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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 < 0.001), substantial diffuse redness (P = 0.012), substantial diffuse fibrin (P = 0.003), fecal or bile as exudate (P = 0.001), nonappendiceal source of infection (P < 0.001), IAV Score groups (P < 0.001), organ dysfunctions (P < 0.001), and 30-day mortality (P = 0.035). CONCLUSIONS: Various cytokines associate with the IAV and outcome. IL-8 showed the best overall performance. The results emphasize the role of the surgeons' perception of the IAV. IAV provides an approximation of the magnitude of the systemic inflammatory response.
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Citocinas/sangre , Infecciones Intraabdominales/inmunología , Anciano , Femenino , Humanos , Infecciones Intraabdominales/complicaciones , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
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.
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Neutrófilos/fisiología , Pancreatitis/complicaciones , Pancreatitis/patología , Transducción de Señal/fisiología , Adulto , Anciano , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
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. and IAP.
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Lipoproteínas/sangre , Pancreatitis/sangre , Trombina/metabolismo , Tromboplastina/metabolismo , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Coagulación Sanguínea/fisiología , Pruebas de Coagulación Sanguínea , Células Cultivadas , Femenino , Finlandia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/diagnóstico , Insuficiencia Multiorgánica/mortalidad , Pancreatitis/diagnóstico , Pancreatitis/mortalidad , Pancreatitis/fisiopatología , Recuento de Plaquetas , Tasa de SupervivenciaRESUMEN
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.
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Subgrupos Linfocitarios/metabolismo , Insuficiencia Multiorgánica/patología , Pancreatitis/patología , Transducción de Señal/inmunología , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Tolerancia Inmunológica , Subgrupos Linfocitarios/inmunología , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/diagnóstico , Insuficiencia Multiorgánica/inmunología , Pancreatitis/diagnóstico , Pancreatitis/inmunología , Fosforilación/inmunologíaRESUMEN
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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01017107.
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Pancreatitis/tratamiento farmacológico , Proteína C/uso terapéutico , Enfermedad Aguda , Adulto , Bilirrubina/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/prevención & control , Pancreatitis/diagnóstico por imagen , Proyectos Piloto , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
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.
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Pancreatitis/inmunología , Pancreatitis/patología , Enfermedad Aguda , Coagulación Sanguínea , Citocinas/biosíntesis , Humanos , Tolerancia Inmunológica , Inflamación/sangre , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Insuficiencia Multiorgánica/etiología , Pancreatitis/complicaciones , Pancreatitis/terapia , Pronóstico , Sepsis/inmunología , Sepsis/patologíaRESUMEN
OBJECTIVES: To outline signaling profiles and transmigration capacity of monocytes of patients with severe acute pancreatitis. DESIGN: Prospective study. SETTING: University hospital intensive care unit. PATIENTS: 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. INTERVENTIONS: Blood samples were collected after admission to the intensive care unit. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.
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Monocitos/fisiología , Insuficiencia Multiorgánica/sangre , Pancreatitis Aguda Necrotizante/sangre , Transducción de Señal/fisiología , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Cuidados Críticos/métodos , Enfermedad Crítica/terapia , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Citometría de Flujo , Hospitales Universitarios , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/complicaciones , Insuficiencia Multiorgánica/diagnóstico , Pancreatitis Aguda Necrotizante/complicaciones , Pancreatitis Aguda Necrotizante/diagnóstico , Pancreatitis Aguda Necrotizante/terapia , Fosforilación , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Valores de Referencia , Medición de Riesgo , Factor de Transcripción STAT5/metabolismo , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Proteínas Supresoras de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
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.
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Eliminación de Gen , Mutagénesis Insercional/genética , Pancreatitis Crónica/genética , Pancreatitis/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Finlandia , Genotipo , Alemania , Humanos , Masculino , Persona de Mediana Edad , Pancreatitis/metabolismo , Pancreatitis Crónica/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Adulto JovenRESUMEN
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.
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Factor V/genética , Pancreatitis/genética , Inhibidor 1 de Activador Plasminogénico/genética , Polimorfismo Genético , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pancreatitis/sangreRESUMEN
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.
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Proteínas HSP70 de Choque Térmico/genética , Receptores de Lipopolisacáridos/genética , Pancreatitis Alcohólica/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pancreatitis Alcohólica/inmunología , Fenotipo , Estudios Prospectivos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Hiperglucemia/complicaciones , Insuficiencia Multiorgánica/complicaciones , Obesidad Mórbida/complicaciones , Pancreatitis/complicaciones , Enfermedad Aguda , Adulto , Glucemia/análisis , Índice de Masa Corporal , Cuidados Críticos , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Insulina/uso terapéutico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pancreatitis/fisiopatología , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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, p >0.05). There was no correlation between BMI and IL-1beta, IL-6, IL-10, IL-1 receptor antagonist or procalcitonin. CONCLUSIONS: 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.
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Índice de Masa Corporal , Mediadores de Inflamación/sangre , Pancreatitis Aguda Necrotizante/patología , Adulto , Proteína C-Reactiva/análisis , Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina , Femenino , Antígenos HLA-DR/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Precursores de Proteínas/sangre , Estadística como AsuntoRESUMEN
OBJECTIVES: 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. METHODS: 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 (R&D Systems, Minneapolis, Minn) were used to measure the adipokine levels in the patients' plasma on admission and during the hospital stay. RESULTS: 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 (P > 0.05). 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 (P > 0.05). 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 (P > 0.05). Maximum variation of adiponectin level (the highest value minus the lowest value) was greater in severe AP than in mild AP (P = 0.001). CONCLUSIONS: 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.
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Adiponectina/sangre , Leptina/sangre , Pancreatitis/sangre , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pancreatitis/etiología , Estudios RetrospectivosAsunto(s)
Glucemia/análisis , Calcio/sangre , Interleucina-10/sangre , Insuficiencia Multiorgánica/diagnóstico , Pancreatitis/complicaciones , Enfermedad Aguda , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Insuficiencia Multiorgánica/etiología , Pancreatitis/diagnóstico , Pancreatitis/terapia , Valor Predictivo de las Pruebas , Valores de Referencia , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
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.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Tolerancia Inmunológica , Interferón gamma/farmacología , Monocitos/inmunología , Pancreatitis/inmunología , Enfermedad Aguda , Adulto , Femenino , Antígenos HLA-DR/análisis , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
OBJECTIVE: Mutations in the Kazal type 1 serine protease inhibitor (SPINK1) gene have recently been associated with chronic pancreatitis (CP), an established risk factor for pancreatic cancer. The aim of this study was to investigate the frequency of the SPINK1 gene mutations (N34S and P55S) in patients with CP, or pancreatic cancer, and in healthy subjects in Finland. MATERIAL AND METHODS: The N34S and P55S mutations were determined by PCR amplification followed by solid-phase minisequencing in 116 patients with CP and in 188 with pancreatic cancer. In patients with CP, alcohol was the aetiological factor in 87 (75%), pancreas divisum in 4 (3%), gallstones in 5 (5%) and 20 patients (17%) had an idiopathic disease; 459 healthy individuals were enrolled as controls. RESULTS: The frequency of the N34S mutation was significantly higher in patients with CP (14/116, 12%) than in controls (12/459, 2.6%) (p<0.0001). There was no difference in the frequency of the P55S mutation between patients with CP (1/116, 0.9%) and controls (6/459, 1.3%). The N34S mutation was present in 9 (10%) out of 87 patients with alcoholic CP, and in 5 (25%) patients with idiopathic CP. No SPINK1 mutations were found in patients with CP caused by anatomical variations or gallstones. Among the 188 patients with a pancreatic malignant tumour, the N34S mutation was present in 7 cases (3.7%). The frequency of the N34S mutation in healthy controls in this study was significantly higher than earlier reported in other countries (p=0.03). CONCLUSIONS: The SPINK1 N34S mutation was significantly associated with an increased risk of CP. The association of the N34S mutation with alcoholic CP was marginally stronger than in earlier studies, whereas in the Finnish population in general, this mutation was significantly more frequent than reported elsewhere.
Asunto(s)
Proteínas Portadoras/genética , Neoplasias Pancreáticas/genética , Pancreatitis/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Finlandia , Humanos , Masculino , Persona de Mediana Edad , Mutación , Inhibidor de Tripsina Pancreática de KazalRESUMEN
OBJECTIVES: 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). METHODS: 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. RESULTS: The N34S mutation was found in 29 (7.8%) of the patients and in 12 (2.6%) of the controls (P < 0.0001, 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. CONCLUSION: SPINK1 N34S mutation enhances the susceptibility of AP.
Asunto(s)
Proteínas Portadoras/genética , Pancreatitis/genética , Mutación Puntual , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Inhibidor de Tripsina Pancreática de KazalRESUMEN
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 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. CONCLUSIONS: The first vaginal delivery can result in occult sphincter defects and the use of vacuum extraction increases the risk.
Asunto(s)
Canal Anal/lesiones , Incontinencia Fecal/epidemiología , Complicaciones del Trabajo de Parto/epidemiología , Adulto , Canal Anal/diagnóstico por imagen , Canal Anal/fisiopatología , Parto Obstétrico , Incontinencia Fecal/etiología , Femenino , Finlandia/epidemiología , Humanos , Incidencia , Manometría , Registros Médicos , Paridad , Embarazo , Estudios Prospectivos , Estudios Retrospectivos , Ultrasonografía , Extracción Obstétrica por AspiraciónRESUMEN
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.