Topical delivery of steroids in inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) represent two similar but probably not uniform entities of inflammatory bowel disease (IBD). Since up to now no curative treatment is available the therapeutic goal in active IBD is elimination or at least alleviation of symptoms and maintenance of remission. Glucocorticoids have been successfully used in the treatment of symptoms and inflammation. Due to the minor systemic side effects a topical drug delivery targeting the active substances directly to the inflamed sites would be the favorable administration. In this review the use of topical corticosteroids is discussed, based on a short description of their pharmacological properties.

Loss of sensory and noradrenergic innervation in benign colorectal adenomatous polyps--a putative role of semaphorins 3F and 3A.

BACKGROUND: Nerve fibers can exert trophic/anti-trophic effects on epithelial cells. Substance P (SP) is a pro-proliferative neuropeptide, whereas sympathetic noradrenaline is anti-proliferative at high concentrations. METHODS: Density of noradrenergic and sensory nerve fibers and presence of nerve repellent factors specific for noradrenergic (semaphorin 3F) and sensory nerve fibers (semaphorin 3A) were investigated in colorectal adenomas. KEY RESULTS: The pedunculus was innervated by noradrenergic fibers, whereas the mucosa was sparsely innervated. The control submucosa compared with control mucosa demonstrated increased density of noradrenergic fibers. Control tissue was much better innervated than the polyp. This was accompanied by strong expression of semaphorin 3F in epithelial cells. Density of sensory SP+ nerve fibers was higher in control colon mucosa compared with polyp mucosa, and SP+ cell clusters and semaphorin 3A-positive cells appeared in the intercrypt space in polyps, but not in control tissue. CONCLUSIONS & INFERENCES: This study demonstrated a marked loss of noradrenergic and sensory nerve fibers in polyp mucosa, which was associated with a strong increase of semaphorin 3F and 3A. Up-regulation of the sympathetic repellent semaphorin 3F in the polyps possibly triggers sympathetic repulsion and polyp growth due to the loss of anti-proliferative noradrenaline and presence of SP from local SP+ cells.

RAP-PCR fingerprinting reveals time-dependent expression of matrix-related molecules following stem-cell based TGFß1-induced chondrocyte development.

Different approaches of engineering cartilage to treat defects in the articulating surfaces of the joints have been designed, which mainly use mesenchymal stem cells or autologous chondrocytes for in situ transplantation. However, these cells are poorly characterized with respect to viability, degree of differentiation and morphology or production of extracellular matrix. At present, one of the key approaches to generate chondrocytes is the stimulation of stem cells with transforming growth factor (TGF) ß1. To characterize the molecular alterations occurring during the cellular transformation induced by TGF-ß1 exposure, the differentiation process of bone marrow-derived stem cells into chondrocytes was investigated using an in vitro chondrogenesis model and the RNA arbitrarily primed PCR (RAP-PCR) fingerprinting technique. Distinct genes were found to be differentially regulated during chondrocyte development beginning on day 1: collagen type I, non-muscle myosin MYH9, followed by manganese superoxide dismutase and sodium-potassium ATPase on day 7. The results suggest that using RAP-PCR for differential display fingerprinting is a useful tool to investigate the differentiation process of bone marrow-derived stem cells following TGF-ß1-stimulation.

[69 year-old patient with chronic abdominal pain and anemia in neurofibromatosis]. / 69-jähriger Patient mit chronischen Bauchschmerzen und Anämie bei Neurofibromatose.

The case of a patient with neurofibromatosis type 1 with chronic abdominal pain and iron deficiency anemia is described. Diagnostic procedures including esophagogastroduodenoscopy and ileocolonoscopy did not disclose a definitive cause. CT scan and MRI revealed multiple intraluminal tumors in the small bowel, especially in the ileum. These findings were verified by double balloon enteroscopy. Endoscopic resection was not performed due to size and number of the polyps, and the patient was sent for diagnostic laparotomy. A conglomerate tumor of the ileum was resected. Histopathological analysis revealed 13 inflammatory polyps and 2 gastrointestinal stroma tumors.

Type 2 diabetes and lipoprotein metabolism affect LPS-induced cytokine and chemokine release in primary human monocytes.

AIMS/HYPOTHESIS: Obesity and insulin resistance are characterized by a chronic and low grade state of inflammation and the pro-inflammatory response of monocytes is affected in type 2 diabetes mellitus (T2D). We aimed to investigate whether LPS-induced monocytic cytokine and chemokine release depends on serum lipoprotein parameters in T2D patients. METHODS: Primary human monocytes were isolated from 29 patients with known T2D and from 20 healthy volunteers. Anthropometric and disease-related parameters such as age, gender, BMI, WHR, diabetes duration, diabetes complications, and diabetes control (HbA1c) were documented. Monocytes were stimulated for 18 h with LPS (1 µg/ml). Unstimulated monocytes served as control. The supernatant concentrations of CCL2, CCL3, CCL4, CCL5, MIF and resistin were measured by ELISA. RESULTS: LPS-stimulation significantly (p<0.001) increased CCL chemokine and resistin concentrations in healthy controls and in patients with T2D, whereas MIF release was not affected in both groups. LPS-induced CCL2 and resistin concentrations were significantly higher in T2D patients when compared to healthy controls. In T2D patients, LPS-induced CCL3 concentration was higher in males when compared to females (p=0.039) and supernatant resistin concentration upon stimulation with LPS showed a significant and positive correlation with age (r=0.6; p=0.001). LPS-induced CCL2 concentration was significantly and positively correlated with serum triglyceride concentration (r=0.4; p=0.009) in T2D patients. Furthermore, LPS-induced CCL4 concentration was significantly and positively correlated with total (r=0.4; p=0.035) and LDL cholesterol (r=0.4; p=0.033) concentration. CONCLUSIONS: LPS responsiveness of monocytes is altered in T2D and is affected by the respective serum lipoprotein metabolism.

Serum BAFF strongly correlates with PsA activity in male patients only--is there a role for sex hormones?

OBJECTIVES: To determine the relationship between serum levels of B cell activating factor belonging to the TNF family (BAFF) and disease activity (DAS28) in psoriatic arthritis (PsA) patients. METHODS: Twenty-two male and 31 female psoriasis patients fulfilling the CASPAR criteria for PsA were recruited for the study. Disease activity was recorded using the disease activity score for 28 joints (DAS28). Whole blood and serum samples were analysed for serum BAFF, estradiol, and testosterone levels. RESULTS: Serum BAFF levels were positively correlated with DAS28 only in male PsA patients (r=0.669, p<0.001). In male but not female patients, serum testosterone was negatively correlated with DAS28 (r=-0.632, p=0.002), and serum BAFF (r=-0.520, p=0.018), respectively. The serum BAFF/ serum testosterone (B/T) ratio showed a strong correlation with DAS28 in male patients (r=0.743, p<0.0001) and, again, no correlation was found in female participants (r=0.019, p=0.93). A linear regression analysis showed that the B/T is a good predictor of DAS28 (r2=0.586, p<0.001). On the other hand, estradiol levels did neither correlate with PsA activity in male nor female patients in our study population. CONCLUSIONS: Even though a role for B cells in the pathogenesis of PsA has not been established, BAFF levels correlate with disease activity in male PsA patients. Furthermore, serum testosterone in male patients negatively correlates with disease activity and BAFF, respectively. The serum BAFF/serum testosterone ratio might be used as predictor of disease activity in male PsA patients.

Risk factors associated with long-term prognosis of patients with Staphylococcus aureus bacteremia.

OBJECTIVE: To estimate risk factors associated with long-term outcome (i.e., 1-year survival) in patients with Staphylococcus aureus bacteremia (SAB). METHODS AND MATERIALS: This was a retrospective study in which the microbiological laboratory data records of patients admitted to the University Hospital of Regensburg between January 2004 and June 2005 were examined to identify those patients with blood cultures positive for S. aureus. Corresponding clinical records for all patients were reviewed using a standardized questionnaire. Of the 119 patients identified with SAB, 80 were available for the >1-year follow-up. RESULTS: Crude 1-year mortality was 47.5; 30- and 90-day mortality was 28.8 and 37.5%, respectively. In-hospital mortality was 28.8%. There were no significant differences in 1-year survival in terms of age, gender, antibiotic resistance, and mode of acquisition (nosocomial vs. community-acquired). A significantly better survival was observed with an identifiable focus present, if the chosen empiric antibiotic therapy was adequate or if the body mass index of the patient was >24. CONCLUSION: In summary, in this patient cohort, considerable additional mortality due to SAB beyond 30 or 90 days was present. Our results suggest that long-term survival data should be taken into account in outcome studies involving patients with S. aureus bacteremia.

Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome.

The AMP activated kinase plays an important role in metabolic control, and pharmacologic enhancement of AMPK activity is used to improve insulin resistance. We hypothesized that high dose of folic acid supplementation might improve insulin sensitivity and hepatic inflammation and examined this by a dietary intervention in (a) the high fat fed rat model of the metabolic syndrome, which shows sole hepatic steatosis as well as (b) in rats fed with a high cholesterol, high cholate diet inducing nonalcoholic steatohepatitis (NASH). Male Wistar rats were fed with folic acid supplemented (40 mg/kg) high fat diet [based on lard, fat content 25% (wt/wt)] or NASH inducing diet (containing 15% fat, 1.25% cholesterol, 0.5% sodium cholate). Metabolic profiling was performed by measuring the animals' visceral fat pads, fasting plasma glucose, insulin, and adipokines as well as in vivo insulin tolerance tests. Hepatic steatosis and inflammation were analyzed semiquantitatively by histological analysis. Folic acid supplementation reduced visceral obesity and improved plasma adiponectin levels. In vivo insulin sensitivity was improved, and in HF-FA rats folic acid increased activation of hepatic AMPK. Further, folic acid supplementation improved hepatic inflammation in animals fed with NASH-inducing diet. Dietary folic acid improved parameters of insulin resistance and hepatic inflammation in rodent models. This might be due to an increased AMK activation.

Splanchnic sympathectomy prevents translocation and spreading of E coli but not S aureus in liver cirrhosis.

INTRODUCTION: Spontaneous bacterial peritonitis (SBP) is mainly caused by bacterial translocation of enteric Gram-negative bacteria, predominantly Escherichia coli. The sympathetic nervous system (SNS) is activated in advanced cirrhosis, particularly in the splanchic circulation, and exerts potent immunosuppressive actions. However, the role of splanchnic SNS activity in bacterial translocation and bacterial spreading in cirrhosis remains unclear. METHODS: E coli or Stapylococcus aureus (10(6) CFU) were given intraperitoneally. After 6 h, mesenteric lymph nodes (MLN), liver, spleen, lung and peripheral blood were harvested from ascitic cirrhotic rats (LC) and healthy controls with and without splanchnic sympathectomy (SE). The bacterial tissue burden was determined by standard microbiological culture techniques. In vitro phagocytic activity of peritoneal polymorphonuclear leucocytes was assessed by FACS analysis. RESULTS: Under basal conditions SE reduced bacterial translocation to MLN in LC rats from 45% to 17%. LC rats had a marked increase in bacteraemia after E coli and S aureus challenge and an increased incidence and degree of E coli translocation to MLN, liver, spleen and lung compared with control rats. SE prevented bacteraemia in LC rats after E coli but not after S aureus challenge. Prior SE abolished the difference in incidence as well as the bacterial tissue burden in each organ after E coli application in LC rats, being no longer significantly different from control rats with or without SE. The protective effects of SE against E coli were associated with a greater influx of mononuclear cells into the peritoneal cavity and increased phagocytic activity of peritoneal polymorphonuclear leucocytes. CONCLUSIONS: In cirrhosis with bacterial peritonitis, hyperactivity of the splanchnic sympathetic nervous system contributes to the translocation of E coli but not S aureus to MLN and extraintestinal sites. This indicates a key role for sympathetic drive in the impairment in host defence against Gram-negative bacteria in cirrhosis.

Semiquantitative characterization of hepatocellular carcinoma (HCC)--perfusion with contrast-enhanced ultrasound and perfusion analysis.

BACKGROUND: At the moment, there is only poor specificity of HCC-detection in tumors smaller than 2 cm in a cirrhotic liver. Thus, efforts have to be made to optimize the distinction between regenerative nodules and HCC. AIMS: The aim of our study was to describe the particular perfusion pattern of hepatocellular carcinoma using a specific quantification software. METHODS: We evaluated 25 patients with proven hepatocellular carcinoma, who underwent dynamic contrast-enhanced ultrasound (CEUS) using a second generation contrast agent (SonoVue, Bracco, Germany). Retrospectively, we applied the quantification software Qontrast (Bracco, Milan, Italy) to obtain contrast-enhanced sonographic perfusion maps for each lesion. RESULTS: We found a close positive correlation of the perfusion parameters peak, time-to-peak and regional blood volume between the entire tumors, the center (center/total) and the periphery of the tumors (periphery/total), respectively. Moreover, we found significant higher peak values, a significant higher regional blood volume and a trend to lower time-to-peak in the center of the tumors compared to the tumor periphery. CONCLUSION: These results suggest a better established vascular bed in the center of the tumors. This could be a sonographic marker of HCC in contrast to regenerative nodules.

[Rheumatoid arthritis and autoimmune hemolysis: B-cell depletion for remission induction in a patient with rheumatoid arthritis and cold agglutinin disease]. / Rheumatoide Arthritis und Autoimmunhämolyse: Remissionsinduktion durch B-Zell-Depletion bei einer Patientin mit rheumatoider Arthritis und Autoimmunhämolyse durch Kälteagglutinine.

Autoimmune hemolysis is a rare complication of systemic rheumatic diseases. We report on a 68-year-old female patient with established, long-standing rheumatoid arthritis, who complained of progressive weakness and worsening of her arthralgia under therapy with leflunomide. Physical and laboratory examination revealed autoimmune hemolysis due to cold agglutinin disease. As hemolysis and arthritis were refractory to steroid treatment, B-cell depletion with rituximab was performed leading to a marked reduction of hemolytic parameters as well as remission of her rheumatoid arthritis.

Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double-blind cross-over diet intervention study.

BACKGROUND: Environmental factors are thought to play an important role in the development of Crohn's disease (CD). Immune responses against auto-antigens or food antigens may be a reason for the perpetuation of inflammation. METHODS: In a pilot study, 79 CD patients and 20 healthy controls were examined for food immunoglobulin G (IgG). Thereafter, the clinical relevance of these food IgG antibodies was assessed in a double-blind cross-over study with 40 patients. Based on the IgG antibodies, a nutritional intervention was planned. The interferon (IFN)gamma secretion of T cells was measured. Eosinophil-derived neurotoxin was quantified in stool. RESULTS: The pilot study resulted in a significant difference of IgG antibodies in serum between CD patients and healthy controls. In 84 and 83% of the patients, respectively, IgG antibodies against processed cheese and yeast were detected. The daily stool frequency significantly decreased by 11% during a specific diet compared with a sham diet. Abdominal pain reduced and general well-being improved. IFNgamma secretion of T cells increased. No difference for eosinophil-derived neurotoxin in stool was detected. CONCLUSION: A nutritional intervention based on circulating IgG antibodies against food antigens showed effects with respect to stool frequency. The mechanisms by which IgG antibodies might contribute to disease activity remain to be elucidated.

[19-year-old kick-boxer with hematemesis and splenomegaly]. / 19-jähriger Kampfsportler mit Hämatemesis und Splenomegalie.

Traumatic portal vein thrombosis is a rare cause of nonmalignant, noncirrhotic portal hypertension. We report a case of a 19-year old patient, who presented with variceal bleeding and splenomegaly. Diagnosis was based on the history of kickboxing and an otherwise negative etiological investigation. The patient underwent endoscopic therapy and portosystemic shunt operation (Warren-shunt) due to cavernous transformation and severe hypersplenism. Thereafter the patient remained asymptomatic.

Contrast-enhanced ultrasound in diagnosing liver malignancy.

PURPOSE: The use of contrast enhancers has widened the possibilities of sonographic imaging, and allows the differentiation of characteristic enhancement patterns leading to diagnosis in focal liver lesions. The aim of our study was to evaluate contrast ultrasound signs in diagnosing malignant liver lesions. METHODS: 86 patients with 100 solid liver lesions were enrolled. A baseline gray-scale sonogram was obtained with a multifrequency 4 C convex array probe, followed by contrast-enhanced sonography with a low mechanical index (<0.2) over 300 seconds. Final diagnosis was confirmed by histology or in case of haemangioma by CT/NMR and quantitative contrast harmonic imaging (CHI) with perfusion analysis (contrast). RESULTS: 55 malignant (6 HCC, 46 secondary malignant lesions - 3 of them lymphoma, 3 cholangiocarcinoma), and 45 benign lesions (8 FNH, 1 von Meyenburg complex, 1 granuloma, 3 adenoma, 21 hemangioma, 2 focal fat storage imbalances, 7 abscesses, one scar, and in one case normal liver) were found. 51/55 malignant (all but one filia and three HCC), but also 17/45 benign lesions showed hypoperfusion in the late phase. The ultrasound pattern in the arterial phase differed in malignant lesions: 22 lesions were initially hypervascular, 20 had rim enhancement and in 13 lesions there was a non-specific vascularisation. In all but one malignant lesion a diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue was observed. Only three benign lesions with this later sign were falsely diagnosed as malignant: one adenoma, one epitheloid granuloma, and a scar. Quantitative perfusion pattern was analyzed exemplary. Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue as a sign for malignancy had a positive predictive value of 95%, a sensitivity of 98%, a negative predictive value of 98%, and a specificity of 93%. CONCLUSIONS: Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue is a helpful sign in contrast enhanced ultrasound to diagnose malignancies.

Fatty acids as metabolic mediators in innate immunity.

BACKGROUND: Increasing data support the hypothesis of a local and systemic crosstalk between adipocytes and monocytes mediated by fatty acids. The aim of this study was to characterize the immunomodulatory effects of a large panel of fatty acids on cytokines and chemokines in monocytic THP-1 cells and primary human monocytes. We tested whether anti-inflammatory fatty acids are able to inhibit the binding of lipopolysaccharide (LPS) to its receptor, toll-like receptor/MD-2 (TLR4/MD-2). MATERIALS AND METHODS: Resistin, monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor (TNF) were measured by enzyme-linked immunosorbent assay. Proteins were analysed by Western blot. A designed Flag-tagged TLR4/MD-2 fusion protein (LPS trap) was used to investigate the effect of fatty acids on binding of LPS to its receptor. In 30 patients with type 2 diabetes mellitus (T2D), the correlation of serum triglyceride levels with LPS-induced monocyte activation was analysed. RESULTS: Eleven fatty acids investigated exerted differential effects on the monocytic release of cytokines and chemokines. Eicosapentaenoic acid had potent anti-inflammatory effects on human primary monocytes and THP-1 cells; 100 and 200 microM eicosapentaenoic acid dose-dependently inhibited LPS binding to the LPS trap. LPS-induced release of monocytic MCP-1 and TNF was significantly and positively correlated with serum triglyceride levels in 30 patients with T2D. CONCLUSIONS: Monocytic activation is differentially regulated by fatty acids and depends on triglyceride levels in T2D. The main finding of the present study shows that eicosapentaenoic acid inhibits the specific binding of LPS to TLR4/MD-2. Eicosapentaenoic acid represents a new anti-inflammatory LPS-antagonist.