterinärmedizin bereits in den frühen 1980er Jahren diskutiert. Trotz dieser bereits vor vielen Jahren erhobenen Vermutungen, wurde der Zusammenhang zwischen der Entstehung einer Pankreatitis und einem zeitgleich vorliegenden Bandscheibenvorfall auch im Hinblick auf mögliche Risikofaktoren wie dem Einfluss der Narkose oder dem Einsatz von Medikamenten (v. a. Glukokortikoide und nichtsteroidale Antiphlogistika) bisher nicht näher untersucht. Ziele der Untersuchungen: Im Rahmen der vorliegenden prospektiven Studie sollte untersucht werden, ob Bandscheibenvorfälle ein Risikofaktor für die Entstehung einer Pankreatitis beim Hund darstellen. Ferner sollte geklärt werden, ob die Narkose und die Gabe von Glukokortikoiden und/oder nichtsteroidalen Antiphlogistika zusätzlich das Risiko der Entstehung einer Pankreatitis bei Hunden mit einem Bandscheibenvorfall erhöhen. Material und Methoden: Insgesamt wurden 106 Hunde, bei denen aufgrund der klinischen Symptome der Verdacht einer Rückenmarksläsion bestand, an fünf aufeinander folgenden Tagen klinisch untersucht. Besonderes Augenmerk wurde hierbei auf Symptome gelegt, welche typischerweise bei Pankreatitiden zu beobachten sind (reduziertes Allgemeinbefinden, Schwäche, Anorexie, dolentes Abdomen, Vomitus, Regurgitieren, Diarrhoe, Fieber, Dehydratation). Ferner wurde am Tag 0 und Tag 4 der stationären Aufnahme die Konzentration der caninen pankreasspezifischen Lipase im Serum gemessen (Spec cPL und Snap cPL). Am Tag 0 wurde von dem Vorliegen einer Pankreatitis ausgegangen, wenn klinische Befunde im Sinne einer Pankreatitis sowie eine abnorm erhöhte Konzentration der caninen pankreasspezifischen Lipase im Serum (>400 μg/L) auffällig waren. Am Tag 4 erfolgte zudem eine sonographische Untersuchung des Abdomens. Somit basierte die Diagnosestellung einer Pankreatitis an diesem Tag auf dem Vorliegen von zwei der folgenden drei Kriterien: klinische Befunde im Sinne einer Pankreatitis, abnorm erhöhte Konzentration der caninen pankreasspezifischen Lipase im Serum, sonographische Hinweise für das Vorliegen einer Pankreatitis. Im Rahmen der statistischen Auswertung wurden zudem auch Patienten erfasst, welche in einem oder in mehreren der oben genannten Kriterien ein fragliches Ergebnis aufwiesen. Entsprechend ihrer neurologischen Ausfallserscheinungen sowie der Befunde im Rahmen der bildgebenden Diagnostik (Myelographie, Computertomographie, Kernspintomographie) wurden die Patienten in eine der folgenden drei Untersuchungsgruppen eingeteilt: 1. Hunde mit einem chirurgisch versorgten Bandscheibenvorfall (n = 71) 2. Hunde mit einem konservativ therapierten Bandscheibenvorfall (n = 20) und 3. Hunde mit einer akuten intramedullären Läsion (n = 15). Die statistische Auswerte erfolgte aufgrund der geringen Stichprobengrößen vorwiegend deskriptiv. Die Daten wurden mittels des Shapiro-Wilk-Tests auf Normalverteilung überprüft, die durchgeführten Gruppenvergleiche erfolgten unter Verwendung des Kruskal-Wallis und Mann-Whitney-U-Tests. Zudem wurden die betrachteten Merkmale mit dem Fisher Test und dem Chi-Quadrat-Test auf Unabhängigkeit überprüft. Das Signifikanzniveau wurde für alle Tests mit p < 0,05 festgelegt. Ergebnisse: Basierend auf den klinischen Symptomen und der Konzentration der caninen pankreasspezifischen Lipase im Serum konnte insgesamt am Tag 0 bei vier Hunden (3,8 %) eine Pankreatitis diagnostiziert werden. Am Tag 4 waren es, basierend auf den drei Kriterien, welche für die Diagnosestellung einer Pankreatitis herangezogen werden, insgesamt acht Patienten (7,5 %). Hunde mit einem Bandscheibenvorfall (chirurgisch beziehungsweise konservativ therapiert) wiesen am Tag 0 beziehungsweise Tag 4 in 4,3 % (n = 4) beziehungsweise 7,7 % (n = 7) der Fälle eine Pankreatitis auf. Aufgrund der geringen Häufigkeiten in den einzelnen Untersuchungsgruppen, war eine Berechnung eines signifikanten Unterschieds zwischen den Gruppen nicht möglich. Hinsichtlich einer möglichen Korrelation zwischen einer Narkose und der Entstehung einer Pankreatitis bei Hunden mit einer Rückenmarksläsion konnte kein signifikanter Zusammenhang festgestellt werden. Auch die Gabe von Glukokortikoiden und/oder nichtsteroidalen Antiphlogistika hatte hier keinen signifikanten Einfluss auf die Entstehung einer Pankreatitis. Schlussfolgerung: Vergleicht man die Ergebnisse der vorliegenden Studie mit der in der Literatur angegebenen Prävalenz für akute Pankreatitiden beim Hund (0,7-3,5 %), so kann geschlussfolgert werden, dass eine Rückenmarksläsion, insbesondere ein Bandscheibenvorfall, als Risikofaktor für die Entstehung einer akuten Pankreatitis beim Hund in Betracht gezogen werden muss. Demgegenüber erhöhen weder die Narkose noch die Gabe von Glukokortikoiden und/oder nichtsteroidalen Antiphlogistika zusätzlich das Risiko der Entstehung einer Pankreatitis bei Hunden mit einer Rückenmarksläsion. / Objective: The suspicion that dogs with intervertebral disc disease are at greater risk of developing pancreatitis is being discussed in veterinary medicine since the early 1980s. So far no study has been published examining the correlation between intervertebral disk disease and the development of pancreatitis in dogs, especially in combination with general anaesthesia and anti-inflammatory medication (glucocorticoids and/or nonsteroidal anti-inflammatory drugs). The aim of this study was therefore 1) to evaluate intervertebral disk disease as possible risk factor of pancreatitis and 2) to ascertain if general anaesthesia and the administration of glucocorticoids and/or nonsteroidal anti-inflammatory drugs further increase the risk of pancreatitis in dogs with intervertebral disk disease. Material and methods: One hundred and six dogs with symptoms associated with spinal cord injury were clinically examined over a period of five days. Special attention was payed to symptoms usually seen with pancreatitis such as anorexia, vomitus and abdominal pain. Furthermore the concentration of canine pancreatic lipase in the blood serum was measured with Spec cPL and Snap cPL at day 0 and day 4 after admission. At day 0 the diagnosis of pancreatitis was based on clinical symptoms associated with pancreatitis in combination with an increased concentration of canine pancreatic lipase in the blood serum (>400 μg/L). A sonography of the pancreas was performed at day 4 to evaluate the organ itself and the surrounding tissue for lesions associated with pancreatitis. Therefore the diagnosis of pancreatitis at day 4 was based on positive results in at least two of the three following criteria: symptoms associated with pancreatitis, elevation of the concentration of canine pancreatic lipase in the blood serum, sonographic changes of the pancreas parenchyma and the surrounding tissue associated with pancreatitis. For statistical analysis questionable results in one or more of these criteria were also documented. According to the neurologic symptoms and the findings of diagnostic imaging (myelography, computed tomography and magnetic resonance imaging), dogs were categorized in one of the following groups: 1. dogs with surgically treated intervertebral disk disease (n = 71), 2. dogs with medically treated intervertebral disk disease (n = 20), 3. dogs with an acute intramedullary lesion (n = 15). Due to the small sample size, statistics were primarily performed descriptively. Data were tested for normal distribution using the Shapiro-Wilk test. If Group comparisons were feasible, they were performed using the Kruskal-Wallis test and the Mann-Whitney-U test. Fisher test and the Chi-Square test were used to test for association between group affiliation and possible risk factors for the development of pancreatitis. A value of P < 0.5 was considered significant for all analysis. Results: Based on clinical symptoms and an elevated concentration of the canine pancreatic lipase (> 400μg/l) at day 0, four dogs (3.8 %) were diagnosed with pancreatitis. According to the clinical symptoms, the concentration of the canine pancreatic lipase and sonographic changes, a total number of eight dogs (7.5 %) were diagnosed with pancreatitis at day 4. Considering only the dogs with intervertebral disk disease (surgically and medically treated) 4.3 % (n = 4) and 7.7 % (n = 7) were diagnosed with pancreatitis at day 0 and day 4, respectively. Due to the small sample size, the calculation of significant differences between the three subgroups was not feasible. There was no significant correlation between general anaesthesia and the development of pancreatitis. Furthermore, the administration of glucocorticoids and/or nonsteroidal anti-inflammatory drugs is not significantly associated with the genesis of pancreatitis.

Abstract Various genetic aetiologies — including mitochondrial diseases, chromosomal disorders, and other monogenic diseases — are involved in status epilepticus (SE), a common neurologic emergency occurring in children and adults that exhibits high rates of morbidity and mortality. The exact frequency of mitochondrial SE is currently undefined. Furthermore, patients with pathogenic variants of POLG1 encoding mitochondrial DNA polymerase gamma have an increased risk of acute liver failure (ALF) induced by the common antiepileptic drug, valproic acid (VPA), which is problematic due to these patients also often experiencing drug-resistant seizures. Overall, the role of liver transplantation (LT) in VPA-ALF due to mitochondrial disease has been controversial. In the present work, large retrospective cohort studies were conducted for two main purposes: (1) to determine the genetic aetiologies of SE among Finnish paediatric and adult patients by specifically focusing on the common mitochondrial genetic defects associated with an increased risk of SE and (2) to examine whether common POLG1 p.Q1236H and p.E1143G variants are connected to liver or pancreatic toxicity upon exposure to VPA monotherapy. This thesis also describes the characteristics of VPA-ALF associated with the pathogenic POLG1 variant p.W748S and the prognosis of LT in a retrospective case series. Mitochondrial diseases explained 4.5% of SE cases in the study cohort. Patients with mitochondrial SE suffered from refractory SE significantly more often than patients with other forms of genetic or non-genetic SE. Additionally, mortality rates were higher in patients with mitochondrial or chromosomal disorders compared with the other groups, reflecting the severity of the underlying condition and the higher frequency of refractory SE. POLG1 variants p.Q1236H and p.E1143G could not be identified as risk factors for VHT or pancreatic toxicity, implying that VPA treatment might be suitable for patients harbouring these variants when other pathogenic variants are absent. Finally, the homozygous status of the pathogenic POLG1 variant p.W748S and older age of the patient during the presentation of VPA-ALF seem to be associated with higher survival rates following LT, which should be considered in the management of VPA-ALF. / Tiivistelmä Useita perinnöllisiä syitä, kuten mitokondriotauteja, kromosomihäiriöitä ja muita geenimuutoksia on tunnistettu status epilepticuksen (SE) eli pitkittyneen epileptisen kohtauksen taustalla. SE on yleinen neurologinen hätätilanne, johon liittyy merkittävää oheissairastavuutta ja kuolleisuutta sekä lapsilla että aikuisilla. Mitokondriotauteihin liittyvän SE:n tarkkaa esiintyvyyttä ei tiedetä. Potilailla, joilla on patogeenisia variantteja mitokondrioiden DNA-polymeraasia koodaavassa tuman POLG1-geenissä, on todettu kohonnut riski yleisesti käytetyn epilepsialääkkeen valproaatin (VPA) aiheuttaman akuutin maksavaurion kehittymiselle. Tämä tekee lääkehoidon valinnasta ongelmallista, koska näillä potilailla on usein epilepsialääkkeille resistenttejä kohtauksia. Maksansiirron merkitys akuutin maksavaurion hoidossa mitokondriotauteja sairastavilla potilailla on ollut kiistanalainen. Tutkimuksen tavoitteena oli selvittää SE:n perinnöllisiä syitä suomalaisilla lapsi- ja aikuispotilailla retrospektiivisesti kerätyssä laajassa potilasaineistossa. Tutkimuksessa keskityttiin yleisimpiin mitokondriaalisiin perinnöllisiin muutoksiin, joiden on aiemmin todettu liittyvän SE:n lisääntyneeseen riskiin. Tutkimuksen toisena päätavoitteena oli selvittää väestössä yleisten POLG1-geenin muutosten eli varianttien p.Q1236H ja p.E1143G yhteyttä maksatoksisuuteen tai haimatoksisuuteen VPA-monoterapian aikana. Lisäksi tutkittiin VPA:n aiheuttaman maksavaurion kliinisiä erityispiirteitä patogeeniseen POLG1-varianttiin p.W748S liittyen sekä mutaatiostatuksen vaikutusta maksansiirron jälkeiseen ennusteeseen. Mitokondriotaudit selittivät 4,5 % SE-tapauksista tämän väitöskirjatyön potilasaineistossa ja näillä potilailla SE pitkittyi hoitoresistentiksi tai erittäin resistentiksi merkitsevästi muita potilasryhmiä useammin. Kuolleisuus oli suurin potilailla, joilla todettiin mitokondriotauti tai kromosomihäiriö, liittyen todennäköisimmin vakavaan taustasairauteen ja hoitoresistentin SE:n suurempaan esiintyvyyteen. Tutkittuja POLG1-variantteja p.Q1236H ja p.E1143G ei voitu tunnistaa maksa- tai haimatoksisuuden riskitekijöiksi, mikä tarkoittaa, että VPA-hoito voisi sopia näille potilaille, mikäli muita patogeenisiä variantteja ei todeta. Patogeenisen POLG1-variantin p.W748S homotsygoottisuus ja nuoruusikä tai varhainen aikuisikä maksavaurion ajankohtana ovat maksansiirron ennustetta parantavia tekijöitä, mikä tulisi ottaa huomioon hoitopäätöksiä tehtäessä.

Abstract Acute infected necrotizing pancreatitis (ANP) is a very complex disease with a high risk of complications and death. ANP is difficult to treat and is often associated with poor outcomes. Despite the increasing data on the technical details required to perform a mini-invasive necrosectomy for walled-off necrosis (WON), relatively few studies have focused on the presence and consequences of pancreatic duct disruption in the context of APN. Moreover, the long-term prognosis of patients with acute pancreatitis (AP) is scant. The aim of this study was to examine the diagnosis, treatment and prophylaxis of pancreatic fistulas (PFs) associated with APN. In addition, the long-term prognosis of AP was evaluated. The study population consists of the patients with AP treated at Oulu University Hospital, Finland (Studies I–IV) and Copenhagen University Hospital, Denmark (Study II) during 1995–2015. In the first part of the study, all consecutive patients following open necrosectomy for infected ANP were demonstrated to have PF. Endoscopic transpapillary pancreatic stenting (ETPS) was attempted and proven to be an effective and safe treatment for patients with PF. In Study II, prophylactic pancreatic stenting in the early stage of the disease was tested in a randomized controlled trial to the patients with ANP to prevent PFs associated with the disease. However, the study showed that the patients with ANP did not benefit from early prophylactic pancreatic ductal stenting (PPDS); instead, it seemed to be harmful for the patients. The results of Study III showed that single drain amylase level measurement after surgical necrosectomy is unreliable. According to this study, serial measurements are recommended to diagnose PFs after necrosectomy. Study IV including 1644 patients showed that AP, especially alcohol AP, was associated with a high long-term mortality. On the other hand, AP without an alcohol aetiology had a minimal impact on survival. In conclusion, in patients with infected ANP, a PF has to be considered in treatment, but the prevention of ductal leak with PPDS is not recommended. In addition, the poor long-term outcome among alcohol AP patients was due to alcohol-related diseases. / Tiivistelmä Akuutti nekrotisoiva haimatulehdus ja erityisesti siihen liittyvä bakteeri-infektio on sairaus, johon liittyy korkea komplikaatio- ja kuolleisuusriski. Tautia usein komplisoi infektion lisäksi nekroosiin liittyvä haimafisteli, joka tekee hoidosta entistä haasteellisemman. Viime aikaisissa tutkimuksissa on käsitelty runsaasti mini-invasiivista nekrosektomiaa, mutta suhteellisen vähän on tutkimuksia nekrotisoivaan haimatulehdukseen liittyvästä fisteliongelmasta. Haimatulehdus-potilaiden pitkäaikaisennuste on myös epäselvä. Tämän väitöskirjatutkimuksen tavoitteena oli selvittää nekrotisoivaan haimatulehdukseen liittyvän haimafistelin yleisyyttä, diagnostiikkaa, ehkäisyä ja hoitoa. Lisäksi tarkasteltiin akuuttiin haimatulehdukseen sairastuneiden potilaiden pitkäaikaisennustetta. Ensimmäisessä osatyössä ilmeni, että kaikille potilaille, joille suoritettiin haiman nekrosektomia kehittyi fisteli ja endoskooppinen transpapillaarinen haimateiden stenttaus (ETPS) osoittautui hyväksi ja turvalliseksi hoidoksi fistelin hoidossa. Toisessa prospektiivisessa randomoidussa kontrolloidussa osatyössä tutkittiin profylaktista haimateiden stenttausta nekrotisoivassa haimatulehduksessa. Tutkimus osoitti, etteivät potilaat hyötyneet stenttauksesta: toimenpiteestä oli enemmän haittaa kuin hyötyä. Tämän tutkimuksen mukaan protetisointia ei suositella tehtäväksi taudin alkuvaiheessa. Kolmannessa osatyössä selvitettiin haiman nekrosektomian jälkeisen haimafistelin diagnosointia. Tutkimustuloksen mukaan haimafistelin osoittamiseksi dreenieritteen amylaasitasoa mittaamalla tarvitaan useita mittauskertoja, koska yksittäisen mittauksen sensitiivisyys on matala. Neljännessä osatyössä analysoitiin Oulun yliopistollisessa sairaalassa 1995–2012 akuutin haimatulehduksen sairastaneiden työikäisten potilaiden pitkäaikaisennustetta ja kuolinsyitä. Noin kymmenen vuoden seurannassa tutkimusryhmän (n = 1 644) kuolleisuus oli yli nelinkertainen verrattuna ikä- ja sukupuolivakioituihin verrokeihin (n = 8 220). Merkittävin kuolleisuutta lisäävä tekijä oli alkoholi. Tutkimuksemme osoitti, että infektoituneen haimanekroosiin liittyvä haimafisteli on huomioitava hoidossa. Varhaisesta profylaktisesta haimateiden protetisoinnista ei tutkimuksessa osoitettu olevan hyötyä. Alkoholin aiheuttaman haimatulehduksen pitkäaikaisennusteen mortaliteetti on korkea johtuen alkoholin käytöstä ja siihen liittyvistä sairauksista.

A dependência de álcool acomete de 10 a 12% da população mundial, estando a associação entre uso abusivo do álcool e pancreatite crônica bem estabelecida. A suscetibilidade pancreática ao álcool é variável e apenas 5 a 10% dos etilistas crônicos desenvolvem pancreatite crônica, sendo o papel dos fatores genéticos neste processo praticamente desconhecido. O gene CFTR (cystic fibrosis transmenbrane conductance regulator) codifica proteína que funciona na membrana plasmática de células epiteliais e que tem papel chave na função pancreática exócrina normal, promovendo a regulação, da secreção de fluídos e bicarbonato, importantes para a diluição e a alcalinização do suco pancreático. Quando a função desta proteína é inadequada, observa-se obstrução de pequenos ductos por rolhas protéicas. Várias pesquisas buscam documentar a associação fibrose cística - pancreatite crônica, porém os resultados são conflitantes. Este trabalho pesquisou a freqüência de polimorfismos no trato de politiminas e poli TGs no intron 8 do gene CFTR em pacientes portadores de pancreatite crônica alcoólica. Foram estudados três grupos de pacientes: Grupo A - adultos alcoolistas com diagnóstico de pancreatite crônica; Grupo B - adultos alcoolistas sem pancreatopatia ou cirrose hepática e Grupo C - adultos sadios não alcoolistas. O DNA genômico para análise do gene CFTR foi extraído do sangue periférico, pesquisando-se a freqüência de polimorfismos no trato de politiminas e poli TGs no intron 8. O genótipo 5T/7T foi mais encontrado no grupo A do que no B (p = 0,0481), não havendo diferença quando comparados os grupos A e C (p = 0,1317). Pacientes com pancreatite crônica por álcool com o genótipo 5T/7T tiveram menor incidência de diabetes melito do que aqueles com outros genótipos (p = 0,0465). A combinação de haplótipos 10TG 7T / 11TG 7T foi mais freqüente nos grupos B e C do que no A e poderia, eventualmente, ser um fator protetor contra o desenvolvimento da pancreatite crônica. (p = 0,0080 e 0,0162). Em conclusão, há diferenças no intron 8 do gene CFTR em pacientes com pancreatite crônica alcoólica, quando comparados com alcoolistas não pancreatopatas e indivíduos com o genótipo 5T/7T teriam maior risco de desenvolver pancreatite crônica quando se tornam alcoolistas crônicos. / The alcohol dependence affects from 10 to 12% of the world-wide population, being the association between alcohol abuse and chronic pancreatitis well established. The pancreatic susceptibility to the alcohol is only 5 to 10%, being the paper of the genetic factors practically unknown. The CFTR gene (cystic fibrosis transmenbrane conductance regulator) codifies a protein that functions in the epithelial cells and has a role in pancreatic exocrine function, promoting regulation of the secretion of fluids and bicarbonate, important for the dilution and the alcalinization of the pancreatic juice. When the function of this protein is inadequate, blockage of small ducts occurs. Some research regist the association cystic fibrosis - chronic pancreatite, however the results are conflicting. This work searched the frequency of polymorphisms in the polyT and poly TGs tracts in intron 8 of CFTR gene in patients with alcoholic chronic pancreatitis. Three groups of patients have been studied: Group A - adult alcoholics with chronic pancreatitis; Group B - adult alcoholics without pancreatic disease or hepatic cirrhosis and Group C - non alcoholics healthy adults. DNA analysis of CFTR gene was made after extraction from peripheral blood samples. The 5T/7T genotype was more frequently found in group A that in B (p = 0.0481), with no difference when compared to group C (p = 0,1317). Patients with alcoholic chronic pancreatitis and 5T/7T genotype had less incidence of diabetes mellitus that those with other genotypes (p = 0,0465). The haplotype combination 10TG 7T / 11TG 7T was more frequent in groups B and C that in A and it could, eventually, be a protective factor against the development of alcoholic chronic pancreatitis. (p = 0,0080 and 0,0162). In conclusion, we found differences when these tree groups are compared and individuals with 5T/7T genotype would have greater risk to develop chronic pancreatitis if they become alcoholics.

Introdução: A infusão parenteral de emulsão lipídica (EL) de óleo de peixe (OP), rica em ácidos graxos ômega-3 (AG n-3), está associada à diminuição do perfil de mediadores pró-inflamatórios em estudos experimentais e clínicos. AG n-3 se incorporam em poucas horas em membranas celulares e geralmente são administrados após a agressão inflamatória. A pancreatite aguda (PA) experimental é modelo de inflamação, local e sistêmico, bem estabelecido. Objetivo: O presente estudo avaliou o efeito da infusão parenteral de EL de OP por curto período, antes da indução de PA, sobre a modulação da resposta inflamatória sistêmica e sobrevida. Métodos: Após cateterização do sistema venoso central, ratos isogênicos Lewis receberam infusão parenteral de EL de óleo de peixe ou solução salina durante 48 horas, quando então foram submetidos à pancreatite aguda, pela injeção retrógrada de 0,5 mL de solução de taurocolato de sódio a 3% no duto pancreático. Após indução de PA, nos períodos de 2, 12 e 24 horas, os animais foram sacrificados para coleta de amostras de sangue e de tecidos para dosagem de marcadores inflamatórios e histopatológicos. Paralelamente, 20 animais de cada grupo foram observados até sete dias após indução de PA, para avaliação de sobrevida. Resultados: O tratamento com EL de óleo de peixe foi associado com diminuição de citocinas pró-inflamatórias IL-1beta (p=0,0006) e IL-6 (p=0,05), diminuição de IL-4 (p= 0,0019) e tendência no aumento de anti-inflamatória IL-10 (p= 0,06), após 24 horas de PA; e com aumento da expressão pulmonar e hepática de proteínas de choque térmico HSP 90, 2 e 12 horas após PA, respectivamente. Após infusão de EL de óleo de peixe, não foram encontrados efeitos sobre os níveis de malonaldeído no fígado e na histopatologia do pâncreas, no período de 2 e 12 horas pós pancreatite aguda; e na taxa de sobrevida, em relação aos demais grupos (p > 0,05). Conclusão: Nossos resultados sugerem que a infusão parenteral de EL de OP 48 horas antes da indução de pancreatite aguda experimental parece influenciar favoravelmente a produção de citocinas inflamatórias e HSP90 hepática e pulmonar, sem impactar sobre a histopatologia da lesão pancreática e a taxa de sobrevida / The parenteral infusion of fish oil (FO) lipid emulsion (LE), rich in omega-3 fatty acids (n-3 FA), is associated with the decrease of pro-inflammatory mediators profile in experimental and clinical studies. N-3 FA are incorporated in a few hours in cell membranes and are generally administered after the inflammatory injury. The experimental acute pancreatitis (AP) is an inflammation, local and systemic well-established model. This study evaluated the effect of parenteral infusion of fish oil LE for a short period before AP induction, on the modulation of systemic inflammatory response and survival. For this, after the central venous catheterization Lewis rats received parenteral infusion of fish oil LE or saline solution for 48 hours, when they were induced to acute pancreatitis by retrograde injection of 0.5 mL of sodium taurocholate at 3% in pancreatic duct. After AP induction, in periods of two, 12 and 24 hours, the animals were sacrificed to collect blood samples and tissues for measurement of inflammatory markers and histopathological. In parallel, 20 animals in each group were observed up to 7 days after induction of AP, for survival analysis. The treatment with fish oil LE was associated with decreased of pro-inflammatory cytokines IL-1beta (p = 0.0006) and IL-6 (p = 0.05), reduction of IL-4 (p = 0.0019) and upward trend of anti-inflammatory IL-10 (p = 0.06) after 24 hours of AP; and increased pulmonary and hepatic expression of heat shock proteins HSP 90 two and 12 hours after AP, respectively. After infusion of fish oil LE, there were no effects on malondialdehyde levels in the liver and the pancreas histopathology in the periods of 2 and 12 hours after acute pancreatitis; and survival rate, compared to the other groups (p > 0.05). Our results suggest that parenteral infusion of FOLE 48 hours before the induction of experimental acute pancreatitis appears to favorably influence the production of inflammatory cytokines; hepatic and pulmonary HSP90, without impacting on the histopathology of pancreatic injury and the survival rate

Objetivo: Uma série de casos sugerindo uma possível associação de pancreatite aguda (PA) e síndrome de ativação macrofágica (SAM) em lúpus eritematoso sistêmico pediátrico (LESP) foi reportada em dez crianças no nosso serviço, no entanto, não existem dados relativos à comparação entre PA e SAM em grandes populações de LESP e LES adulto (LESA). Métodos: Este estudo incluiu 362 pacientes LESP e 1.830 pacientes LESA. SAM foi diagnosticada de acordo com os critérios diagnósticos preliminares e PA de acordo com a presença de dor abdominal e/ou vômitos associados a um aumento de enzimas pancreáticas e/ou alterações radiológicas pancreáticas nos exames de ultrassonografia e/ou tomografia abdominal. Dados demográficos, características clínicas, SLEDAI-2K, SLICC/ACR-DI e tratamento foram avaliados. Resultados: A frequência de PA foi significantemente aumentada no LESP em comparação ao LESA [12/362 (3,3%) vs. 20/1830 (1,1%), p=0,003], com similar duração da PA nos dois grupos [22 (6-60) vs. 15 (4-90), dias, p=0,534]. As frequências de SAM (85% vs 30%, p=0,003) e óbito (31% vs. 0%; p=0,017) foram significantemente elevadas em crianças com PA comparadas com adultos com PA. Na análise dos pacientes com PA e SAM em comparação com os com somente PA sem SAM demonstrou que a idade dos pacientes com PA e SAM foi significantemente menor em comparação com aqueles sem SAM [15 (8,8- 55) vs. 33,5 (10,2-45,7) anos, p=0,007]. As frequências de febre (94% vs. 37%, p=0,001), leucopenia (82% vs. 19%, p=0,0001), trombocitopenia (65% vs. 19%, p=0,013), hipertrigliceridemia (87% vs. 42%, p=0,037) e hiperferritinemia (93% vs. 37%, p=0,011) foram significantemente aumentadas nos pacientes com PA e SAM comparados aos pacientes com somente PA. A concomitância de febre e hiperferritinemia foi significantemente mais freqüente no primeiro grupo (86% vs. 12%, p=0,0015). Conclusões: Este estudo forneceu novos dados que evidenciaram que SAM ocorreu na maioria dos LESP com PA com uma maior mortalidade em comparação com LESA. Além disso, foram identificados em pacientes com PA e SAM, um conjunto de parâmetros clínicos e laboratoriais associado com as duas complicações / Objective: We previously reported a case series of acute pancreatitis (AP) and macrophage activation syndrome (MAS) in childhood (cSLE) patients, however there are no data regarding the comparison of AP and MAS in large populations of cSLE and adult SLE (aSLE). Methods: This study included 362 cSLE and 1,830 aSLE patients. MAS was diagnosed according to preliminary diagnostic guidelines and AP according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Demographic data, clinical features, SLEDAI-2K, SLICC/ACR-DI and treatment were assessed. Results: Higher and significant frequency of AP in cSLE compared to aSLE patients [12/362(3.3%) vs. 20/1830(1.1%), p=0.003], with similar AP duration [22(6- 60) vs. 15(4-90) days, p=0.534]. MAS (85% vs. 30%, p=0.003) and death by MAS complication (31% vs. 0%, p=0.017) were significantly higher in children with AP compared with aSLE with AP. Further analysis of patients with AP and MAS compared with AP without MAS demonstrated that age in MAS patients was significantly lower compared with those without this complication [15(8.8-55) vs. 33.5(10.2-45.7) years, p=0.007]. The frequencies of fever (94% vs. 37%,p=0.001), leucopenia (82% vs. 19%,p=0.0001), thrombocytopenia (65% vs. 19%,p=0.013), hypertriglyceridemia (87% vs. 42%,p=0.037) and hyperferritinemia (93% vs. 37%,p=0.011) were also more frequently observed in AP patients with MAS compared in AP patients without MAS. Fever and hyperferritinemia concomitantly were more frequent in the former group (86% vs. 12%, p=0.0015). Conclusions: This study provides novel data demonstrating that MAS occur in the majority of cSLE with AP with a higher mortality compared to aSLE. In addition, we identified in AP patients, a cluster of MAS clinical and laboratorial parameters more associated with this complication

A ocorrência de translocação bacteriana durante a pancreatite aguda tem sido descrita como o principal fator responsável pela ocorrência de infecção pancreática. O objetivo deste trabalho foi determinar o efeito da administração da indometacina na ocorrência de translocação bacteriana e infecção pancreática. Foi utilizado um modelo experimental de pancreatite aguda com taurocolato de sódio 2,5%. Noventa ratos wistar machos foram divididos em três grupos: Sham, Pancreatite e Indometaciana. Foram analisadas, a ocorrência de translocação bacteriana e a incidência de infecção pancreática. A indometacina foi capaz de reduzir a população bacteriana e a incidência de infecção pancreática na pancreatite aguda experimental, no entanto a indometacina não foi capaz de alterar os índices de mortalidade / Increased gut bacterial translocation (BT) in AP has been correlated with pancreatic infection. Thepurpose of this study was to determinate if the BT and pancreatic infection can be reduced in severe AP after Indomethacin administration. An experimental model of severe AP by injection taurocholic acid 2.5%. Ninety male wistar rats were divided in 3 groups: Sham, Pancreatitis, and Indomethacin. We analyzed the occurrence of BT to the pancreas and pancreatic infection with bacterial cultures. Bacterial translocation or bacterial accumulation was not observed in the Sham group. We concluded based in our data that the administration of Indomethacin may reduce the bacterial population in the pancreas and the occurrence of pancreatic infection. Moreover Indomethacin could not reduce the mortality rate in this experimental model

A pancreatite crônica é uma desordem complexa, na qual a interação entre fatores ambientais e genéticos resulta na enfermidade. O presente estudo incluiu 148 pacientes com diagnóstico de pancreatite crônica, 110 etilistas crônicos e 297 controles sadios com o objetivo de investigar a frequência de tabagismo e das mutações N34S e P55S do gene SPINK1 e R254W do gene CTRC nesta população. Foi aplicado questionário presencial e realizada reação de sequenciamento para a pesquisa das mutações genéticas, após assinatura do Termo de Consentimento Livre e Esclarecido. Os portadores de pancreatite crônica possuíam etiologia alcoólica em 74% das vezes e idiopática em 26%. A pancreatite alcoólica apresentou-se de maneira distinta da pancreatite crônica idiopática, sendo que o primeiro grupo é composto por maior prevalência do gênero masculino (88,18% versus 34,21%), por maior média de idade (55,64 anos versus 45,20 anos), menor frequência de caucasianos (63,89% versus 84,21%), menor escolaridade (23,30% concluíram ensino médio ou superior versus 57,89%) e maior frequência de repercussões da doença, como diarréia (54,21% versus 24,24%), emagrecimento (56,07% versus 24,24%), diabete melito (57,94% versus 36,36%) e ocorrência de pseudocistos pancreáticos (31,78% versus 12,12%), repercussões estas que não foram acompanhadas de maior frequência de alterações morfológicas, como calcificações pancreáticas ou dilatação do ducto pancreático principal. A frequência de tabagismo foi significativamente maior em pacientes com pancreatite crônica alcoólica do que em etilistas sem pancreatite crônica, podendo ser considerado cofator de risco para o desenvolvimento da pancreatite crônica entre alcoolistas (p = 0,002); a frequência da mutação N34S do gene SPINK1 em pacientes com pancreatite crônica foi de 3,38%, maior do que a frequência de 0,49% encontrada nos grupos controle (p = 0,016); a frequência de 2,03% da mutação P55S do gene SPINK1 e a frequência de 0,67% da mutação R254W do gene CTRC, encontradas nos pacientes com pancreatite crônica, não diferiram estatisticamente quando comparadas às frequências, de 0,49% de ambas mutações, encontradas nos grupos controle. (p = 0,120 e 0,751). Pela investigação da associação de tabagismo e da mutação N34S do gene SPINK1 com as características clínicas e morfológicas da pancreatite crônica, verificou-se que a mutação N34S não se associou a maior gravidade da apresentação clínica ou morfológica da pancreatite crônica; no entanto o tabagismo associou-se a maior frequência de diabete melito entre os portadores de pancreatite crônica. Concluiuse que o tabagismo e a mutação N34S do gene SPINK1 podem ser considerados cofatores de risco para o desenvolvimento da pancreatite crônica / Chronic pancreatitis is a complex disorder in which the interaction between environmental and genetic factors results in the disease. This study included 148 patients with chronic pancreatitis, 110 chronic alcoholics and 297 healthy controls in order to investigate the frequency of smoking and N34S and P55S mutation of SPINK1 gene and R254W of CTRC gene in this population. A questionnaire was applied and gene sequencing was done, after having the Informed Consent Statement. Those with chronic pancreatitis had alcoholic etiology in 74% of cases and idiopathic in 26%. Alcoholic pancreatitis presented in a distinct way of idiopathic chronic pancreatitis. The first group is composed of a higher prevalence of males (88.18% versus 34.21%), by higher mean age (55.64 years versus 45.20 years), lower frequency of Caucasians (63.89% versus 84.21%), lower education (23.30% completed secondary or higher education versus 57.89%) and worst impact from the disease such as diarrhea (54.21% versus 24.24%), weight loss (56.07% versus 24.24%), diabetes mellitus (57.94% versus 36.36%) and occurrence of pancreatic pseudocysts (31.78% versus 12 , 12%). These effects were not accompanied by increased frequency of morphological changes, such as pancreatic calcifications or dilation of the main pancreatic duct. The frequency of smoking was significantly higher in patients with alcoholic pancreatitis than in alcoholics without chronic pancreatitis, therefore tabagism may be considered as a cofactor for the development of chronic pancreatitis among alcoholics (p = 0.002); the frequency of N34S mutation of SPINK1 gene in patients with chronic pancreatitis was 3.38%, higher than the rate of 0.49% found in the control groups (p = 0.016); the frequency of 2.03% of the P55S mutation of SPINK1 gene and the frequency of 0.67% of the CTRC gene R254W mutation found in patients with chronic pancreatitis were not statistically different when compared to the frequencies of 0.49% of both mutations, found in the control groups. (p = 0.120 and 0.751) For the investigation of the association of smoking and N34S mutation of SPINK1 gene with the clinical and morphological features of chronic pancreatitis, it was noticed that the N34S mutation did not determine a greatest severity in the presentation of chronic pancreatitis, however smoking was associated with a higher frequency of diabetes mellitus in patients with chronic pancreatitis. It was concluded that smoking and the N34S mutation of SPINK1 gene are positively correlated with chronic pancreatitis

O infiltrado inflamatório, a perda maciça de células acinares e a fibrose se destacam como alterações da pancreatite alcoólica crônica, o que é reflexo da expressão gênica. O -tocoferol regula a expressão de vários genes, entre eles moduladores de proteínas extracelulares e de inflamação. O presente trabalho teve como intuito avaliar o efeito da suplementação com vitamina E sobre a expressão gênica pancreática de marcadores inflamatórios, em ratos com pancreatite alcoólica crônica induzida por dieta líquida contendo etanol (com ou sem suplementação de -tocoferol), ciclosporina A e ceruleína, por meio da técnica quantitativa de PCR em tempo real. Além disso, foram realizadas determinações de -tocoferol plasmático e hepático, lipídeos totais hepáticos, e análise histopatológica do pâncreas e fígado dos animais submetidos aos diferentes tratamentos (Grupo 1: Controle; Grupo 2: Pancreatite alcoólica crônica; Grupo 3: Pancreatite alcoólica crônica e suplementação com vitamina E). Os animais que receberam suplementação com vitamina E apresentaram maiores valores de -tocoferol plasmático e hepático [(G1: 14,27 ± 1,5 umols/L plasma; 125,47 ± 18,5 nmols/g fígado; 5,1 ± 0,8 nmols/mg lipídeo hepático); (G2: 21,64 ± 3,0 umols/L plasma; 126,54 ± 10,5 nmols/g fígado; 2,8 ± 0,7 nmols/mg lipídeo hepático); (G3: 43,91 ± 6,1 umols/L plasma*; 1595,90 ± 802,7 nmols/g fígado*; 17,3 ± 8,8 nmols/mg lipídeo hepático*)] (*p<0,01). O pâncreas dos animais do Grupo 1 apresentou histologia normal, ao passo que nos Grupos 2 e 3 apresentou focos de destruição tecidual leve a moderada, presença de infiltrado de células mononucleares (linfócitos e plasmócitos) e proliferação de tecido conjuntivo de sustentação, mostrando um quadro ainda em estágios iniciais de pancreatite alcoólica crônica. O fígado do Grupo 1 apresentou histologia normal, e dos Grupos 2 e 3, esteatose macro e microvesicular em grau variável, entre 30 a 60%. A análise de PCR em tempo real mostrou aumento de expressão de todos os 13 genes biomarcadores do processo inflamatório nos Grupos 2 e 3, provocado pela pancreatite alcoólica crônica, em relação ao Grupo 1 (p<0,01). A suplementação com vitamina E na presença de pancreatite no Grupo 3, em relação ao Grupo 2, diminuiu o número de transcritos para 5 genes (-SMA, COX-2, IL-6, MIP-3, TNF-) (p<0,01), aumentou o número de transcritos para 1 gene (Pap) (p<0,01), e não modificou os 7 genes restantes (Col1a1, IL-4, IL-8, IL-10, MCP-1, Mif, MMP-2) (p>0,05). A suplementação com vitamina E apresentou efeitos anti-inflamatórios e benéficos na expressão gênica pancreática de alguns biomarcadores do processo inflamatório em ratos com pancreatite alcoólica crônica, comprovando sua participação em alguns mecanismos da resposta inflamatória no pâncreas. / The inflammatory infiltrate, the massive loss of acinar cells and fibrosis are highlighted as changes in alcoholic chronic pancreatitis, which is a gene expression reflection. The -tocopherol regulates many genes expression, including extracellular proteins and inflammation modulators. This study was aimed to evaluate the vitamin E supplementation effect on pancreatic gene expression of inflammatory markers in rats with alcoholic chronic pancreatitis induced by liquid diet containing ethanol (with or without -tocopherol supplementation), cyclosporin A and cerulein through the quantitative real time PCR technique. Moreover, -tocopherol content in plasma and liver were analyzed, total lipid content in liver, and pancreas and liver histopathology of animals subjected to different treatments (Group 1: Control, Group 2: Alcoholic chronic pancreatitis, Group 3: Alcoholic chronic pancreatitis and vitamin E supplementation). The animals that received vitamin E supplementation had higher -tocopherol amounts in plasma and liver [(G1: 14,27 ± 1,5 umols/L plasma; 125,47 ± 18,5 nmols/g liver; 5,1 ± 0,8 nmols/mg liver lipid); (G2: 21,64 ± 3,0 umols/L plasma; 126,54 ± 10,5 nmols/g liver; 2,8 ± 0,7 nmols/mg liver lipid); (G3: 43,91 ± 6,1 umols/L plasma*; 1595,90 ± 802,7 nmols/g liver*; 17,3 ± 8,8 nmols/mg liver lipid*)] (*p<0,01). The pancreas of animals in Group 1 had normal histology, whereas in Groups 2 and 3 presented tissue destruction foci with mild to moderate mononuclear cells infiltration (lymphocytes and plasma cells) and connective tissue proliferation, showing an early stage occurrence of alcoholic chronic pancreatitis. The Group 1 liver showed normal histology, and Groups 2 and 3, macro and microvesicular steatosis in varying degrees, from 30 to 60%. The quantitative real time PCR analysis showed increased expression of all 13 inflammatory biomarkers genes in Groups 2 and 3, caused by alcoholic chronic pancreatitis, compared to Group 1 (p<0,01). Vitamin E supplementation in the presence of pancreatitis in Group 3, compared to Group 2, decreased the transcripts number for five genes (-SMA, COX-2, IL-6, MIP-3, TNF-) (p<0,01), increased the transcripts number for one gene (Pap) (p<0,01), and did not alter the seven remaining genes (Col1a1, IL-4, IL-8, IL-10, MCP-1 , Mif, MMP-2) (p>0,05). Vitamin E supplementation showed anti-inflammatory and beneficial effects on pancreatic gene expression of some inflammation biomarkers in rats with alcoholic chronic pancreatitis, confirming its participation in the inflammatory response mechanisms in the pancreas.

Peptídeos antimicrobianos, também chamados na literatura médica de AMPs (Antimicrobial Peptides), são agrupamentos de 12 a 50 aminoácidos que têm funções antimicrobianas e imunorregulatórias. Os AMPs são produzidos principalmente nos epitélios, destacando-se o epitélio intestinal, onde participam da homeostase da barreira intestinal. A Pancreatite Aguda (PA) é uma doença com altas taxas de mortalidade e morbidade, na qual frequentemente ocorre translocação de bactérias e endotoxinas para o epitélio intestinal e para a corrente sanguínea. A translocação bacteriana ocorre, principalmente, devido à falência da barreira intestinal. Em idosos, a PA tende a ser uma doença mais grave, porém os mecanismos que justificam essa maior gravidade ainda não são bem compreendidos. O objetivo deste trabalho é fazer um estudo da expressão gênica dos peptídeos antimicrobianos alfa-defensina 5 e 7 e da catelicidina CRAMP em ratos jovens e idosos submetidos a um modelo de Pancreatite Aguda. Ratos jovens e idosos foram submetidos à PA utilizando-se Ácido Taurocólico 2,5% e, após doze horas, foram sacrificados. Foi coletado 1cm do íleo terminal para realização de RTPCR para os genes das alfa-defensinas 5 e 7 e da catelicidina CRAMP. Adicionalmente, foram quantificados os níveis de mRNA das citocinas TNF-alfa e IL10. Através da técnica de Milliplex, foram dosadas no soro as citocinas IFN-y, IP-10, IL-10, IL-6, IL-18, TNF-alfa, IL-1beta e Leptina. Como resultado, detectou-se maior expressão gênica das alfa-defensinas 5 e 7 no grupo de animais idosos, na vigência de insulto pancreático, quando comparado a animais jovens na mesma condição. Com relação à CRAMP, não houve diferença significativa entre os grupos. Igualmente, obteve-se expressão significativamente maior de TNF-alfa no íleo terminal dos ratos idosos com Pancreatite Aguda. Interessantemente, as dosagens de citocinas séricas foram semelhantes entre os grupos, demonstrando que a diferença entre a resposta inflamatória de ratos idosos e jovens é localizada. Peptídeos antimicrobianos, portanto, devem apresentar um papel central na resposta inflamatória decorrente de injúria pancreática / Antimicrobial peptides, also called AMPs, are 12-50 amino acids molecules that have antimicrobial and immunoregulatory properties. AMPs are produced mainly in epithelial cells, and participate in the homeostasis of the intestinal barrier. Acute pancreatitis (AP) is a disease with high mortality and morbidity and presents a worst outcome when bacterial translocation occurs to the intestinal epithelium and to the bloodstream. Bacterial translocation occurs mainly due to the failure of the intestinal barrier. In the elderly, AP has a worst prognosis, but the mechanisms that justify that higher severity, compared to the young, are poorly understood. The objective of this work is to study the gene expression levels of antimicrobial peptides ?-defensins 5 and 7 and the cathelicidin CRAMP in young and elderly rats submitted to acute pancreatitis. Young and old rats received a taurocholic acid 2.5% injection in the pancreatic ductus and after twelve hours, were sacrificed. 1cm of the terminal ileum was collected for detection of AMPs gene expression levels. In addition, RT-PCR was performed to detect TNF-alfa and IL-10 mRNA levels. Using Milliplex technique, serum levels of IFN-gamma, IP-10, IL-10, IL-6, IL-18, TNF-alfa, IL-1beta and Leptin were measured. As a result, we detected significant higher mRNA levels of alfa-defensins 5 and 7 in the elderly (pancreatitis group). CRAMP gene expression was not significantly different between groups. TNF-alfa gene expression levels was significantly higher in old rats (pancreatitis group). Any difference in the cytokines serum levels could be detected when old and young rats in the pancreatitis groups were compared. We conclude that AMPs may play a pivotal role in the development of acute pancreatic injury