Publicación a texto completo no autorizada por el autor / El documento digital no refiere asesor / Determina la correlación entre los hallazgos por colangioresonancia y los hallazgos por colangiopancreatografía endoscópica retrograda en el diagnóstico de coledocolitiasis realizado en el Hospital Nacional Daniel Alcides Carrión de enero a junio del 2017. Desarrolla una investigación observacional, retrospectivo, sin grupo control y de corte transversal. Utiliza como muestra 57 historias clínicas (45 de mujeres y 12 de varones) de pacientes con sospecha de coledocolitiasis sometidos a colangioresonancia y a colangiopancreatografía retrógrada endoscópica con el fin de comparar los hallazgos obtenidos en ambas técnicas diagnósticas. Además se buscó obtener el número de casos en el que ambas técnicas presentaban los mismos hallazgos. La técnica considerada gold estándar en este estudio fue la CPRE. Encuentra que la validez de la colangioresonancia como método diagnóstico se evalúa por dos componentes: la sensibilidad, que en este estudio fue de 94.1%, y la especificidad, que fue en este estudio de 66.7%, con un intervalo de confianza del 95%. El grado de confiabilidad de la Colangioresonancia como método diagnóstico se evalúa por el valor predictivo positivo, que en este estudio fue de 96%; y el valor predictivo negativo, que en este estudio fue de 57.14%, con un intervalo de confianza del 95%. Concluye que hay concordancia entre los hallazgos por CPRE y Colangioresonancia en 85.96% de los casos en el diagnóstico de coledocolitiasis. / Tesis

Lesão hepática é uma das complicações decorrentes de pancreatite aguda (PA) e mostra uma correlação positiva com a gravidade da doença. Recentemente foi demonstrado que tratamento com solução hipertônica (SH) reduz inflamação e mortalidade na PA. O presente trabalho investigou os efeitos de SH na modulação do estresse oxidativo, apoptose e remodelamento tecidual no fígado durante a PA. Ratos machos foram divididos em quatro grupos: C animais que não foram submetidos à PA ou tratamento; past animais submetidos à indução de PA e que não receberam tratamento; pas animais submetidos à PA e tratados com solução fisiológica (NaCl 0.9%); pah animais submetidos à indução de PA e que receberam SH (NaCl 7.5%). PA foi induzida pela injeção retrógrada de ácido taurocólico (2.5%) no ducto bilo-pancreático. Após 4, 12 e 24 horas os animais foram sacrificados para coleta das amostras de interesse (fígado e plasma) submetidas a ensaios para análise de expressão (western blot e PCR) de Óxido Nítrico Sintase induzível (iNOS), metaloproteinases (MMP) -2 e -9, Heat Schock Protein (HSP) 47, 60, 70 e 90, colágenos tipos I e III, caspases 2 e 9, APAF-1 e AIF, formação de nitrotirosina (imunohistoquímica), peroxidação lipídica (TBARs), atividade de alaninoaminotransferase (ALT), produção de nitrito/nitrato (Reação de Griess) e das citocinas TNF-, IL-1, IL-6 e IL-10 (ELISA). O tratamento com SH reduziu significantemente o estresse oxidativo hepático com a redução da expressão gênica de iNOS (p<0,01 vs. pas), dos níveis de nitrito/nitrato (P<0,01 vs. pas), liberação de ALT (p<0,01 vs. pas) e inibição da formação de peroxinitrito após 12 horas da indução de PA. Conseqüentemente, a expressão de HSP70 não foi ativada devido à proteção hepática causada pela administração de SH. A expressão e atividade de MMP-9 aumentaram significativamente nos grupos pas e past, entretanto o tratamento com SH manteve os níveis basais (p<0,05 vs. past, pas). Aumento da expressão de HSP47 e alterações na expressão de colágeno indicaram intenso remodelamento de matriz extracelular nos grupos não tratados ou tratados com solução fisiológica, permanecendo semelhante ao controle no grupo pah. Não ocorreram mudanças significativas na expressão das proteínas envolvidas no processo apoptótico. A SH diminui o estresse oxidativo no período crítico da PA, resultando na diminuição da lesão hepática e do remodelamento tecidual, mantendo dessa forma a integridade de matriz extracelular / It has been shown an hepatic injury following pancreatitis and a positive correlation with severity of the disease. Hypertonic Solution (HS) reduced morbidity and mortality in experimental pancreatitis. We hypothesize that hypertonic solution resuscitation of acute pancreatitis (AP) may exert antiinflammatory effects by modulating hepatic oxidative stress, apoptosis and matrix extracellular remodeling in liver. Wistar rats were divided in four groups: C- control animals not subjected to insult or treatment; NT- subjected to pancreatitis induction and receiving no treatment; NS- subjected to pancreatitis induction and receiving normal saline (0.9% NaCl); HSsubjected to pancreatitis induction and receiving hypertonic saline (7.5% NaCl). AP was induced by retrograde infusion of 2,5% sodium taurocholate into the pancreatic duct transduodenally. At 4, 12 and 24 h following pancreatitis induction, liver tissue samples were assayed in order to analyse expression of metalloproteinases (MMPs) -2 and -9, iNOS, collagens (type I and III), Heat Shock Proteins (HSPs) 47, 60, 70 and 90, caspases -2 and -7, APAF-1 and AIF, production of the cytokines TNF-, IL-1, IL-6 and IL-10, Nitrite/nitrate and ALT, Lipid peroxidation and formation of Nytrotirosine. Hypertonic solution resuscitation significantly modulates the oxidative stress in liver by reduction of iNOS gene expression (p<0,01 vs. NS), nitrite and nitrate levels (p<0,01 vs. NS), lipid peroxidation (p<0,05 vs. NT), ALT release (p<0,01 vs. NS) and peroxinitrite inhibition after 12 hours of pancreatitis induction. Consequently, the HSP70 production has not been activated due to the hypertonic solution effect in hepatic protection. At 4 h and 12 h, MMP-9 expression and activity increased in the NS and NT groups, although remaining at basal levels in the HS group (p<0.05 vs. past, pas). At 12 h, MMP-2 expression increased in the NS group (p<0.05 vs. c) but not in the HS group. At 4 h after pancreatitis induction, HSP47 expression increased in the NS and NT groups. Greater extracellular matrix remodelling occurred in the NS and NT groups than in the HS group, probably as a result of the hepatic wound-healing response to repeated injury. However, the collagen content in hepatic tissue remained at basal levels in the HS group. The proteins involved in apoptosis remained unchanged in all groups. Hypertonic saline is hepatoprotective, since it decreases oxidative stress in the critical time resulting in diminished liver damage, reducing hepatic remodelling, maintaining the integrity of the hepatic extracellular matrix during pancreatitis. Hypertonic saline-mediated regulation of MMP expression might have clinical relevance in pancreatitis-associated liver injury

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Os triterpenos pentacÃclicos sÃo compostos naturais com atividade antiinflamatÃria e citoprotetora e sÃo relativamente atÃxicos. A pancreatite aguda, uma inflamaÃÃo aguda do pÃncreas, pode levar à sÃndrome da resposta inflamatÃria sistÃmica (SRIS) e à sÃndrome da disfunÃÃo mÃltipla de ÃrgÃos (MODS), condiÃÃes que podem levar o paciente ao Ãbito. Neste trabalho, a mistura de triterpenos pentacÃclicos alfa,&#946;-amirina, isolada do Protium hepthaphyllum, foi investigada quanto aos seus efeitos nos modelos de pancreatite aguda induzida por L-arginina em ratos e por ceruleÃna em camundongos. No modelo de pancreatite aguda induzida por L-arginina, ratos Wistar machos foram tratados com a mistura de alfa,&#946;-amirina (10, 30 e 100 mg/kg, v.o.) ou com o veÃculo (2% de Tween 80 em Ãgua destilada, 10ml/kg) 48, 24 e 1,5h antes da administraÃÃo de L-arginina (2 x 2,5 g/kg; 1 h de intervalo) ou com metilprednisolona (30 mg/kg, i.m.) 30 min antes da administraÃÃo de L-arginina. Na pancreatite induzida por ceruleÃna, camundongos Swiss machos foram tratados com a mistura de alfa,&#946;-amirina (10, 30 e 100 mg/kg, v.o.) ou com o veÃculo (2% de Tween 80 em Ãgua destilada, 10ml/kg) 48, 24 e 1,5h antes da administraÃÃo de ceruleÃna (5 x 50 &#956;g/kg; 1 h de intervalo) ou com talidomida (200 mg/kg, v.o.) 1h antes da administraÃÃo de ceruleÃna. Animais tratados apenas com salina (0,9%, NaCl) foram incluÃdos nos dois modelos. Foram analisados o edema pancreÃtico, nÃveis sÃricos de amilase, lipase e citocinas (TNF alfa, IL-6), mieloperoxidase, substÃncias reativas ao Ãcido tiobarbitÃrico (TBARS), histologia e imunohistoquÃmica (TNF-alfa, iNOS e nitrotirosina) pancreÃtica. L-arginina e ceruleÃna aumentaram significativamente o edema pancreÃtico e os nÃveis sÃricos de amilase, lipase, TNF alfa, IL-6. A avaliaÃÃo histopatolÃgica do pÃncreas revelou a presenÃa de edema, infiltraÃÃo neutrofÃlica, hemorragia, vacuolizaÃÃo e necrose acinar. Foi observado um aumento acentuado na expressÃo de TNF alfa, iNOS e nitrotirosina na avaliaÃÃo por imunohistoquÃmica. O prÃ-tratamento com alfa e beta-amirina (10, 30 e 100 mg/kg, v.o.), metilprednisolona (30 mg/kg, i.m.) ou talidomida (200 mg/kg, v.o.) atenuaram significativamente a severidade da pancreatite aguda induzida tanto por L-arginina, quanto por ceruleÃna, evidenciado pela reduÃÃo do edema pancreÃtico, amilase, lipase e citocinas sÃricas, mieloperoxidase e TBARS pancreÃtico. AlÃm disso, o tratamento com alfa,&#946;-amirina e com as drogas de referÃncia suprimiram as alteraÃÃes histopatolÃgicas e a expressÃo de citocinas e nitrotirosina pancreÃticas. Em conjunto, esses resultados indicam que alfa,&#946;-amirina melhora a severidade da pancreatite aguda induzida por L-arginina ou ceruleÃna por agir como antiinflamatÃrio e antioxidante. / Triterpenes are natural compounds with anti-inflammatory and cytoprotective effects relatively non-toxic. Acute pancreatitis, an inflammation of the pancreas, may lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), conditions that can lead the patient to death. In this study, a mixture of triterpenes isolated from Protium hepthaphyllum was investigated for their effects in models of acute pancreatitis. In the model of acute pancreatitis induced by L-arginine, male Wistar rats were treated with a mixture of &#61537;,&#946;-amyrin (10, 30 and 100 mg/kg, p.o.) or with vehicle (2% Tween 80 in distilled water, 10 ml/kg) 48, 24 and 1.5 h before the administration of L-arginine (2 x 2.5 g/kg, 1 h apart) or with metilprednisolone (30 mg/kg, i.m.) 30 min before the administration of L-arginine. In cerulein-induced pancreatitis, male Swiss mice were treated with a mixture of &#61537;,&#946;-amyrin (10, 30 and 100 mg/kg, p.o.) or with vehicle (2% Tween 80 in distilled water, 10 ml/kg) 48, 24 and 1.5 h before administration of cerulein (5 x 50 mg/kg, 1 h apart) or with thalidomide (200 mg/kg, p.o.) 1h before administration of cerulein. Animals treated with saline (0.9% NaCl) were included in both models. We analyzed the pancreatic edema, serum amylase, lipase and cytokines (TNF-&#61537;, IL-6), myeloperoxidase, reactive substances to thiobarbituric acid (TBARS), histology and immunohistochemistry (TNF-&#61537;, iNOS and nitrotyrosine) pancreatic. L-arginine and cerulein significantly increased pancreatic edema and serum levels of amylase, lipase, TNF-&#61537; and IL-6. Histopathologic evaluation of pancreas revealed the presence of edema, neutrophil infiltration, hemorrhage, acinar vacuolization and necrosis. We observed a marked increase in the expression of TNF-&#61537;, iNOS and nitrotyrosine in the evaluation by immunohistochemistry. The pre-treatment with alpha and beta-amyrin (10, 30 and 100 mg/kg, p.o.), metilprednisolone (30 mg/kg, i.m.) or thalidomide (200 mg/kg, p.o.) significantly attenuated the severity of acute pancreatitis induced by either L-arginine, and by cerulein, as evidenced by the reduction of pancreatic edema, amylase, lipase and serum cytokines, myeloperoxidase and pancreatic TBARS. Furthermore, treatment with &#61537;,&#946;-amyrin and the reference drugs suppressed the histopathological changes and expression of cytokines and nitrotyrosine pancreatic. Together, these results indicate that the mixture of &#61537;,&#61538;-amyrin reduces the severity of acute pancreatitis induced by L-arginine or cerulein acting as anti-inflammatory and antioxidant agent.

INTRODUÇÃO: O comprometimento pancreático em pacientes com Doença de Crohn (DC) é objeto de poucos estudos, porém as poucas séries sobre o assunto indicam um acometimento de uma parcela significativa dos pacientes, variando de 1,2% a 58%. O ultra-som endoscópico (EUS) apresenta a vantagem de apresentar uma sensibilidade muito maior que o ultra-som abdominal e a tomografia computadorizada. Quando comparado à colangiopancreatografia retrógrada endoscópica, este possui, além de uma maior sensibilidade, um índice de complicações significativamente menor. OBJETIVOS: Avaliar a incidência de alterações pancreáticas ao ultra-som endoscópico em pacientes com Doença de Crohn, correlacionando com fatores clínicos, bioquímicos e endoscópicos. MÉTODOS: Cinqüenta e um pacientes com DC, com idade entre 18 e 60 anos (média de 38 anos), sem história prévia de doença pancreática, diabetes mellitus ou alcoolismo, foram submetidos ao exame de EUS. O grupo controle foi formado por 20 pacientes submetidos ao EUS e que não apresentavam história de doença pancreato-biliar ou de Crohn. Dados clínicos, endoscópicos e laboratoriais foram coletados para posterior correlação. Onze variáveis ecoendoscópicas foram analisadas, tanto ductais quanto parenquimatosas. Os pacientes com três ou mais alterações foram submetidos à colangiorressonância magnética (CRNM). Para análise da função pancreática, foi realizado dosagens de elastase fecal em 39 pacientes. RESULTADOS: Dos pacientes analisados, 56% pertenciam ao sexo feminino, com tempo médio de diagnóstico da enfermidade de 7 anos e índice de atividade da doença (CDAI) médio de 102. Dois pacientes, (3,9%) apresentaram quatro alterações ecoendoscópicas, três pacientes, (5,9%) possuíram três alterações, 11 pacientes, (21,5%) tiveram duas alterações e 13 pacientes, (25,5%) apresentaram apenas uma alteração ao EUS. As alterações parenquimatosas totalizaram 39 achados, contra 11 alterações ductais. Apenas três pacientes (16%) do grupo controle apresentaram uma alteração ecoendoscópica (p<0,001). Os pacientes com três ou mais alterações ao EUS realizaram a CRNM, que não mostrou alterações em nenhum dos casos. Quatro pacientes, (10%) apresentaram dosagens de elastase fecal compatíveis com insuficiência pancreática exócrina, sem apresentar correlação com a ecoendoscopia. O único fator preditivo correlacionado com o número de alterações ao EUS foi doença ileal exclusiva. CONCLUSÕES: Os pacientes com DC possuíram uma alta incidência de anormalidades na morfologia pancreática (aproximadamente 10% com três ou mais alterações no EUS). Estas alterações foram localizadas predominantemente em parênquima, o que pode justificar a falta de correlação com a CRNM / BACKGROUND: Pancreas injury usually is not mentioned as an extra-intestinal manifestation of Crohns disease, but the few available series suggest pancreatic injury in a significant proportion of these patients, ranging from 1.2% to 58% in this series. Endoscopic ultrasound (EUS) presents the advantage of having a much higher sensitivity than the abdominal ultrasound or computadorized tomography in evaluating pancreas abnormalities. Compared to the endoscopic retrograde cholangiopancreatography, EUS has at least an equal sensitivity, with a lower complication rate. AIMS: To evaluate the incidence of pancreatic alterations by means of the EUS in Crohns disease, correlating them with clinical, endoscopic and biochemical data. METHODS: Fifty one patients with Crohns disease, age between 18 and 60 years-old (mean = 38), without previous history of pancreatic disease, diabetes mellitus or alcoholism, were submitted to EUS. The control-group was formed by 20 patients submitted to EUS with no previous history of pancreatic or Crohns disease. Clinical, endoscopic and biochemical data were collected in order to determine possible predictive factors. Eleven variables were analyzed, both in pancreatic parenchyma and ducts. The patients with 3 or more alterations were submitted to magnetic resonance. Pancreatic function was determined using fecal elastase assay in 39 patients. RESULTS: Of the 51 analyzed patients, 56% were female, with mean diagnosis time of seven years (1-25) and Crohns disease Activity Index (CDAI) of 102 (20-419). Two patients (3.9%) presented 4 alterations in the EUS exam, 3 (5.9%) presented 3 alterations, 11 (21.5%) had 2 alterations and 13 (25.5%) had 1 alteration in the EUS, which were statistically significant when compared to the control-group, in whom only 16% presented 1 exam alteration (p<0.001). The parenchymal abnormalities were more common, totalizing 39 findings when compared to 11 ductal abnormalities. The patients with 3 or more alterations in the exam were submitted to magnetic resonance; however, pancreatic lesions were not detected. Four patients (10%) had low fecal elastase measurement, suggestive of exocrine pancreatic insufficiency. None of these patients had significant pancreatic alterations in EUS. The only predictive factor that correlated with the number of alterations in EUS was isolated ileal disease. CONCLUSIONS: Patients with Crohns disease had a higher incidence of pancreatic abnormalities (10% with 3 or more alterations in endoscopic ultrasound) in comparison to the control-group. These alterations were found most frequently in the pancreatic parenchyma, which might explain the lack of correlation with the magnetic resonance, which is more prone to detect duct abnormalities. The only predictive factor to these alterations on EUS was ileal disease

A pancreatite é o resultado da atividade corrosiva das enzimas digestivas pancreáticas e, independente dos vários agentes etiológicos e dos mecanismos etiopatogênicos, tem como resultado a ativação enzimática intra-parenquimatosa, a destruição tecidual e a necrose isquêmica. Trata-se de uma afecção, grave, com incidência aumentada em vítimas de traumatismo raquimedular. Nesses doentes, a suspeita clínica de pancreatite pode ser difícil, pois os sinais e sintomas podem estar diminuídos ou ausentes em decorrência do déficit sensorial esplâncnico. Avaliaram-se, prospectivamente, 78 doentes com traumatismo raquimedular internados no IOT-HCFMUSP, dosando-se os níveis séricos das enzimas amilase e lipase em 3 períodos de tempo pré-determinados, entre os dias de 1 a 3, de 10 a 12 e de 15 a 20 após o traumatismo. A incidência de pancreatite aguda foi maior nos pacientes com traumatismo raquimedular ASIA A e que apresentaram íleo adinâmico / Acute pancreatitis is a result of corrosive activity of pancreatic digestive enzymes, and many etiologic agents trigger acute pancreatitis by a variety of different mechanisms, but the ultimate result is a tissue destruction. The incidence in spinal cord injury patients is higher than the normal population. The clinical diagnosis of acute pancreatitis in spinal cord injury patients is hampered by a lower or lost visceral sensitivity, as a result in a necessity of laboratory investigations to confirm diagnosis. A prospective study with 78 acute spinal cord injury patients of The Clinical Hospital of the College of Medicine of University of São Paulo is performed. The incidence of pancreatitis is larger in patients of spinal cord injury ASIA A and with ileus paralytic

Introdução: O sucesso da cateterização da via biliar é de importância para o diagnóstico e terapêutica nas afecções biliopancreáticas nos procedimentos de colangiopancreatografia retrógrada endoscópica (CPRE) e está associado a complicações graves e mortalidade. O objetivo do estudo foi comparar o sucesso, perfil laboratorial e as complicações da técnica de fistulotomia papilar direta com o acesso cateter e fio-guia. Métodos: No período de julho de 2010 a maio de 2017 foram selecionados e randomizados para CPRE em dois grupos: cateterização com cateter e fioguia (Grupo I) e a fistulotomia papilar (Grupo II). As curvas de amilase, lipase e proteína C reativa (T0, 12 e 24 horas) e as complicações (pancreatite, sangramento e perfuração) foram avaliadas após CPRE. Resultados: Foram incluídos 102 pacientes (66 do sexo feminino e 36 do masculino, com idade média de 59,11±18,7 anos) e divididos em 51 pacientes para Grupo I e 51 no Grupo II. Os sucessos das cateterizações dos Grupos I e II foram de 76,47% e 100%, respectivamente (p=0,0002). Doze pacientes (23,53%) do Grupo I foram considerados pacientes de cateterização difícil e submetidos à fistulotomia papilar com sucesso no acesso biliar. Foram observadas 13,7% (2 perfurações e 5 pancreatites leves) e 2 % (1 paciente com perfuração e pancreatite) complicações nos Grupos I e II, respectivamente (p=0,062). Conclusão: A fistulotomia papilar demonstrou maior eficácia na cateterização da via biliar e com menor índice de amilasemia e lipasemia em comparação a cateterização com papilótomo e fio guia. As complicações foram semelhantes entre as duas técnicas / Background: The success of biliary tract cannulation is important for the diagnosis and treatment of biliopancreatic diseases in endoscopic retrograde cholangiopancreatography (ERCP) procedures. ERCP is associated with severe complications and mortality. The aim of the study was to compare the success, laboratory profile and complications of the direct papillary fistulotomy technique with standard catheter and guidewire access. Methods: In the period from July 2010 to May 2017, two groups were selected and randomized for ERCP: cannulation with catheter and guidewire (Group I) and papillary fistulotomy (Group II). The curves of amylase, lipase and C-reactive protein (T0, 12 and 24 hours) and complications (pancreatitis, bleeding and perforation) were evaluated after ERCP. Results: A total of 102 patients (66 females and 36 males, mean age 59.11 ± 18.7 years) were divided into 51 patients for Group I and 51 for Group II. The success of cannulation was 76.47% and 100%, in Groups I and II, respectively (p = 0.0002). Twelve patients (23.53%) of Group I were considered to have difficult cannulation and were submitted to fistulotomy with successful biliary access. There were 13.73% (2 perforations and 5 mild pancreatitis) and 2% (1 patient with perforation and pancreatitis) complications in Groups I and II, respectively (p=0,062). Conclusion: Papillary fistulotomy demonstrated greater efficacy in the bile duct cannulation and presented lower serum amylase and lipase compared with standard catheter and guidewire cannulation. Complications were similar in the two techniques

Abstract Heavy alcohol consumption places a substantial burden on health all over the world. Metabolites of alcohol evoke alterations that lead to tissue damage in many organs. Phosphatidylethanol (PEth) is a unique phospholipid formed in the cellular membranes during the metabolism of ethanol after alcohol consumption. PEth has attracted special attention as it is postulated to be a reliable marker of long term heavy alcohol consumption. The aims of present study were to investigate the immunogenicity of phosphatidylethanol in mice and to analyze the plasma antibodies binding to phosphatidylethanol in humans. In this study a clear immune response was generated in mice immunized with PEth in human low density lipoprotein (LDL) carrier. Mouse monoclonal IgM antibodies binding specifically to phosphoethyl head group of PEth were generated using hybridoma technology. Since PEth was shown to be immunogenic in mice, plasma was analyzed for the presence of antibodies also in humans. PEth-specific antibodies of IgG, IgA and IgM isotypes in plasma were detected in heavy drinkers of alcohol with or without pancreatitis as well as in the controls. The plasma levels of the antibodies binding to PEth were significantly lower in the study subjects with heavy alcohol use and in this present study sample the low IgA levels to PEth were better indicators of heavy alcohol consumption as compared to the some of the traditional markers of heavy alcohol use. The antibody levels to PEth associated significantly to plasma antibodies binding to malondialdehyde-acetaldehyde adducts that are known to be formed during alcohol metabolism but not to antibodies binding to phosphocholine which is generated by lipid oxidation in humans. In conclusion, this study demonstrates that phosphatidylethanol is immunogenic in mice when using carriers such as human LDL in the immunization process. The binding of the monoclonal antibodies specifically to the PEth head group suggests that it would be feasible to develop a diagnostic immunoassay to PEth. The presence of antibodies binding to PEth in plasma indicates that PEth may be a target of humoral immunity in humans. / Tiivistelmä Runsas alkoholinkulutus aiheuttaa maailmanlaajuisesti merkittäviä terveydellisiä haittoja. Alkoholin aineenvaihduntatuotteet muuttavat kudoksien rakenteita ja aiheuttavat kudosvaurioita. Fosfatidyylietanoli on alkoholin aineenvaihdunnan tuloksena solukalvoilla syntyvä fosfolipidi, jota on tutkittu kahdenkymmenen vuoden ajan lupaavana alkoholin suurkulutuksen merkkiaineena. Tutkimuksen tavoitteena oli selvittää fosfatidyylietanolin immunisoinnin aiheuttamaa vasta-aineiden muodostumista koe-eläinmallina käytetyissä hiirissä sekä määrittää ihmisten plasmanäytteistä vasta-aineita, jotka sitoutuvat fosfatidyylietanoliin. Tutkimuksessa havaittiin immuunivasteen muodostuminen hiirissä, jotka immunisoitiin ihmisen LDL hiukkasiin liitetyllä fosfatidyylietanolilla. Hiiren monoklonaalisia fosfatidyylietanoliin sitoutuvia IgM-luokan vasta-aineita tuotettiin tutkimuksessa soluviljelyn avulla. Fosfatidyylietanolin aiheuttama vasta-aineiden muodostuminen hiirillä johdatti mittaamaan fosfatidyylietanoliin sitoutuvia vasta-aineita myös ihmisiltä. Tutkimuksessa havaittiin fosfatidyylietanoliin sitoutuvia IgG-, IgA- ja IgM-luokan vasta-aineita alkoholin suurkuluttajilla, alkoholihaimatulehdusta sairastavilla ja verrokkihenkilöillä. Vasta-aineiden pitoisuudet olivat alkoholia runsaasti käyttävillä koehenkilöillä merkitsevästi pienemmät kuin verrokkiryhmällä. Matalat IgA-vasta-ainepitoisuudet osoittautuivat aineistossa paremmaksi alkoholin suurkulutuksen osoittajiksi kuin eräät tavanomaisesti käytetyt alkoholinkäytön merkkiaineet. Plasman fosfatidyylietanoli-vasta-aineiden ja alkoholin aineenvaihdunnan seurauksena syntyvien malondialdehydi-asetaldehydi-addukteihin sitoutuvien vasta-aineiden määrän välillä havaittiin merkitsevä yhteys, jota ei havaittu rasvojen hapettumisen seurauksena syntyvien fosfokoliini-vasta-aineiden ja fosfatidyylietanoli-vasta-aineiden välillä. Tutkimus osoittaa, että hiirillä voidaan aikaansaada vasta-ainevälitteinen immuunivaste, kun ne rokotetaan ihmisen LDL-hiukkaseen liitetyllä fosfatidyylietanolilla. Fosfatidyylietanoliin spesifisesti sitoutuvien monoklonaalisten vasta-aineiden tuottaminen voi tulevaisuudessa johtaa immunologisen diagnostisen määritysmenetelmän kehittämiseen. Fosfatidyylietanoliin sitoutuvien plasman vasta-aineiden havaitseminen viittaa siihen, että fosfatidyylietanoli on vasta-ainevälitteisen immuunivasteen kohde myös ihmisillä.

Background: Necrotizing pancreatitis is a life-threatening presentation of acute pancreatitis. The mortality of 20–80% initially depends on the persistence of organ failure and systemic inflammatory response syndrome (SIRS) and, in the later course of the disease, on secondary infection of the necrosis. The questions whether prophylactic antibiotics aiming to prevent this infection should be administered and which antibiotic is the best to use, as well as the problem of fungal infection under antibiotic treatment are still intriguing and insufficiently solved. Methods: A search of the literature using PubMed was carried out, supplemented by a review of the programmes of the Digestive Disease Week (DDW) and the United European Gastroenterology Week (UEGW). Results: Despite the widely practised prophylactic antibiotic administration in severe pancreatitis, no evidence for the benefit of this strategy exists. One of the drawbacks might be a tendency for disastrous fungal infection under prophylactic antibiotics. Bacterial translocation from the gut in the second week after the onset of symptoms is the major source for infection of pancreatic necrosis and provides a clear indication for antibiotic treatment. However, routine fine-needle aspiration for a calculated antibiotic therapy cannot be recommended, and all other tests offer only indirect signs. Important factors such as enteral versus parenteral feeding and the method of necrosectomy are mostly neglected in the trials but seem to be essential for the outcome of the patient. Conclusions: Even though most meta-analyses including the newer double-blind, placebo-controlled trials on prophylactic antibiotics showed no beneficial effects in the prevention of infection of necrosis and/or outcome of the patients, this strategy is still widely used in clinical routine. Since nearly all trials published so far show systematic problems (i.e. inaccurate definition of the severity of the disease, poor statistical testing, and neglect of differences in the route of nutrition), there is a need for randomized controlled prospective trials with exact definitions of the disease. / Hintergrund: Die nekrotisierende Pankreatitis weist eine Mortalität von 20–80% auf. Initial ist vor allem das Ausmaß des Organversagens entscheidend für die Prognose des Patienten. In der zweiten Krankheitswoche stellt dann die sekundäre Infektion der Nekrosen durch die Translokation von Darmkeimen das entscheidende Problem dar. Zur Vermeidung einer solchen Infektion werden klinisch sehr häufig Breitspektrumantibioktika prophylaktisch eingesetzt. Dies wird aber zunehmend kritisch diskutiert, und es existieren kontroverse Empfehlungen. Methoden: Eine Literaturrecherche unter Einbeziehung von PubMed und der Programme der Digestive Disease Week (DDW) und der United European Gastroenterology Week (UEGW) wurde durchgeführt. Ergebnisse: Die meisten Studien können den prophylaktischen Einsatz von Antibiotika bei der schweren Pankreatitis nicht rechtfertigen. Einige Studien belegen vielmehr eine Selektion resistenter Keime und vor allem auch eine erhöhte Rate von schwer therapierbaren Pilzinfektionen unter einer solchen Therapie. Daher sollte erst nach dem Nachweis einer Nekroseinfektion mit einer Antibiotikatherapie begonnen werden, wobei keine Routine-Feinnadelpunktion der Nekrose zum Keimnachweis durchgeführt werden sollte. Es stehen daher nur indirekte, meist bildgebende Verfahren für den Infektionsnachweis zur Verfügung. Entscheidende Faktoren wie die enterale Ernährung und die Methode der Nekrosektomie wurden bisher bei den meisten Studien vernachlässigt, scheinen aber essenziell für das Behandlungsergebnis des Patienten zu sein. Schlussfolgerungen: Die meisten publizierten Studien weisen eine sehr heterogene Definition der Erkrankung, uneinheitliche Behandlungsprotokolle und Ungenauigkeiten bei der statistischen Testung auf. Gerade entscheidende Faktoren wie die enterale Ernährung werden größtenteils komplett vernachlässigt. Es besteht daher ein Bedarf für randomisierte placebokontrollierte Studien, die diese Probleme berücksichtigen und suffiziente Schlussfolgerungen zur Antibiotikatherapie der schweren Pankreatitis zulassen.

Context: Beta-site alpha-amyloid protein cleaving enzyme1 (BACE1) plays a key role in the pathogenesis of Alzheimer’s disease. Additional to its moderate expression in the brain, high levels of BACE1 mRNA were found in the pancreas. Murine Bace1 has been immunohistochemicaly detected at the apical pole of acinar cells within the exocrine pancreas of mice and Bace1 activity was observed in pancreatic juice. In vitro experiments revealed enteropeptidase as a putative substrate for Bace1 suggesting a role in acute pancreatitis.

Die Pathophysiologie der akuten Pankreatitis ist durch eine immunologische Dysregulation gekennzeichnet, deren genaue Mechanismen unvollständig verstanden sind. Zur Untersuchung des Einflusses des Stressproteins p8 wurde die akute experimentelle Pankreatitis in einer p8-defizienten Mauslinie induziert und das Immunsystem phänotypisiert. Auf die Entwicklung des Immun- und Organsystems hat eine p8-Deletion keinen Einfluss, jedoch ist die Immunseneszenz verbunden mit einer Splenomegalie, Milzsiderose und extramedullärer Hämatopoese. Die akute Pankreatitis verläuft bei Fehlen von p8 wesentlich schwerer, begleitet von einem stärkeren Verlust an CD4+ T-Zellen in Blut und Milz. In der Phase der Rekonvaleszenz kommt es unter p8-Defizienz zu einem gehäuften Auftreten lymphozytärer Apoptosen in der Milz, begleitet von einer schweren Mikroarchitekturstörung und Verlust von Lymphfollikeln. Es kann erstmals eine antiapoptotische Wirkung von p8 auf aktivierte Milzlymphozyten während der postinflammatorischen Immunrekonstitution postuliert werden, wobei die involvierten Signalwege weiter untersucht werden müssen.