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Background: There is a wide variety of disease severity in patients with complicated intraabdominal infection (cIAI). The prognostic role of intraabdominal view (IAV) was recently studied, and an IAV score was introduced. The aim of this study was to analyze the associations between the preoperative levels of eight relevant circulating cytokines and IAV components, the IAV score, as well as outcome. Materials and methods: This was a single-center prospective study. The study cohort consisted of operatively managed adult patients with a cIAI. Preoperative plasma levels of eight cytokines were determined. The operating surgeon filled a form describing IAV. Outcomes analyzed were 30-day mortality and the development of organ dysfunctions requiring intensive care unit admission. Results: A total of 131 patients with cIAI were analyzed, 30-day mortality was 9.9% (n = 13), and 28 (21.4%) patients had postoperative organ dysfunctions. All components of IAV, the IAV score, and outcomes were associated with various cytokine levels. Interleukin-8 was the most competent marker associating with all the variables assessed in this study: diffuse peritonitis (P

Aims Oxidative stress may contribute to the development of chronic pancreatitis (CP). The enzymes manganese superoxide dismutase 2 (MnSOD, SOD2) and catalase (CAT) counteract free radical activity within the mitochondria and the cytosol. Moreover, CAT activity contributes to the transformation of ethanol to acetaldehyde, a toxic intermediate product of ethanol metabolism, which has been associated with pancreatic damage. Common functional polymorphisms have been described in the MnSOD gene [rs4880, NM_000636.3:c.47 T > C, alanine (ALA) to valine (Val)] and in the CAT promoter region [rs1001179, NG_013339.1:g.4760 C > T]. We investigated whether these polymorphisms are associated with alcoholic CP. Methods We genotyped 470 patients with alcoholic CP for these MnSOD and CAT polymorphisms. We also analysed these variants in 357 healthy control subjects, and in an additional control group of 113 individuals with non-alcoholic CP. We used the age at onset of CP as marker of disease severity and investigated whether different genotypes are associated with different ages at onset. In patients with alcoholic CP, we investigated whether an interaction exists between smoking behaviour and genotypes by comparing genotype distributions in smokers and non-smokers. Results We did not observe significant differences of genotype frequencies between patient groups and controls. In patient groups, we did not find significant differences in the ages at onset between different genotypes. We did not observe an interaction between these polymorphisms. We did not find an association of these variants with smoking behaviour. Conclusions The investigated MnSOD and CAT polymorphisms do not predispose to the development of alcoholic CP. Short summary Patients with alcoholic pancreatitis and controls were genotyped for polymorphisms in oxidative stress genes. There were no significant differences of genotype frequencies between patients and controls, and no association with the age at onset of disease was observed. The polymorphisms are not associated with the development of alcoholic pancreatitis.

Objectives: Genotype assessment has been suggested to be a tool for predicting disease severity in acute pancreatitis (AP). To study this hypothesis, we performed genotype analysis of tumor necrosis factor (TNF) −308 A/G, CD14 −159C/T, and HSPA1B +1267 A/G polymorphisms. Methods: This is a case-control association study of 397 patients with AP (214 of whom had an alcohol-induced AP) and 300 controls. The control group comprised 218 subjects with detailed data of alcohol consumption, 70 of whom were heavy drinkers (daily alcohol intake >40 g), and 92 blood donors. The severity of AP was determined according to the Atlanta classification. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-assisted genotyping method. Results: Major allele frequency in TNF gene was 0.87 for patients with AP and 0.86 for controls. For CD14, the gene major allele frequency was 0.60 for patients and 0.63 for controls. For HSPA1B, the major allele frequencies were 0.52 for patients and 0.49 for controls, respectively. The allele frequencies did not differ significantly between AP patients with organ failure and those with mild disease, patients with alcohol-induced AP, or those with biliary AP. The patients with septic infectious complications (n = 47) had genotype distribution no different from those with mild, uncomplicated disease (n = 245). Conclusions: The TNF, CD14, and HSPA1B polymorphisms studied seem not to play a role in determining the severity of AP or the risk of alcohol-induced AP and thus do not serve as a tool for predicting disease severity.

This study was designed to evaluate prospectively the results of the overlap technique in primary sphincter reconstruction after obstetric tear.Obstetric tears in 44 women were operated on with primary overlap reconstruction. These women were investigated six to nine months after the operation. Results were compared with those of a historical control group of 52 women whose obstetric sphincter rupture had been treated with the end-to-end technique.The overlap group had significantly more incontinence symptoms after delivery and repair of the sphincter tear than before delivery (P0.0001); however, their incontinence symptoms were significantly fewer than those of the end-to-end group (P = 0.004). The prevalence of persistent rupture of the external anal sphincter was significantly lower in the overlap group (6/44, 13.6 percent) than in the end-to-end group (39/52, 75 percent; P0.0001). Internal anal sphincter rupture occurred in 5 patients (11.4 percent) in the overlap group and in 40 patients (76.9 percent) in the end-to-end group (P0.0001).The overlap technique should be adopted as the method of choice for primary sphincter repair after obstetric tear.

Purpose: The homozygous p.C282Y variant of the HFE gene is a major risk factor for hereditary hemochromatosis, a disorder of iron metabolism resulting in progressive iron accumulation in a variety of organs including the pancreas. Heterozygosity of p.C282Y and p.H63D may increase susceptibility to chronic liver and pancreatic disease. This study determines the frequencies of p.C282Y and p.H63D alterations in patients with chronic pancreatitis and pancreatic adenocarcinoma. Methods: In total, 958 patients (349 with alcoholic pancreatitis, 343 with idiopathic pancreatitis, 64 with familial chronic pancreatitis, 34 with acute pancreatitis, and 168 with pancreatic adenocarcinoma) were enrolled and compared with 681 healthy and 100 alcoholic controls. Furthermore, 45 parent–offspring trios were included for segregation analysis. Genotyping of p.C282Y and p.H63D was performed by restriction fragment length polymorphism or melting curve analyses. Results: No significant differences were found in heterozygosity for p.C282Y and p.H63D when patients with alcoholic (8.0/21.5%), idiopathic (7.3/24.5%), or familial (9.8/23.0%) pancreatitis, or pancreatic adenocarcinoma (5.4/28.6%) were compared with healthy (6.2/24.8%) and alcoholic (7.0/25.0%) controls. Neither genotype was associated with the presence of secondary diabetes mellitus in patients with chronic pancreatitis. Conclusion: Although hemochromatosis is associated with pancreatic pathology, the p.C282Y and p.H63D variants do not play a significant role in the pathogenesis of chronic pancreatitis or pancreatic adenocarcinoma.

Obesity is a risk factor for a severe form of acute pancreatitis (AP). Because the underlying mechanisms are poorly known, we studied relationship between the severity of AP and plasma levels of leptin and adiponectin, 2 adipokines regulating the course of systemic inflammation.The study comprises 12 patients with severe AP and 12 control patients with mild AP matched by age (+/-10 years), body mass index (+/-3 kg/m), sex, and etiology of AP. Quantikine Human Adiponectin and Quantikine Human Leptin Immunoassays (RD Systems, Minneapolis, Minn) were used to measure the adipokine levels in the patients' plasma on admission and during the hospital stay.Median leptin concentrations on admission were 6.1 ng/mL (range, 1.6-72.9 ng/mL) in the severe AP group and 9.0 ng/mL (range, 2.5-36.3 ng/mL) in the mild AP group (P0.05). In severe AP, the value at days 2 to 4 (7.7 ng/mL; range, 1.6-13.9 ng/mL) did not differ from respective on-admission value (P0.05). In mild AP, the value at days 2 to 4 (3.8 ng/mL; range, 1.6-12.9 ng/mL) was lower than the respective on-admission value (P = 0.005). Adiponectin concentrations on admission were 5642 ng/mL (range, 1201-19,400 ng/mL) for severe AP and 6314 ng/mL (range, 1980-24,340 ng/mL) for mild AP (P0.05). Maximum variation of adiponectin level (the highest value minus the lowest value) was greater in severe AP than in mild AP (P = 0.001).In patients matched by age, sex, body mass index, and etiology, the on-admission plasma levels of adiponectin and leptin do not correlate with disease severity, suggesting that the adipokines do not affect the course of AP.

OBJECTIVES Severe acute pancreatitis (AP) is frequently associated with immune suppression, which increases the risk of infections, organ failure, and death. Our aims were to measure monocyte function (ie, HLA-DR expression and tumor necrosis factor-alpha [TNF-alpha] production as markers of immune suppression) in patients with severe AP and to determine whether treatment of blood samples with granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or interferon-gamma (IFN-gamma) corrected the functional defects of monocytes in vitro. METHODS The study consisted of 28 patients with severe AP who were treated at intensive care unit and in whom the proportion of HLA-DR-positive monocytes in the circulation was less than 70%, and 28 matched control subjects who were selected from healthy laboratory personnel. HLA-DR density was determined by whole blood flow cytometry. Monocyte TNF-alpha production in response to bacterial lipopolysaccharides (LPSs) was studied in a whole blood assay. Aliquots of blood were supplemented with IFN-gamma (all 28 patients), GM-CSF (the last 24 patients), or both (the last 12 patients). RESULTS The median proportion of HLA-DR-positive monocytes was 45% in patients (range, 18%-73%) and was 98% in controls (range, 86%-100%; P < 0.001). TNF-alpha levels in response to LPSs were lower in patients (545 pg/mL; range, 84-1990 pg/mL) than in controls (1415 pg/mL; range, 660-5490 pg/mL; P < 0.001). The proportion of HLA-DR-positive cells correlated positively with TNF-alpha levels (r = 0.56; P < 0.01). Both GM-CSF and IFN-gamma increased HLA-DR expression of monocytes in patients (98%; range, 74%-100% for GM-CSF; 99%; range, 86%-100% for IFN-gamma; both P < 0.001). The combination restored monocyte HLA-DR expression (99%; range, 96%-100%; P = 0.002). Compared with basal levels, GM-CSF increased TNF-alpha production of monocytes both in blood samples from patients (median, 1320 pg/mL; range, 35-8015 pg/mL) and controls (median, 3450 pg/mL; range, 1040-9835 pg/mL; both P < 0.001). IFN-gamma increased TNF-alpha production by monocytes in patients (683 pg/mL; range, 186-2705 pg/mL; P < 0.05) but not in controls (1658 pg/mL; range, 765-4755 pg/mL; P = 0.31). With the combination of GM-CSF and IFN-gamma, the TNF-alpha levels of monocytes in patients (3185 pg/mL; range, 545-8280 pg/mL) and in controls (2800 pg/mL; range, 1080-6860 pg/mL) were comparable. CONCLUSIONS The proportion of HLA-DR-positive monocytes correlates with TNF-alpha production, and they both reflect the degree of immune suppression. The low proportion of HLA-DR-positive monocytes in AP can be reversed in vitro by GM-CSF and/or IFN-gamma. The GM-CSF and IFN-gamma treatments also increase LPS-induced TNF-alpha production. By the combination of GM-CSF and IFN-gamma, but not by either agent alone, LPS-induced TNF-alpha production of monocytes was equally high in patients and in controls.

Background. The aim of this prospective study was to establish the incidence of anal incontinence and sphincter defects after first vaginal delivery. Methods. A total of 99 nulliparous and pregnant women were examined prospectively 4 weeks (mean) before delivery and 4 months (mean) after delivery. Of the study population, 75 (76%) women had vaginal delivery and 24 (24%) had cesarean section. Vacuum extraction was necessary in 20 (20%) cases. The symptoms of anal incontinence were asked about using a standard questionnaire. Clinical examination, endoanal ultrasound (EAUS) and anal manometry were performed before and after delivery. Results. The symptoms of mild anal incontinence, mainly gas incontinence, increased after vaginal delivery more than after cesarean section ( P < 0.032). Occult anal sphincter defects were noted in 17 (23%) of the 75 women after vaginal delivery by using EAUS. After vacuum extraction, anal sphincter defects were noted in nine (45%) out of 20 women. No new sphincter defects were ...

Immune suppression plays a role in the pathogenesis of acute pancreatitis. The purpose was to describe plasma anti-inflammatory cytokines and blood monocyte human leucocyte antigen (HLA)-DR expression, a cellular marker of immune suppression, in relation to clinical outcome in acute pancreatitis.We studied 74 patients with acute pancreatitis admitted within 72 h after symptom onset; 27 had mild disease and 47 severe disease, of whom 20 developed organ failure. Plasma cytokine concentrations and monocyte HLA-DR density were determined at admission and 1, 2, 3, 7, 14 and 21 days later.The levels of interleukin-1 receptor antagonist, interleukin-6 and interleukin-10 correlated inversely to monocyte HLA-DR expression; each marker correlated with disease severity. Interleukin-4, -11 and -13 levels were low. Organ failure occurred at median 36 h (range 8 to 158) after admission and was predicted at admission by the combination of interleukin-6 and interleukin-10 with sensitivity of 95%, specificity of 88% and positive likelihood ratio of 7.6 (95% confidence interval 3.3 to 17). Patients with secondary infections had a lower proportion of HLA-DR positive monocytes than did controls at day 14 (median: 32% versus 65%; n = 7) and at day 21 (median: 49% versus 83%; n = 6), P0.05 each. In the organ failure group, HLA-DR expression did not differ between survivors and non-survivors.Determining the severity of anti-inflammatory reaction at admission and monitoring the course of immune suppression provide a means for predicting clinical outcome in acute pancreatitis.

Immune suppression plays an important role in the pathogenesis of acute pancreatitis. Monocyte expression of HLA (human leucocyte antigen)-DR, a cellular marker of immune suppression, was determined in relation to the development of organ dysfunction in patients with acute pancreatitis. A total of 310 consecutive patients with acute pancreatitis, admitted to a university hospital within 72 h of pain onset, were studied; 194 (63%) had mild disease (group I), 87 (28%) had severe disease without organ dysfunction (group II), and 29 (9%) had severe disease with organ dysfunction (group III). HLA-DR expression, defined both as the proportion of monocytes that were HLA-DR-positive and as monocyte HLA-DR fluorescence intensity, was determined at admission, using whole-blood flow cytometry. Of the patients in group III, 13 (45%) developed organ dysfunction within 24 h of admission. The proportion of HLA-DR-positive monocytes and monocyte HLA-DR density were both related to the severity of pancreatitis (P

Mast cell tryptase, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) possibly play a role in the pathogenesis of acute pancreatitis (AP). The aim is to describe their serum levels in relation to severity of AP.Seventy patients with AP were studied. Thirty-one had mild acute pancreatitis and 39 severe AP of whom 21 developed organ dysfunction. Serum concentration of tryptase was determined with fluoroimmunoassay (UniCAP), and VEGF and bFGF with ELISA at admission and on days 1, 2, and 7 post-hospitalization.The peak tryptase levels and tryptase levels at 2nd day after symptom onset, although mostly within normal range, were significantly higher in patients with organ dysfunction than in patients without organ dysfunction (6.6 microg/l (inter quartile range 4.8 to 12.6) versus 4.0 microg/l (2.7 to 6.2); P = 0.018 and 6.0 microg/l (4.4 to 7.6) versus 3.4 microg/l (2.3 to 4.8); P = 0.006, respectively). Median serum VEGF and bFGF concentrations increased during follow-up, were significantly higher on day 7 than on days 0, 1, and 2, but were not related to development of organ dysfunction.Mast cell activation, as defined by serum tryptase levels, may play a role in the development of remote organ dysfunction in patients with AP. However, neither tryptase nor the factors VEGF and bFGF serve as predictors of organ dysfunction in clinical AP.

Acute pancreatitis (AP) is a common disease with wide variation of severity. The diagnosis of AP is usually based on high serum amylase or lipase values but the accuracy of these methods is considered unsatisfactory. One in five of the patients develops a severe disease and carries a considerable risk of development of organ failure and high mortality. Early detection of patients with severe AP and especially those with increased risk of organ failure is importance since such patients seem to benefit from treatment in an intensive care unit started as soon as possible after presentation. In addition to enzymological methods, increasing interest has been focused on laboratory markers reflecting the level of inflammatory response in AP. At present, in routine clinical work the most commonly used severity marker is serum C-reactive protein, the concentration of which rises too slowly to be used for early prediction of severity. New therapies aiming at modifying the course of systemic inflammation in AP are being developed and therefore monitoring the patient's immune inflammatory status is needed. In this review article we present the current knowledge of laboratory tests, which has been evaluated for diagnostic and prognostic purposes in AP.

Background: Early identification of patients at risk of developing a severe attack of acute pancreatitis (AP) is of great importance because rapid therapeutic interventions improve outcome. At a cutoff of 50 μg/L, trypsinogen-2 measured by a rapid urinary dipstick is a sensitive and specific diagnostic test in AP. The trypsinogen-2 concentration correlates with the severity of the disease, and a test with a higher cutoff might therefore be useful for prediction of disease severity.Methods: We increased the detection limit of the urinary trypsinogen-2 test strip (Actim Pancreatitis) from 50 μg/L to 2000 μg/L and evaluated the prognostic value of this test. The results were compared with those obtained with serum C-reactive protein and the acute physiology and chronic health evaluation II (APACHE II) score. The study population consisted of 150 consecutive patients with AP (42 with severe disease).Results: The sensitivity of the rapid urinary test strip (detection limit, 2000 μg/L) for prediction of severe AP, both on admission and at 24 h, was 62%; specificities were 87% and 85%, respectively, positive predictive values were 65% and 62%, and negative predictive values were 85% and 85%. C-Reactive protein had a sensitivity of only 38% on admission, but at 24 h, it was 83%; specificities were 90% and 70%, respectively, whereas positive predictive values were 59% and 52%, and NPVs were 79% and 91%, respectively. On admission the positive-likelihood ratio for the urinary trypsinogen-2 test strip was 4.8, and at 24 h it was 4.2; for C-reactive protein, the values were 3.7 and 2.7, respectively.Conclusions: The urinary trypsinogen-2 dipstick is a simple and rapid method for prediction of severe acute pancreatitis.

Objective: To investigate whether marker(s) of systemic inflammation detect, at an early stage of acute pancreatitis, patients who may ultimately develop severe disease. Design: Prospective study. Setting: University hospital emergency unit. Patients: Thirty patients with mild acute pancreatitis (SEV 0 group) and 27 with severe acute pancreatitis. Of the latter, 11 did not develop organ failure (SEV 1 group), whereas the other 16 patients developed acute respiratory failure and 9 of them also developed renal failure (SEV 2 group). Interventions: Blood samples were collected at admission to the hospital (T 0 ), and at 12 hrs (T 12 ) and 24 hrs (T 24 ) after admission. Measurements and Main Results: The plasma concentrations of procalcitonin (PCT), soluble E-selectin (sE-selectin), soluble interleukin-2 receptor (slL-2R), and the serum concentration of C-reactive protein (CRP) were monitored. PCT levels at To were significantly higher in the SEV 1 group (median 0.4 nglmL, range 0.2-2.3) and the SEV 2 group (0.8 ng/mL, 0.2-73.5) than in the SEV 0 group (0.3 ng/mL, 0.1-3, p

Background This study was designed to evaluate the validity of a new rapid urinary trypsinogen-2 test strip (Actim Pancreatitis) for detection of acute pancreatitis in patients with acute abdominal pain. Methods A total of 525 consecutive patients presenting with abdominal pain at two emergency units was included prospectively and tested with the Actim Pancreatitis test strip. Urine trypsinogen-2 concentrations were also determined by a quantitative method. The diagnosis and assessment of severity of acute pancreatitis was based on raised serum and urinary amylase levels, clinical features and findings on dynamic contrast-enhanced computed tomography. Results In 45 patients the diagnosis of acute pancreatitis could be established. The Actim Pancreatitis test strip result was positive in 43 of them resulting in a sensitivity of 96 per cent. Thirty-seven false-positive Actim Pancreatitis test strips were obtained in patients with non-pancreatic abdominal pain resulting in a specificity of 92 per cent. Nine patients with severe acute pancreatitis were all detected by the dipstick. Conclusion A negative Actim Pancreatitis strip result excludes acute pancreatitis with high probability. Positive results indicate the need for further evaluation, i.e. other enzyme measurements and/or radiological examinations. The test is easy and rapid to perform, unequivocal in its interpretation and can be used in healthcare units lacking laboratory facilities.

Acute and chronic pancreatitis result in considerable morbidity, are increasing in incidence, and have a high mortality rate. Due to the inaccessibility of the pancreas to study, our understanding of the pathophysiology of pancreatitis remains limited. Our current knowledge of the evolution of pancreatitis can be described as a progression from an initial injury to both the acinar and ductal components of the exocrine pancreas to local and systemic inflammatory responses [1]. If resolution fails to occur, infection or chronicity may supervene. In this special issue we present a series of review and original papers that shed light both on our evolving understanding of the basic mechanisms causing pancreatitis as well as current treatment controversies. Lessons about Basic Mechanisms — Toll-like receptors (TLR) belong to the superfamily of interleukin-1 receptors and enable the innate immune system to recognize different groups of pathogens, while initiating appropriate and distinct immunological responses. TLR4 proteins, expressed on the cell surface, are receptors for the Gram-negative bacteria cell membrane component, lipopolysaccharide (LPS, endotoxin). The heat shock protein HSP60 may play an important role in the protection of the pancreas against damage and against early zymogen activation in acute pancreatitis. J. Bonior et al. report a series of experiments investigating the effects of endotoxemia induced in newborn rats on TLR4, HSP60 and proapoptotic Bax, caspase-9 and -3, or antiapoptotic Bcl-2 protein expression in the pancreatic acinar cells of adult animals. Their results indicate that exposure of the infant rats to LPS promote the induction of HSP60 via TLR4 in their adult life and, in turn, activated Bax/Bcl-2 and caspase-9 and -3. It is likely that this process could play a part in the LPS-induced protection of the pancreatic tissue against acute damage in this experimental model. Melatonin, a product of the pineal gland, is released from the gut mucosa in response to food ingestion and specific receptors for melatonin have been detected in many gastrointestinal tissues including the pancreas. Melatonin has been shown to attenuate the severity of acute pancreatitis. J. Jaworek et al. review the protective effects of melatonin on acute pancreatitis, reported in many experimental studies and supported by clinical observations. They conclude that the beneficial effects of melatonin are sufficient to warrant clinical evaluation as a supportive therapy in acute pancreatitis. The causal relationship between tissue injury and pancreatitis and the mechanisms whereby tissue injury induces pancreatic inflammation is examined in a series of experiments reported by Nakumura et al. Although DNA has historically been believed to be immunologically inert, it is now appreciated that DNA can be released into the systemic circulation when cells undergo necrosis/apoptosis and recognized by the immune system. These authors hypothesised that cytosolic double-stranded DNA released by injured host cells may act as a “danger signal,” which affects pancreatic stellate cells by increasing the expression of several inflammatory genes in the rat. Research into the pathogenesis of pancreatitis is hampered by the inaccessibility and hazards of pancreatic tissue sampling during the course of the disease as well as by the ethical constraint that pancreatic tissue sampling is not a routine part of disease management. Infected pancreatic necrosis (and some cases of sterile necrosis) is an indication for intervention and I. Kovalska et al. have put together a remarkable series of 224 operative and postmortem specimens subjected to histological analysis. This study underlines the importance of early pancreatic microcirculation and local coagulation disorders in the pathogenesis of acute necrotising pancreatitis and that, despite aggressive surrounding necrosis, the islets of Langerhans are preserved in 74.1% of cases, most probably due to fibrin capsule formation. This emphasises the importance of the movement in modern surgery to undertake removal of necrotic pancreas using minimally invasive and organ-preserving approaches [2]. Bridging the gap from bench to bedside, the editors of this special issue review the pro- and anti-inflammatory mediators that drive acute pancreatitis. This review examines the prospects for inflammatory mediators being identified as successful therapeutic targets. We explore the role of immunomodulation, monitoring the state of immune dysfunction by monocyte HLA-DR, signalling pathways of circulating leukocytes, and the narrow therapeutic window for intervention in acute pancreatitis. New Insights into Current Treatment — The search for a specific therapy to treat pancreatitis remains the paramount goal of research in this field. Despite extensive efforts so far, no agent has proved successful. Further efforts to mount a therapeutic damage control strategy to contain an inappropriate inflammatory response are justified and remain ongoing. The APCAP (activated protein C in acute pancreatitis) trial randomised 32 patients with severe acute pancreatitis to receive either recombinant activated protein C (drotrecogin alfa activated) or placebo for 96 hours [3]. The results of the intervention and placebo groups were comparable. However, trials such as this also provide the opportunity to examine the systemic inflammatory response in great detail as it modulates with time and according to treatment. In this issue, L. Kyhala et al. present the time course of the patients' plasma or serum levels of soluble markers (IL-8, IL-6, IL-10, IL-1ra, sE-selectin, PCT) and monocyte and neutrophil cell surface (CD11b, CD14, CD62L, HLA-DR) markers of systemic inflammatory response during the first 14 days after the randomization within APCAP. With an increasing elderly population in many parts of the world, the effect of ageing on systemic inflammation, focusing on that induced by acute pancreatitis, has become more important than ever. Several reports have related an increased susceptibility to a proinflammatory status called inflammaging, which decreases the capacity of the immunological system to respond to antigens. M.C.C. Machado et al. review the effects of aging on the systemic inflammation in pancreatitis. They discuss the effects of cellular senescence and how this probably contributes to the chronic inflammatory state related to ageing. State-of-the-art imaging remains a cornerstone of current management in acute pancreatitis. Early diagnosis and staging of complications are important clinical objectives. In this special issue, the method by which perfusion to an organ is measured by CT, and its clinical utility is reviewed by Y. Tsuji et al. They make the case that perfusion CT is a promising technique for diagnosis of local and systemic complications of severe acute pancreatitis at an early stage. Discriminating between focal chronic pancreatitis and pancreatic cancer remains challenging. Contrast-enhanced endoscopic ultrasound using Doppler techniques can reveal different vascularisation patterns in pancreatic tissue altered by chronic inflammatory processes and pancreatic cancer. M. Hocke et al. review the basics of contrast-enhanced high and low mechanical index endoscopic ultrasound and explain the pathophysiological differences behind the vascularisation of chronic pancreatitis and pancreatic carcinoma and how to use these techniques in daily clinical practice. Pancreatic pseudocyst is a complication that develops in both acute and chronic pancreatitis. It may remain asymptomatic or develop life-threatening complications. A. K. Khanna et al. address the therapeutic dilemma of whether or not to treat a patient with a pancreatic pseudocyst, as well as when and with which technique. Conclusion: From Early Accounts to Future Hopes — An early account of acute pancreatitis may have been furnished by the death of Alexander the Great (Alexander III of Macedon (20/21 July 356–10/11 June 323 BCE)). Alexander ascended to the throne and was to become the most successful of Greek generals, extending Hellenic influence throughout the known world. However, a case for acute pancreatitis being retrospectively applied to Alexander's death certificate can be made: a rich meal and heavy alcohol consumption preceded the onset of the disease and were probably the precipitating factors; the course of the disease is typical of acute pancreatitis in its onset, severity and irreversibility; fever and the subsequent systemic effects point towards acute necrotising pancreatitis with sepsis and multiple-organ failure [4]. If the cause of death was indeed acute pancreatitis, then perhaps the chief lesson to be learnt from this account is to reinforce the fact of our lack of progress in our understanding and particularly, in treating this condition. It should be remembered that (despite recent advances in critical care medicine) no specific treatment for acute pancreatitis has, as yet, proved superior to that employed by Alexander's generals; a forlorn plea for divine intervention, to the gods of the ancient Greeks. We hope, however, that ongoing research, such as that contained within this special issue of the International Journal of Inflammation, provides the insight and inspiration necessary to make progress in our endeavours to obtain sufficient understanding to discover an effective treatment for this disease.

Background/objectives Circulating polymorphonuclear leukocytes (PMNLs) may contribute to development of organ dysfunction in acute pancreatitis (AP). We outlined aberrations in PMNL signaling profiles in patients with AP complicated by organ dysfunction and immune suppression. Methods Study comprised 13 patients treated at intensive care unit due to severe AP complicated by vital organ dysfunction. Mean proportion (SEM) of HLA-DR-positive monocytes was 55.0% (4.1%). 13 healthy volunteers served as reference subjects. Phosphorylation of PMNL NFκB, p38, ERK1/2 and STAT3, -5 and -6 was determined using whole blood flow cytometry. Transmigration of PMNLs was studied using endothelial EA-HY cell monolayer. Results Proportions of NFκB phosphorylation-positive PMNLs were lower in the patients' than in reference subjects' blood samples supplemented with tumor necrosis factor. p38 phosphorylation was normal while ERK1/2 phosphorylation was decreased. STAT3 was constitutively activated in five patients. Proportion of patients' pSTAT6-positive cells was normal while fluorescence intensity was decreased. STAT5 phosphorylation was normal. Transmigration of patients' PMNLs was increased. Conclusions In patients with AP complicated by organ dysfunction proportion of pNFκB-positive PMNLs is decreased. This impairs patients' defense mechanisms against infection. Despite immune suppression, PMNL transmigration was increased and p38 phosphorylation capacity was not depressed, which may contribute to end organ inflammation and dysfunction.

Background: Being a central link between inflammation and coagulation, tissue factor (TF) and its inhibitor (TFPI) might be associated with the severity of acute pancreatitis (AP) and the development of organ failure (OF). Methods: The study comprises 9 severe AP patients with OF and 24 reference patients (11 mild AP and 13 severe AP without OF). Plasma samples were collected on admission. TF-induced thrombin generation in plasma samples was studied using the thrombogram method. In vivo thrombin generation was estimated by prothrombin fragment F1+2. Free and total TFPI levels were measured. To evaluate coagulation status the activated partial thromboplastin time, prothrombin time, platelet count, D-dimer, fibrinogen, antithrombin (AT) 3 and protein C (PC) were determined. Results: There was no significant difference in F1+2 levels between the patient groups. Patients with severe AP tended to show low platelet counts, PC and AT3 levels, and high D-dimer levels. In 11 patients the standard TF stimulation did not trigger thrombin generation in the thrombogram. All deaths occurred in these patients. Free TFPI levels and free/total TFPI ratios were significantly higher in these patients and in non-survivors. Conclusion: Failure of TF-initiated thrombin generation in the thrombogram assay explained by high levels of circulating free TFPI may be associated with OF and mortality in AP.

Acute pancreatitis (AP) is a common disease, which usually exists in its mild form. However, in a fifth of cases, the disease is severe, with local pancreatic complications or systemic organ dysfunction or both. Because the development of organ failure is the major cause of death in AP, early identification of patients likely to develop organ failure is important. AP is initiated by intracellular activation of pancreatic proenzymes and autodigestion of the pancreas. Destruction of the pancreatic parenchyma first induces an inflammatory reaction locally, but may lead to overwhelming systemic production of inflammatory mediators and early organ failure. Concomitantly, anti-inflammatory cytokines and specific cytokine inhibitors are produced. This anti-inflammatory reaction may overcompensate and inhibit the immune response, rendering the host at risk of systemic infection. At present, there is no specific treatment for AP. Increased understanding of the pathogenesis of systemic inflammation and development of organ dysfunction may provide us with drugs to ameliorate physiological disturbances.

To outline signaling profiles and transmigration capacity of monocytes of patients with severe acute pancreatitis.Prospective study.University hospital intensive care unit.Thirteen patients with severe acute pancreatitis. All patients had organ dysfunction (acute respiratory distress syndrome in 12, renal dysfunction in eight). Healthy volunteers served as reference subjects.Blood samples were collected after admission to the intensive care unit.Phosphorylation of nuclear factor-kappaB and p38, signal transducers and activators of transcription (STATs) 1, 3, 5, and extracellular signal-regulated kinases 1/2 in appropriately stimulated and nonstimulated samples were studied using phospho-specific whole-blood flow cytometry. Monocyte chemotactic protein-1-induced transmigration of monocytes among mononuclear cells obtained by density gradient centrifugation was studied using Transwell cell culture inserts covered with confluent layer of endothelial EA-HY cells. Phosphorylation levels of nuclear factor-kappaB induced by tumor necrosis factor, bacterial lipopolysaccharide, muramyl dipeptide, Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis were significantly lower in patients' monocytes than monocytes of healthy reference subjects, whereas mitogen-activated protein kinase p38 phosphorylation levels were normal. Phosphorylation levels induced by interleukin-6 in STAT1 and STAT3 and by combination of phorbol 12-myristate 13-acetate and calcium ionophore A23187 in extracellular signal-regulated kinases 1/2, members of a mitogen-activated protein kinase family, were depressed in patients' monocytes, whereas phosphorylation levels induced by granulocyte-macrophage colony-stimulating factor in STAT5 was normal. In nonstimulated samples, phosphorylation levels were normal. The transmigration percentage of patients' monocytes was significantly lower than that of reference monocytes.In severe acute pancreatitis, monocytes show impaired nuclear factor kappaB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to maintenance of systemic inflammation. Extracellular signal-regulated kinases 1/2 activation is impaired, which may depress monocytes' transmigration and may consequently increase risk of infection. Monitoring of monocyte signaling profiles may aid in finding new therapeutic approaches and predictors of outcome of severe acute pancreatitis.

Introduction: Previous human studies have shown low activity of protein C (APC) in severe acute pancreatitis (SAP). This, together with the findings in animal models, suggests that activated protein C (APC) may protect against pancreatic injury and ameliorate the disease. We, therefore, evaluated its effect on multiple organ dysfunction (MOD) measured by the SOFA (Sequential Organ Failure Assessment) and on organ-failure-free days, and the safety of APC in SAP. Methods: A prospective double blind randomized pilot study was use. The study occurred in one university hospital tertiary intensive care unit (ICU) with eight beds. The patients were chosen according to the following inclusion criteria: 1) Those admitted to the hospital < 96 h from the onset of pain, 2) Those who had a three-fold increase in serum amylase over normal upper range or/and in whom computed tomography (CT) verification of SAP was noted, 3) Those who had one or more organ dysfunction (OD), and 4) Those in whom less than 48 hours had passed since their first OD. Of a total of 215 adult patients with SAP screened between June 2003 and August 2007, 158 fulfilled the study inclusion criteria. After exclusions 32 patients were randomized to the study. The intervention consisted of APC (N = 16) administered intravenously for 96 hours with a dose of 24 μg/kg/hour or placebo (N = 16) with a similar infusion rate. The sample size for the study was calculated according to the primary end-point: the change in SOFA during study drug infusion (Days 0 and 5). Comparisons between the study groups were performed using patient-related changes and calculation of difference in means (DIM, 95% CIs) and regarding categorical variables with Fisher’s exact test. For all comparisons P < 0.05 was considered significant. Results: No serious bleeding was detected clinically or by CT scans in either group. No significant difference in SOFA score change between the APC and placebo groups was found (difference in means (DIM) +2.3, 95% CI -0.7 to +5.3). Treatment with APC was associated with an increase in serum levels of both total and conjugated bilirubin. No differences in ventilator-free days, in renal replacement therapy-free days, in vasopressor-free days, or in days alive outside the hospital were detected. Conclusions: No serious bleeding or differences in the evolution of MOD were detected between APC and the placebo. Instead we found an increase in serum bilirubin in the APC group compared to the placebo group in patients with SAP.

BACKGROUND: Reduction in angiotensin-converting enzyme (ACE) activity has been shown to attenuate pancreatic stellate cell activation and pancreatic fibrosis and suggested as a potential treatment for chronic pancreatitis. The ACE gene insertion/deletion (I/D) polymorphism in intron 16 accounts for nearly half the variation in serum ACE levels. This study determined the frequency of the I/D polymorphism in patients with acute and chronic pancreatitis. METHODS: In total, 887 patients (346 with alcoholic, 443 with nonalcoholic, and 98 with acute pancreatitis) were enrolled, and were compared with 1294 healthy controls. Genotyping of the I/D polymorphism was performed by PCR or melting curve analyses. RESULTS: No significant differences were found in the prevalence of the ACE-deletion genotype frequencies when patients with alcoholic (27.5%), nonalcoholic (26.4%), and acute pancreatitis (32.7%) were compared with controls (26.9%). Likewise, allele frequencies of the ACE deletion polymorphism were not significantly different in patients with alcoholic (53.8%), nonalcoholic (50.6%), and acute pancreatitis (54.1%) and controls (52.7%). CONCLUSION: The I/D polymorphism of the ACE gene was not found to be associated with acute and chronic pancreatitis.

OBJECTIVE Systemic inflammatory reaction in acute pancreatitis (AP) is associated with activation of the coagulation system. The prothrombotic component of the coagulation system, which may promote microvascular thrombosis and vital organ injury, is strengthened by genetic factors such as polymorphism of plasminogen activator inhibitor type 1 (PAI-1) and factor V Leiden (FVL) mutation. This prompted us to study the occurrence of FVL and PAI-1 4G/5G polymorphisms in patients with AP. METHODS This case control association study included 397 patients with AP and 310 controls. Severe AP was determined according to the Atlanta Classification. Genotyping was performed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry-assisted genotyping method. RESULTS Factor V Leiden was identified in 5 (3.3%) of 152 cases of severe AP and in 8 (3.3%) of 245 cases of mild AP. The prothrombotic PAI-1 4G allele frequency was 0.49 for patients with severe AP and 0.57 for patients with mild AP (P < 0.05). Patients with septic infectious complications (n = 47) and patients with organ failure (n = 55) had genotype distribution not different from those with mild, uncomplicated disease (n = 245). CONCLUSIONS The results do not support the hypothesis that prothrombotic polymorphisms such as FVL mutation and PAI-1 4G/5G are associated with AP severity.

Early hyperglycemia in acute pancreatitis (AP) is a prognostic sign of severe attack. Obesity, another risk factor for severe AP, is associated with impaired glucose regulation. We hypothesized that obesity is related to early hyperglycemia in patients with severe AP.Forty-four patients with severe AP with organ failure and 127 control patients with AP (33 severe AP and 94 mild AP) but without organ failure were studied. Plasma glucose and patients' height and weight for calculation of body mass index (BMI) were measured at admission.Body mass index was higher in organ failure patients than in controls (median, 27.0 kg/m2 [interquartile range, 24.9-30.4 kg/m2] vs 25.2 kg/m2 [interquartile range, 23.3-27.9 kg/m2; P = 0.007). Glucose level correlated with BMI in organ failure patients (r = 0.463, P = 0.002) but not in controls (r = 0.096, P = 0.28). Eight (18%) organ failure patients and 7 (5.5%) controls had prior type 2 diabetes (P = 0.025). In a logistic regression model, admission glucose level was the only independent predictor of organ failure.Obesity may contribute to early hyperglycemia in patients with AP. Multivariate analysis indicated that obesity is not an independent risk factor for organ failure, but it correlates with early hyperglycemia, which may predispose to systemic complications in AP.

Obesity is a known risk factor for severe acute pancreatitis (AP), but the mechanism by which it affects the severity of AP is not fully understood. The main objective of this study was to investigate the relationship between obesity and inflammatory markers in AP.Thirty patients with AP who developed organ failure (Group I) and 87 patients with AP who survived without organ failure (Group II) were studied. Patients' height and weight were measured at admission for calculation of body mass index (BMI). Blood samples were taken at admission for measurement of plasma interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist, procalcitonin, C-reactive protein (CRP) and monocyte human leucocyte antigen (HLA)-DR expression.Group I patients had higher BMI values (median 26.2 kg/m2) than Group II patients (25.2 kg/m2), p =0.033. Both CRP values and monocyte HLA-DR expression showed a significant correlation with BMI (Spearman's rank correlation r=0.32, p =0.003 and r= -0.33, p = 0.002, respectively). The correlation between BMI and monocyte HLA-DR expression was significant in Group II patients (r = -0.34, p =0.002) but not in Group I patients (r = -0.02, p0.05). There was no correlation between BMI and IL-1beta, IL-6, IL-10, IL-1 receptor antagonist or procalcitonin.BMI did not affect either proinflammatory or anti-inflammatory cytokine levels in early AP. However, in patients with mild AP, BMI correlated positively with CRP levels and inversely with monocyte HLA-DR expression, which might reflect an amplified inflammatory response in these patients. Taken together, acute inflammatory response in AP, which ultimately determines the severity of AP, was little affected by BMI.

This study aimed to assess the effectiveness of therapeutic endoscopy in the treatment of pancreatic pseudocysts, and to define factors limiting endoscopic therapy.The results of therapeutic endoscopy were evaluated for 170 patients with pancreatic pseudocysts treated at the Department of Surgery, Helsinki University Central Hospital, during the 6-year period from 1998 to 2003.The therapeutic endoscopy success rate was 86.1%, with 23 (13.9%) patients requiring operative treatment because therapeutic endoscopy was unsuccessful or technically impossible. There was little morbidity and no procedure-related mortality. The majority of the 38 complications, which arose from 380 procedures, could be treated conservatively.Endoscopic methods are safe and effective for the treatment of pancreatic pseudocysts. The indications for surgery include inaccessible pancreatic duct, location, or content of the pseudocyst rendering the problem not amenable to endoscopic therapy, as well as complications of the endoscopic treatment.

Mutations in the secretory trypsin inhibitor (SPINK1) gene have been found to be associated with hereditary and chronic pancreatitis. There are no previous reports on SPINK1 mutations in patients with acute pancreatitis (AP).The study population consists of 371 patients with AP, of which 207 patients had mild and 164 had a severe form of the disease. The etiologies of AP were identified. Four hundred fifty-nine blood donors served as controls. SPINK1 N34S and P55S mutations were detected by minisequencing and confirmed by direct sequencing.The N34S mutation was found in 29 (7.8%) of the patients and in 12 (2.6%) of the controls (P0.0001, Fisher exact test). There was no difference in the frequency of the P55SS mutation between the groups. A majority of the patients (n = 229; 61.7%) had alcohol-induced AP. The frequency of the N34S mutation was higher in the subgroups of severe AP (15/164; 9.1%) and alcohol-induced AP (21/229; 9.2%), but the differences were not statistically significant. No differences in age at admission and number of attacks of AP were observed between the groups.SPINK1 N34S mutation enhances the susceptibility of AP.

The aim of this prospective study was to establish the incidence of anal incontinence and sphincter defects after first vaginal delivery.A total of 99 nulliparous and pregnant women were examined prospectively 4 weeks (mean) before delivery and 4 months (mean) after delivery. Of the study population, 75 (76%) women had vaginal delivery and 24 (24%) had cesarean section. Vacuum extraction was necessary in 20 (20%) cases. The symptoms of anal incontinence were asked about using a standard questionnaire. Clinical examination, endoanal ultrasound (EAUS) and anal manometry were performed before and after delivery.The symptoms of mild anal incontinence, mainly gas incontinence, increased after vaginal delivery more than after cesarean section (P0.032). Occult anal sphincter defects were noted in 17 (23%) of the 75 women after vaginal delivery by using EAUS. After vacuum extraction, anal sphincter defects were noted in nine (45%) out of 20 women. No new sphincter defects were found in the cesarean section group. The maximal squeezing pressures were significantly decreased in the patients with external anal sphincter (EAS) defects (P = 0.0025). Vacuum extraction leads to more sphincter defects but does not significantly increase anal incontinence or decrease mean anal sphincter pressures.The first vaginal delivery can result in occult sphincter defects and the use of vacuum extraction increases the risk.

Background: Interest in the use of therapeutic endoscopy for the treatment of pancreatic diseases has been on the increase for several years. Our aim was to assess the efficacy of endoscopic retrograde cholangiopancreaticography (ERCP) in the treatment of pancreatic fistulas. Methods: We evaluated the results of therapeutic ERCP in 50 patients with pancreatic fistula treated at the Helsinki University Central Hospital from 1998 to 2003. Results: The success rate of fistula closure after therapeutic ERCP was 82%. Five patients required operative treatment when ERCP was unsuccessful. There was little morbidity and no procedure-related mortality. Four patients died because severe illnesses made them unfit for any further procedures. Conclusion: ERCP is a safe and effective modality and should be considered as first-line therapy in the management of pancreatic fistula.

Preoperative evaluation was made of the diagnostic value of endoanal ultrasound (EAUS) and endovaginal magnetic resonance imaging (EVMRI) in diagnosing anal sphincter defects as the cause of anal incontinence. Nineteen female individuals with anal incontinence were examined clinically with EAUS and with EVMRI at 1.5 T using a prostatic coil. The findings were evaluated independently and compared with findings at surgery. In diagnosing external anal sphincter defects, EAUS and EVMRI showed almost similar agreement with surgical findings, 12 (63%) out of 19 vs 11 (58%), respectively. Internal anal sphincter defects were equally detected by EAUS and EVMRI as compared with surgical diagnosis. There was considerable variation between radiologists in diagnosing defects by EVMRI. EAUS and EVMRI are equal in diagnosing anal sphincter defects.

PURPOSE: This study was designed to evaluate the clinical outcome of primary anal sphincter repair caused by obstetric tears and to analyze possible risk factors associated with sphincter rupture during vaginal delivery. METHODS: A total of 52 females with a third-degree or fourth-degree perineal laceration during vaginal delivery were examined. The symptoms of anal incontinence were obtained by a standard questionnaire. In addition to a clinical examination, endoanal ultrasound, anal manometry, and pudendal nerve terminal motor latency examinations were performed. A control group consisted of 51 primiparous females with no clinically detectable perineal laceration after vaginal delivery. RESULTS: After primary sphincter repair, 31 females (61 percent) had symptoms of anal incontinence. Fecal incontinence occurred in 10 females (20 percent). According to Hardcastle and Parks’ and Jorge and Wexner’s classifications, the study group had more severe symptoms of anal incontinence than the control group (P < 0.001 in both classification groups). In endoanal ultrasound examination, a persistent defect of the external anal sphincter was found in 39 females (75 percent) in the rupture group compared with 10 females (20 percent) in the control group (P < 0.001). Anal sphincter pressures were significantly lower in the rupture group than in the control group. An abnormal presentation was the only risk factor for anal sphincter rupture during vaginal delivery. CONCLUSIONS: After primary sphincter repair, persistent external anal sphincter defect and symptoms of anal incontinence are common in females who have had a primary sphincter repair after vaginal delivery. The means of improving the results of primary repair should be studied further.

Pathophysiology of sepsis is characterised by a whole body inflammatory reaction and concurrent activation of the host's anti-inflammatory mechanisms. The balance between pro- and anti-inflammatory reactions is critical for the outcome of the patient. Strongly activated phagocytes and high levels of proinflammatory cytokines occur in patients who are at risk of developing circulatory shock and multiple organ dysfunction. Extensive anti-inflammatory reaction, which is characterised by the presence of high levels of circulating anti-inflammatory cytokines and impaired innate and adaptive immune functions, renders critically ill patients prone to secondary infections. Evaluation of the immune-inflammatory status on admission to the hospital may be helpful in the early identification of patients who are bound to develop organ dysfunction. Such patients could possibly benefit from a mode of therapy aimed at modifying the course of inflammatory response. The use of inflammatory markers may also improve diagnosis of severe infection. The present review summarises the studies on markers of inflammation and immune suppression used, first, as predictors of organ dysfunction in patients with systemic inflammation, and, second, as indicators of infection in adults and neonates.

Acute pancreatitis is a common disease varying widely in severity. At present, there is no "gold standard" for the diagnosis of acute pancreatitis. Currently, the diagnosis of acute pancreatitis is based on measurements of serum amylase and/or lipase activity, which are considered unsatisfactory due to their low level of accuracy. Early identification of acute pancreatitis and especially detection of patients with a severe form of the disease is of utmost importance. Premature intrapancreatic activation of trypsinogen is a crucial early event in the pathophysiology of acute pancreatitis. The conversion of trypsinogen to active trypsin is mediated by the release of its activation peptide (TAP). The active trypsin is then able to activate other pancreatic zymogens (i.e. procarboxypeptidase) leading to tissue damage and eventually to autodigestion of the pancreas. To improve the laboratory diagnostics of AP, new methods have been developed to measure this primary pancreatic proteolytic insult. Here we review the current knowledge and clinical implications of trypsin based laboratory methods and carboxypeptidase activation peptide (CAPAP) in the diagnosis and severity assessment of acute pancreatitis.

Few data are available on cellular markers of systemic inflammation and immune suppression in early acute pancreatitis. The aim of this study was to describe the cellular immune inflammatory status of patients with acute pancreatitis in relation to development of organ failure.Prospective study including 89 patients who presented within 72 h of onset of pain. Fifty-eight of them had mild disease (Grade I group), 19 had severe disease with no organ dysfunction (Grade II group) and 12 had severe disease with organ dysfunction (Grade III group). Serial blood samples were collected on admission and following 2 days. Phagocyte surface markers were analysed using flow cytometry.The proportion of HLA-DR-positive monocytes, a marker of immune suppression, and CD11b expression level on neutrophils and monocytes, a marker of systemic inflammation, were related to Grades I-III (P for trend0.001). In Grade III patients, the proportion of HLA-DR-positive monocytes was low on presentation, or decreased rapidly during follow-up, whereas CD11b expression levels were persistently high. L-selectin and monocyte CD14 expression levels were not related to disease severity.Immune suppression develops early, rapidly and unexpectedly in patients with acute pancreatitis. Monitoring immune inflammatory status may provide the means by which to identify patients who benefit from biological response modifier therapy.

Introduction Severe acute pancreatitis is associated with systemic inflammation, compensatory immune suppression, secondary infections, vital organ dysfunction, and death. Our study purpose was to delineate signaling profiles of circulating lymphocytes in acute pancreatitis complicated by organ dysfunction. Methods Sixteen patients with acute pancreatitis, dysfunction of vital organ(s), and immune suppression (proportion of HLA-DR Human Leukocyte Antigen - DR - positive monocytes < 80%) participated. Healthy volunteers served as reference subjects. Using phospho-specific whole blood flow cytometry we studied lymphocyte phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases p38 and extracellular signal-regulated kinases (ERK)1/2, and signal transducers and activators of transcription (STATs) 1, 3, and 6. Statistical comparisons were performed with the Wilcoxon-Mann-Whitney test. Results In blood samples supplemented with tumor necrosis factor, E. coli or S. aureus, phosphorylation levels of NFκB were lower and levels of p38 were higher in patients with acute pancreatitis than healthy subjects. Low NFκB activation involved CD3+CD4+ and CD3+CD8+ lymphocytes. ERK1/2 phosphorylation induced by co-stimulation with phorbol 12-myristate 13-acetate and calcium ionophore A23187 was depressed in patients. STAT3 was constitutively activated in patients' CD3+CD4+ and CD3+CD8+ lymphocytes. Also, IL-6-induced STAT1 phosphorylation was impaired while IL-4-induced STAT6 phosphorylation was enhanced. Conclusions Lymphocytes of patients with acute pancreatitis, organ dysfunction and immune suppression show impaired NFκB activation, which increases infection risk and enhanced p38 activation, which sustains inflammation. Secondly, they indicate constitutive STAT3 activation, which may favor Th17 lineage of CD4+ lymphocyte differentiation. Thirdly, they reveal impaired STAT1 activation and enhanced STAT6 activation, denoting a shift from Th1 towards Th2 differentiation.