[Knowledge of adolescents with inflammatory bowel disease: Results of a multicenter cross-sectional survey]. / Connaissances des adolescents atteints de maladie inflammatoire chronique intestinale : résultats d'une enquête transversale multicentrique.

AIM: To assess knowledge acquired by adolescents about their inflammatory bowel disease (IBD). METHODS: An anonymous questionnaire was given during consultation to adolescents followed for IBD by pediatricians from 13 hospitals between 1 September 2012 and 1 July 2013. After parental consent, these physicians completed a form at the inclusion of each patient, in which the characteristics of IBD were detailed. The patients mailed back their questionnaire. RESULTS: A total of 124 patients from 12 to 19 years of age were included with a response rate of 82% (all anonymous); 23% of the patients thought that diet was a possible cause of IBD and 22% that one of the targets of their treatment was to cure their disease for good. Of the patients reported having Crohn disease, 46% knew the anoperineal location and 14% knew that Crohn disease can affect the entire digestive tract. Twenty-five percent of the patients were able to name one side effect of azathioprine (88% had already received this treatment), 24% were able to name one side effect of infliximab (54% had already received this treatment), 70% of the adolescents knew that smoking worsens Crohn disease, 68% declared they had learned about their IBD from their pediatrician, and 81% said they would like to receive more information. CONCLUSION: Adolescents with IBD have gaps in their general knowledge and the different treatments of their disease. Their main source of information is their pediatrician, warranting the implementation of customized patient education sessions.

HDL lipid composition is profoundly altered in patients with type 2 diabetes and atherosclerotic vascular disease.

BACKGROUND AND AIMS: We have previously shown that the anti-inflammatory and anti-oxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD). METHODS AND RESULTS: HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (D⁺CVD⁻) and 38 T2D with known history of CVD (D⁺CVD⁺). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC). Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from D⁺CVD⁺ when compared to D⁺CVD⁻ and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100. CONCLUSION: Patients with D⁺CVD⁻ and D⁺CVD⁺ are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. In the present study, a loss of HDL function (as estimated by the HDL oxidant index) is observed only in patients with more advanced atherosclerosis.

[Adolescent with anorexia nervosa: consequences on bone mineralization]. / Anorexie mentale de l'adolescent : conséquences sur la minéralisation osseuse.

INTRODUCTION: Anorexia nervosa is responsible for abnormalities in bone mineralization, which are well known and described in adults, but less well documented in adolescents. The aim of this research was to evaluate the frequency and severity and to determine predictive factors for these abnormalities in a population of adolescents with diagnosed anorexia nervosa. PATIENTS AND METHODS: This retrospective study involved 39 female adolescents with anorexia nervosa having undergone dual energy X-ray absorptiometry prior to the age of 18 years. Clinical (age, Tanner puberty stages, weight, body mass index [BMI] at different times during the anorexia phase and amenorrhea features), radiological (bone mineral density [BMD] in Z-score units and in absolute values), and biological (calcemia and vitamin D) parameters were collected. RESULTS: In total, 20 patients (51%) presented osteopenia (Z-score <-1 DS and >-2.5 DS) and 2 (5%) had osteoporosis (Z-score <-2.5 DS). Five (13%) exhibited a Z-score less than -2 DS. BMD expressed in Z-scores correlated with none of the parameters assessed. At univariate analysis, BMD in absolute values correlated with the age at disease onset, BMI, weight loss at the lowest weight achieved and BMI at the time of densitometry (P<0.01). At multivariate analyses, only the correlation with the age at disease onset persisted (P<0.05). CONCLUSION: Bone loss in anorexia nervosa is a complication that may be present as early as adolescence. It must be systematically searched for in all adolescents with severe malnutrition because, even if BMD correlated with nutritional parameters, no clinical predictor for osteoporosis or osteopenia could be identified in this study.

Transient elastography and portal hypertension in pediatric patients with cystic fibrosis Transient elastography and cystic fibrosis.

BACKGROUND: Esophageal varices (EV) are a complication of cystic fibrosis-associated liver disease. Esophagogastroduodenoscopy (EGD) is currently used to diagnose varices but is invasive for pediatric patients. The goal of this study was to explore the relationship between transient elastography (FibroScan®) and the presence of EV in patients with liver disease defined by clinical, laboratory, sonographic, and/or endoscopic criteria. METHODS: 18 patients with cystic fibrosis underwent EGD and transient elastography. 12 patients had EV. RESULTS: Patients with EV had higher FibroScan values than those without varices with median values of 22.4 kPa (14.4-30.4 kPa) vs. 7.9 kPa (4.4-13.7 kPa) (p=0.01). Using a threshold of 12 kPa, four of six patients without EV would not have needed EGD. CONCLUSIONS: Elastography should be recommended for all cystic fibrosis patients with liver disease to follow its progression. A prospective study is needed to define an elastography threshold value that predicts the presence of EV.

[Body composition analysis in patients with cystic fibrosis. Comparison of 3 methods: dual energy x-ray absorptiometry, bioelectrical impedance analysis, and skinfold measurements]. / Composition corporelle des patients mucoviscidosiques - comparaison de 3 techniques de mesure : anthropométrie, absorptiométrie biphotonique et impédancemétrie.

Nutritional status must be closely monitored in cystic fibrosis (CF) patients. This study compared three methods of measuring body composition in CF patients and then examined the relationships between two simple anthropometric markers of nutritional status - tricipital skinfold thickness (TSK) and arm muscular circumference (AMC) - and the results given by each method. Fifty-five patients with CF, 27 females and 28 males, participated in this study. The mean age at the time of the study was 14 ± 5 years, ranging from 4 to 29 years. The four skinfolds (SK) and arm circumference were measured in all patients and fat mass (FM) and AMC were calculated. Fifty patients underwent dual energy x-ray absorptiometry (DEXA) and 38 underwent bioelectrical impedance analysis (BIA). The values for FM as calculated by the three methods were highly correlated, as were the values for lean body mass (LM) (p<0.001). The LM assessed by anthropometry was overestimated by 8 ± 4% compared with DEXA and by 6 ± 7% compared with BIA. BIA overestimated LM by 4 ± 6% compared with DEXA (p<0.001). The LM values measured by SK, DEXA, and BIA were highly correlated with AMC (p<0.001) and FM calculated using these three techniques were highly correlated with TSK (p<0.001). The measurement of TSK and AMC are simple and rapid ways to evaluate body composition. The excellent correlation between the three methods used to measure body composition suggests that they are valid for use in patients with CF, but the results were not identical. The measurement from each technique must be interpreted according to its own norms and comparisons can only be made if the same technique is used in the same patient.

[Transition from pediatric to adult care: experience of a cystic fibrosis care center]. / Passage de l'enfant à l'adulte: l'exemple d'un centre de ressources et de compétences pour la mucoviscidose.

BACKGROUND AND OBJECTIVE: Even though patients with cystic fibrosis (CF) are continuously improving their life expectancy, guidelines for transition to adult services have not been clearly determined yet. The aim of this study was to analyze the management of this transition in the CF care center of Angers, France. PATIENTS AND METHOD: From their medical files, we analyzed the transfer of 22 patients with CF from pediatric to adult care. The perceptions of patients and caregivers regarding this transition were evaluated using anonymous questionnaires. RESULTS: The initial objective was to transfer patients around 18 years of age, offering them 3 or 4 joint consultations with a pediatrician and adult lung specialist. The median age of transfer was 22 years and the median duration of the transition period was 9 months. Half of the patients had only 1 joint transfer consultation during transition. The patient reaching the age of 18 and maturity were the most common criteria mentioned for transfer. All highlighted problems leaving the pediatric team they had grown attached to and its familiar environment. Caregivers described the transfer as a success, whereas half of the patients were dissatisfied with it, with both patients and caregivers indicating that the transition was too short without enough joint consultations. CONCLUSIONS: This study shows that this period is a major life event for the patient with CF. The transition process must be organized with the patient and independent behaviors should be encouraged. Adult and pediatric teams need to cooperate. Based on this experience and former medical data, we suggest a transition program for patients with CF.

Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population.

BACKGROUND AND AIMS: This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). METHODS: Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. RESULTS: 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p<0.001). CONCLUSIONS: High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps >5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.

JAK and STAT proteins are expressed and activated by IFN-gamma in rat pancreatic acinar cells.

The development of acute pancreatitis (AP) is triggered by acinar events, but the subsequent extra-acinar events, particularly a distinct immune response, appear to determine its severity. Cytokines modulate this immune response and are derived not only from immunocytes but also from pancreatic acinar cells. We studied whether pancreatic acinar cells were also capable of responding to cytokines. The JAK/STAT-pathway represents the main effector for many cytokines. Therefore, expression and regulation of JAK and STAT proteins were investigated in rat pancreatic acinar cells. Western blotting showed expression of JAK1, JAK2, Tyk2, and STAT1, STAT2, STAT3, STAT5, STAT6. In addition, STAT1 was reversibly tyrosine-phosphorylated upon the procedure of acinar cell isolation. In contrast, STAT3-phosphorylation occurred spontaneously after pancreas removal and was not reversible within 8 h. STAT1 phosphorylation was also observed upon treatment with IFN-gamma but not upon EGF, TNF-alpha or IL-6, and inhibited by the JAK2-inhibitor AG-490. Immunohistochemistry revealed cytoplasmic expression of unphosphorylated STAT1 in untreated acinar cells and nuclear translocation of phosphorylated STAT1 following IFN-gamma-treatment. Interestingly, although CCK leads to the activation of multiple stress pathways in pancreatic acinar cells, we found no influence of CCK on phosphorylation of STAT1, STAT3, or STAT5 in the pancreas. In conclusion, our data provide further evidence that pancreatic acinar cells are able to interact with immune cells. Besides stimulating immune cells via cytokine secretion, acinar cells are in turn capable of responding to IFN-gamma via JAK2 and STAT1 which may have an impact on the development of AP.

ANP preconditioning does not increase protection against experimental pancreatitis, observed after general anesthesia and jugular vein catheterization.

It has been widely shown that preconditioning, inducing heat shock proteins, can protect against experimentally induced pancreatitis. Solid evidence indicates that HSP70 plays a central role in this context, possibly by inhibition of premature intracellular trypsinogen activation. Current preconditioning protocols such as whole body hyperthermia are, however, quite strenuous and clinically not applicable. There is little data on other means to induce pancreatic HSPs such as pharmacologic pretreatment.However, in models of ischemic liver reperfusion injury, it has been demonstrated that atrial natriuretic peptide (ANP) can be used for such pharmacologic preconditioning. Evidence indicates that ANP exerts its protective effects via increased cGMP levels, activation of heat shock transcription factor (HSF) and, increased protein levels of HSP70. Pancreatic acinar cells express ANP receptors and respond to ANP treatment with increased cGMP levels. We have, therefore, investigated whether intravenous ANP pretreatment could be used to protect the pancreas against experimental pancreatitis. When given 20 minutes prior to pancreatitis induction, ANP pretreatment had no effect on cerulein-induced pancreatitis. In contrast, 24 hours after preconditioning, induction of HSP70 protein expression and protection against experimental pancreatitis were found. However, controls treated with NaCl without ANP showed a similar response. This indicates that stress caused by general anesthesia and jugular vein catheterization can be sufficient for preconditioning while ANP, in contrast to models of ischemic liver reperfusion injury, does not confer additional protection.

Phosphate diester hydrolysis and DNA damage promoted by new cis-aqua/hydroxy copper(II) complexes containing tridentate imidazole-rich ligands.

The tridentate Schiff base [(2-(imidazol-4-yl)ethyl)(1-methylimidazol-2-yl)methyl)imine (HISMIMI) and its reduced form HISMIMA were synthesized and characterized, as well their mononuclear cis-dihalo copper(II) complexes 1 and 2, respectively. In addition, the dinuclear [CuII(mu-OH)2CuII](2+) complexes (3) and (4) obtained from complexes 1 and 2, respectively, were also isolated and characterized by several physicochemical techniques, including magnetochemistry, electrochemistry, and EPR and UV-vis spectroscopies. The crystal structures of 1 and 2 were determined by X-ray crystallography and revealed two neutral complexes with their tridentate chelate ligands meridionally coordinated. Completing the coordination spheres of the square-pyramidal structures, a chloride ion occupies the apical position and another is bonded in the basal plane. In addition, complexes 1 and 2 were investigated by infrared, electronic, and EPR spectroscopies, cyclic voltammetry, and potentiometric equilibrium studies. The hydrolytic activity on phosphate diester cleavage of 1 and 2 was investigated utilizing 2,4-BDNPP as substrate. These experiments were carried out at 50 degrees C, and the data treatment was based on the Michaelis-Menten approach, giving the following kinetic parameters (complex 1/complex 2): vmax (mol L(-1) s(-1))=16.4x10(-9)/7.02x10(-9); KM (mol L(-1))=17.3x10(-3)/3.03x10(-3); kcat (s(-1))=3.28x10(-4)/1.40x10(-4). Complex 1 effectively promoted the hydrolytic cleavage of double-strand plasmid DNA under anaerobic and aerobic conditions, with a rate constant of 0.28 h(-1) for the decrease of form I, which represents about a 10(7) rate increase compared with the estimated uncatalyzed rate of hydrolysis.

Treatment of hepatic hydrothorax and reduction of chest tube output with octreotide.

Hepatic hydrothorax is a dreaded complication in patients with liver cirrhosis. Placement of chest tubes can alleviate respiratory distress, but patients often succumb due to excessive fluid and protein loss via the open drain. Our case illustrates that high-dose octreotide can strongly reduce hepatic hydrothorax drainage volume. This allows removal of the chest tube, which would otherwise not have been possible.

High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection.

BACKGROUND: Viruses have been identified as one of a variety of potential agents that are implicated in atherogenesis. METHODS AND RESULTS: C57BL/6J mice were killed before or 2, 3, 5, 7, or 9 days after intranasal infection with 10(5) plaque-forming units (pfu) of Influenza A strain WSN/33. Peak infectivity in lungs was reached by 72 hours, and it returned to baseline by 9 days. No viremia was observed at any time. The activities of paraoxonase and platelet-activating factor acetylhydrolase in HDL decreased after infection and reached their lowest levels 7 days after inoculation. The ability of HDL from infected mice to inhibit LDL oxidation and LDL-induced monocyte chemotactic activity in human artery wall cell cocultures decreased with time after inoculation. Moreover, as the infection progressed, LDL more readily induced monocyte chemotaxis. Peak interleukin-6 and serum amyloid A plasma levels were observed at 2 and 7 days after inoculation. HDL apoA-I levels did not change. ApoJ and ceruloplasmin levels in HDL peaked 3 days after infection. Ceruloplasmin remained elevated throughout the time course, whereas apoJ levels decreased toward baseline after the third day. CONCLUSIONS: We conclude that alterations in the relative levels of paraoxonase, platelet-activating factor acetylhydrolase, ceruloplasmin, and apoJ in HDL occur during acute influenza infection, causing HDL to lose its anti-inflammatory properties.

[Barrett's esophagus: screening and prognosis]. / Barrett-Osophagus, Screening und Prognose.

The diagnostic criteria for Barrett's disease have changed very considerably during the last 10 years. Classically, the definition asked for columnar epithelium in the lower esophagus extending for at least 3 cm proximally. Now, the diagnosis rests on the finding of specialised intestinal metaplasia, i.e. columnar epithelium with goblet cells, in the esophagus, regardless of the extension. This is important because it is this type of metaplasia that is associated with an increased risk for the development of esophageal adenocarcinoma and esophageal adenocarcinoma is the tumor with the fastest rising incidence in the western world in recent years. The criteria of the current definition of Barrett's esophagus are described in detail and the implications this change in definition carries for screening and surveillance of patients is discussed.

Oxidized phospholipids induce changes in hepatic paraoxonase and ApoJ but not monocyte chemoattractant protein-1 via interleukin-6.

In this study, we tested if interleukin-6 (IL-6) plays a role in mediating the effects of oxidized phospholipids (OXPL). Treatment of HepG2 cells with oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphoryl choline (OX-PAPC), or biologically active lipids present in mildly oxidized low density lipoprotein, increased apolipoprotein J (apoJ), and decreased paraoxonase (PON) mRNA levels. Antibodies to IL-6 blocked these changes. IL-6 treatment in the absence of OXPL produced the same pattern of mRNA changes observed with OXPL treatment alone. In vivo, OX-PAPC injected into C57BL/6J mice resulted in a marked reduction in PON activity and an increase in apoJ levels in plasma after 16 h. Injection of OX-PAPC into IL-6-deficient C57BL/6J mice (IL-6 -/-) did not alter either PON activity or apoJ levels. We then tested if other mechanisms involved in fatty streak formation depended upon IL-6. Antibody to IL-6 had no effect on OX-PAPC-induced secretion of MCP-1 by endothelial cells nor on MCP-1 mRNA expression in HepG2 cells. C57BL/6J and IL-6 -/- mice fed an atherogenic diet both demonstrated markedly reduced plasma PON activities and the IL-6 -/- mice developed fatty streaks to a greater degree than wild-type mice. We conclude that IL-6 is critical to short term but not long term regulation of PON and that IL-6 is not required for OXPL regulation of MCP-1.

Stress kinase inhibition modulates acute experimental pancreatitis.

AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.

Hyperthermia-induced HSP expression correlates with improved rat renal isograft viability and survival in kidneys harvested from non-heart-beating donors.

Transient sublethal hyperthermia followed by recovery from heat stress, referred to as heat shock preconditioning, exerts a protective effect on ischemia/reperfusion-induced injury in many systems. This effect is considered to be correlated to heat shock proteins (HSPs) and might be a critical factor in kidney graft function and survival. This study was designed to examine the impact of heat shock preconditioning on kidney isograft function and survival in a model utilizing non-heart-beating (NHB) donors. Four groups of male Lewis rats (n = 10/group) subjected either to whole body hyperthermia (groups A and C) or to sham anesthesia (groups B and D) were allowed 24 h recovery. Thereafter, 20 min of warm ischemia (A/B), and in a separate set of experiments 40 min of warm ischemia (C/D), were induced by suprarenal aortic cross clamping before renal procurement. After 24-h preservation with University of Wisconsin solution at 4 degrees C, orthotopic kidney transplantations were performed to syngeneic bilaterally nephrectomized recipients. Tissue specimens were taken to determine HO-1/HSP32, 72, and 90 induction by Western blot analysis. Renal function was measured by means of serum creatinine and creatinine clearance on days 0, 3, and 7 as well as urine volume, protein content, and creatinine levels daily. HO-1/HSP32 and HSP72 were found to be expressed constitutively. Moreover, heat shock strongly induced renal HSP72 and HSP32/HO-1, and to a lesser extent HSP90, expression. For recipients of group A grafts, the graft survival rate was 10/10, whereas it was 7/10 (70 %) in recipients of group B grafts (log rank p < 0.05). Following 40 min of warm ischemia, 6/10 (60 %) recipients survived, whereas all sham treated animals died with anuria within 6 days (log rank p = 0.01). Heat shock preconditioning strongly improved graft viability and reduced functional impairment. Creatinine clearance (CRC) on day 3 post Tx was 0.43 +/- 0.24 ml/min in preconditioned animals (group A) and 0.07 +/- 0.09 ml/min (p < 0.001) in sham preconditioned (group B), whereas it was 0.91 +/- 0.33 ml/min and 0.03 +/- 0.02 ml/min (p < 0.00 001) on day 7 post Tx. Following 40 min NHB time, CRC in survivors of preconditioned graft recipients (group C) was 0.32 +/- 0.2 ml/min (day 3 post Tx) and 0.23 +/- 0.08 ml/min (day 7 post Tx) and was significantly better than CRC of group B (p < 0.01 and p < 0.00001, respectively). CRCs prior to NHB procedures were comparable in all animals ranging between 1.31 and 1.72 ml/min. Serum creatinine as well as proteinuria were significantly increased after transplantation in both groups but recovered within 5 days in recipients of preconditioned grafts, whereas kidneys from donors without HP did not recover function. Histological alterations were also diminished following HP. Hyperthermic preconditioning induces strong and long lasting HO-1/HSP32, HSP72, and HSP90 expression in rat kidneys. HP increases survival following transplantation and improves renal graft function including proteinuria, volume output, and creatinine clearance. HSP induction might be used to develop novel approaches in clinical transplantation.

Map kinase phosphatases (MKP's) are early responsive genes during induction of cerulein hyperstimulation pancreatitis.

Mitogen-activated protein kinase (MAPK) family members such as c-jun N-terminal kinase (JNK) may act as signal transducers early during pancreatitis development and evidence indicates that MAPK phosphatases (MKP) downregulate MAPK. We therefore investigated expression and regulation of pancreatic MKP in vivo. Pancreatic MKP mRNA levels were near or below the detection threshold in unstimulated animals. Cerulein hyperstimulation strongly induced MKP-1, MKP-3, and MKP-5 expression, peaking 30 to 60 min after treatment. Thus, MKP's clearly are early responsive genes during pancreatitis induction. Interestingly, inhibition of MKP-1 expression by Ro-31-8220 maximally induced activation of JNK but not of p38 and ERK in acutely isolated acini. These effects indicate that JNK may indeed be a preferred MKP-1 substrate in vivo.

[Drug treatment of chronic inflammatory bowel diseases: current status and prospects]. / Medikamentöse Behandlung chronisch entzündlicher Darmerkrankungen: aktueller Stand und Ausblick.

The medical treatment of inflammatory bowel disease is dependent on disease activity and bowel involvement. Severe Crohn's disease and ulcerative colitis are primarily treated with corticosteroids. Alternatively, if inflammation is localised in the right colon and ileum, budesonide may be used in view of its low systemic side effects. In distal colitis and perianal disease, topical therapy with steroids is very effective. In moderate disease preparations containing 5-aminosalicylate (5-ASA) may be used. The latter are highly effective applied locally in distal disease. Steroids should be tapered down and whenever possible not used to maintain remission. In patients with ulcerative colitis, 5-ASA is effective in maintaining remission, whereas this medication plays only a limited role in Crohn's disease. Refractory disease or patients with multiple flare-ups should be treated with azathioprine. Infliximab, an anti-TNF-alpha antibody, is a potent therapy for fistulising Crohn's disease or steroid-refractory disease. Other approved and experimental treatments are discussed.

CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates caerulein pancreatitis.

Pancreatic caerulein-induced activation of c-Jun NH(2)-terminal kinase (JNK) has been reported, and JNK has been proposed as a mediator during induction of hyperstimulated pancreatitis. CEP-1347 has recently been described as a specific JNK inhibitor. We tested whether CEP-1347 inhibits caerulein-induced pancreatic JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited acinar caerulein-induced JNK activation with nearly complete inhibition at 2 microM but had no effect on digestive enzyme release. For in vivo studies, rats were pretreated with CEP-1347 before caerulein hyperstimulation. For assessment of JNK activation and histological alterations, animals were killed 30 min or 2 and 4 h after caerulein hyperstimulation, respectively. Pancreatic wet weight, serum enzyme levels, and pancreatic activity of p38 and extracellular signal-regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly activated JNK, p38, and ERK. CEP-1347 pretreatment dose dependently reduced caerulein-induced pancreatic JNK activation without p38 or ERK inhibition. JNK inhibition also reduced pancreatic edema formation and reduced histological severity of pancreatitis. Thus we show that CEP-1347 inhibits JNK activation in vivo and ameliorates caerulein-induced pancreatitis.

Heat shock response is associated with protection against acute interstitial pancreatitis in rats.

We recently reported that hyperthermia induces pancreatic expression of heat shock proteins (HSPs), particularly HSP70 isoforms, and protects against cerulein pancreatitis. We have now studied whether a double hyperthermia amplifies these effects and whether hyperthermia also protects against dibutyltin dichloride (DBTC)-induced pancreatitis. A further aim was to examine whether hyperthermia induces changes in transforming growth factor-beta1 (TGF-beta1). Following pretreatment without or with a single or double hyperthermia, pancreatitis was induced by application of cerulein or DBTC. Pancreatic HSP and TGF-beta1 expression were studied by immunoblotting. Pancreas injury was assessed by light microscopy and serum pancreatic enzyme activity. Hyperthermia as well as DBTC induced HSP72, whereas cerulein did not. A double hyperthermia led to a further increase in HSP72 compared to a single heat stress. In both models, hyperthermia significantly reduced pancreatic injury. Although a double hyperthermia slightly decreased the severity of cerulein pancreatitis compared to a single heat treatment, an improved pancreas protection against DBTC cytotoxicity was not achieved. We also found that hyperthermia induces the expression of TGF-beta1. In conclusion, hyperthermia preconditioning exerts protective effects against two pathophysiologically different types of pancreatitis by a mechanism that involves the up-regulation of HSP70 isoforms as well as TGF-beta1.