Relevance of surgery in patients with non-variceal upper gastrointestinal bleeding.

INTRODUCTION: Upper GI bleeding remains one of the most common emergencies with a substantial overall mortality rate of up to 30%. In severe ill patients, death does not occur due to failure of hemostasis, either medical or surgical, but mainly from comorbidities, treatment complications, and decreased tolerated blood loss. Management strategies have changed dramatically over the last two decades and include primarily endoscopic intervention in combination with acid-suppressive therapy and decrease in surgical intervention. Herein, we present one of the largest patient-based analysis assessing clinical parameters and outcome in patients undergoing endoscopy with an upper GI bleeding. Data were further analyzed to identify potential new risk factors and to investigate the role of surgery. PATIENTS AND METHODS: In this retrospective study, we aimed to analyze outcome of patients with an UGIB and data were analyzed to identify potential new risk factors and the role of surgery. Data collection included demographic data, laboratory results, endoscopy reports, and details of management including blood administration, and surgery was carried out. Patient events were grouped and defined as "overall" events and "operated," "non-operated," and "operated and death" as well as "non-operated and death" where appropriate. Blatchford, clinical as well as complete Rockall-score analysis, risk stratification, and disease-related mortality rate were calculated for each group for comparison. RESULTS: Overall, 253 patients were eligible for analysis: endoscopy was carried out in 96% of all patients, 17% needed surgical intervention after endoscopic failure of bleeding control due to persistent bleeding, and the remaining 4% of patients were subjected directly to surgery. The median length of stay to discharge was 26 days. Overall mortality was 22%; out of them, almost 5% were operated and died. Anticoagulation was associated with a high in-hospital mortality risk (23%) and was increased once patients were taken to surgery (43%). Patients taking steroids presented with a risk of death of 26%, once taken to surgery the risk increased to 80%. Patients with liver cirrhosis had a risk of death of 42%; we observed a better outcome for these patients once taken to theater. Clinically, once scored with Blatchford score, statistical correlation was found for initial need for blood transfusion and surgical intervention. Clinical as well as complete Rockall score revealed a correlation between need for blood transfusion as well as surgical intervention in addition with a decreased outcome with increasing Rockall scores. Risk factor analysis including comorbidity, drug administration, and anticoagulation therapy introduced the combination of tumor and non-steroidal antirheumatic medication as independent risk factors for increased disease-related mortality. CONCLUSION: UGIB remains challenging and endoscopy is the first choice of intervention. Care must be taken once a patient is taking antirheumatic non-steroidal pain medication and suffers from cancer. In patients with presence of liver cirrhosis, an earlier surgical intervention may be considered, in particular for patients with recurrent bleeding. Embolization is not widely available and carries the risk of necrosis of the affected organ and should be restricted to a subgroup of patients not primarily eligible for surgery once endoscopy has failed. Taken together, an interdisciplinary approach including gastroenterologists as well as surgeons should be used once the patient is admitted to the hospital to define the best treatment option.

Measuring the effect of a study meal on portal concentrations of glucagon-like peptide 1 (GLP-1) in non diabetic and diabetic patients with liver cirrhosis: transjugular intrahepatic portosystemic stent shunt (TIPSS) as a new method for metabolic measurements.

BACKGROUND: Diabetes in liver cirrhosis is associated with a blunted insulin response, which might be explained by an impaired release of the incretin hormone glucagon-like peptide 1 (GLP-1) into the portal circulation. AIMS: To investigate basal and stimulated portal venous and peripheral GLP-1 concentrations in non-diabetic (ND) and diabetic (D) patients with liver cirrhosis undergoing transjugular intrahepatic portosystemic stent shunt (TIPSS) implantation. PATIENTS AND METHODS: After elective TIPSS portalvenous and peripheral probes were drawn from 10 ND and 10 D patients with stable liver disease during an oral metabolic test and plasma glucose, immunoreactive GLP-1, insulin and C-peptide were measured. RESULTS: The study meal led to a significant rise in portal GLP-1 levels in ND and D. Basal and stimulated portal GLP-1 concentrations were not significantly different between ND and D. Peripheral GLP-1 did not differ significantly from portal venous levels. Insulin response in ND was more pronounced in the portal blood than in the periphery and was absent in D. CONCLUSION: TIPSS allows a direct evaluation of hormonal changes in the portal circulation during an oral metabolic tolerance test. A disturbed GLP-1 secretion does not play a role in blunting the insulin response observed in patients with hepatogenous diabetes.

Active matrix metalloproteinase-8 and periodontal bacteria-interlink between periodontitis and inflammatory bowel disease?

BACKGROUND: The aim of this study was the investigation of concentration and prevalence of selected periodontal pathogenic bacteria and concentration of active matrix metalloproteinase-8 (aMMP-8) within a group of patients with inflammatory bowel diseases (IBD) and to compare the results with a group of healthy control subjects (HC). METHODS: Fifty-nine IBD patients with Crohn`s disease (CD, n = 30) or ulcerative colitis (UC, n = 29) and 59 HC were included in this cross-sectional study. Based on periodontal probing depth (PD) and clinical attachment level (CAL), periodontitis was classified as healthy/mild, moderate, or severe. aMMP-8 was analyzed from gingival crevicular fluid using enzyme linked immunosorbent assay. Eleven selected periodontal pathogenic bacteria were analyzed in subgingival plaque samples using polymerase chain reaction. RESULTS: IBD patients showed higher CAL (P < 0.01), more severe periodontitis (P = 0.04), gingival bleeding (P < 0.01) and aMMP-8 concentration (P < 0.01) than HC. Only in CD, increasing severity of periodontitis was associated with an increase in aMMP-8 concentration (P = 0.02). The prevalences of Eubacterium nodatum and Eikenella corrodens were significantly lower in IBD compared to HC (P = 0.01). Additionally, the prevalence of Eikenella corrodens was significantly higher in CD compared to the UC group (P = 0.04). Further statistically significant differences in selected bacteria between IBD and HC or CD and UC groups could not be found (P > 0.05). CONCLUSIONS: The results reveal changes in host immune response of IBD patients in terms of aMMP-8. Only in CD increasing aMMP-8 was associated with severity of periodontal disease. The role of periodontal pathogenic bacteria in the interrelationship between IBD and periodontitis remains unclear.

EndoBarrier Gastrointestinal Liner in Type 2 Diabetic Patients Improves Liver Fibrosis as Assessed by Liver Elastography.

Many obese people with type 2 diabetes develop non-alcoholic fatty liver disease, which may progress to liver fibrosis. EndoBarrier gastrointestinal liner is an innovative interventional treatment option for type 2 diabetic patients, which could affect diabetes associated liver disease. The aim of this retrospective study was to analyze the effect of 1-year EndoBarrier therapy on liver fibrosis and steatosis. As an indicator of fibrosis, liver stiffness was assessed by liver elastography at baseline, 2 weeks after EndoBarrier implantation and then every 3 months until explantation. 13/19 patients had elevated liver stiffness at baseline, corresponding to liver fibrosis grade 2 to 4. In these patients, liver stiffness reduced significantly during EndoBarrier therapy from 10.4 kPa (IQR 6.0-14.3) at baseline to 5.3 kPa (IQR 4.3-7.7, p<0.01) by the time of EndoBarrier explantation, corresponding to a normalization of the initially pathologic findings in most patients. Liver steatosis was also assessed by elastographic measurements in terms of the controlled attenuation parameter. In all patients, baseline measurements showed high grade steatosis. Improvements were seen from initially 343 dB/m (IQR 326-384) to 317 dB/m (IQR 269-375, p<0.05) by the time of explantation. However, most patients were still classified high grade steatosis after completion of EndoBarrier treatment. In this observational study, we show that liver fibrosis is a common condition in obese patients suffering from type 2 diabetes, and that EndoBarrier gastrointestinal liner substantially improves liver fibrosis in these patients.

Fasting hyperglucagonemia in patients with transjugular intrahepatic portosystemic shunts (TIPS).

BACKGROUND: Hyperglucagonemia has been described to be associated with insulin resistance in patients with liver cirrhosis. Portosystemic shunts may be involved in the etiology of hyperglucagonemia. To test this hypothesis we investigated fasting peripheral plasma glucagon levels before and after portal decompression by transjugular intrahepatic portosystemic shunting (TIPS). METHODS: Glucagon, insulin, plasma glucose, HbA1c, and C-peptide were determined in peripheral venous samples from 21 non-diabetic (ND)- and 15 diabetic patients (D; 3 treated with insulin, 3 with sulfonylurea, 9 with diet alone) with liver cirrhosis, showing comparable clinical features (gender, age, BMI, creatinine, Child-Pugh-score, complications, and etiology of liver cirrhosis) before, 3 and 9 months after elective TIPS implantation. Insulin resistance was calculated as R (HOMA) according to the homeostasis model assessment (HOMA). RESULTS: Glucagon levels before TIPS were elevated in patients with diabetes compared to patients without diabetes (D: 145.4 +/- 52.1 pg/ml vs. ND: 97.3 +/- 49.8 pg/ml; p = 0.057). 3 and 9 months after TIPS implantation glucagon levels increased significantly in ND (188.9 +/- 80.3 pg/ml and 187.2 +/- 87.6 pg/ml) but not in D (169.6 +/- 62.4 pg/ml and 171.9 +/- 58.4 pg/ml). While plasma glucose, HbA1c, and C-peptide were significantly higher in D than in ND, they did not change significantly 3 and 9 months after TIPS implantation. Insulin was increased in D before TIPS (D: 31.6 +/- 15.9 mU/l vs. ND: 14.8 +/- 7.1 mU/l; p = 0.0001). 3 and 9 months after TIPS insulin significantly increased in ND (26.6 +/- 14.7 mU/l and 23.2 +/- 10.9 mU/l vs. 14.8 +/- 7.1 mU/l before TIPS) but not in D. In ND R (HOMA) also increased from 3.5 +/- 2 mU x mmol/l(2) to 5.7 +/- 3.3 mU x mmol/l(2) after 3 and 5.4 +/- 2.6 mU x mmol/l(2) after 9 months. BMI, liver and kidney function did not change with time. CONCLUSION: In non-diabetic cirrhotic patients TIPS implantation is followed by an increase of glucagon. However, this does not result in a worsening of glycemic control, probably because of a simultaneous increase of insulin.

Presentation, treatment, and prognosis of idiopathic inflammatory muscle disease in a rural hospital.

Twenty-seven adult patients with dermatomyositis or polymyositis were retrospectively evaluated over a mean of four and a half years. Eighty-five percent (23) met the suggested criteria of Bohan and Peter (New England Journal of Medicine, 1975) for definite or probable disease, while 15 percent had possible disease. Upper and lower limb girdle strength was given a value (0 to 5) and averaged. Initially, 26 percent were severely weak and 59 percent moderately weak. All patients were treated with steroids. Within three months, 64 percent had little to no weakness and no patients were severely impaired. These proportions remained relatively constant throughout the study. Eight less severely ill patients received alternate-day prednisone. Only two still require treatment; the remainder have been in remission for a mean period of 19 months. Of 19 who received daily prednisone, five also required cytotoxic drugs and 11 still require treatment. A comparison of the results of this study with those of major urban referral centers reveals that the patients in this study constituted a generally less ill population with a better prognosis. Forty-one percent (11) of patients were able to discontinue all forms of therapy and remain in remission. Thirty percent (eight) achieved remission with only alternate-day steroid therapy, an approach that has been discouraged in the past. Two patients (7 percent) had overt malignancies within one year before to three years after diagnosis of myositis. However, in no instance did a search for occult malignancy give positive results. Cancer detection was accomplished by following clues from history and physical examinations. It is questioned whether extensive evaluations for occult malignancies in patients with idiopathic myositis are cost-effective.

Systemic steroid therapy for acute gout: a clinical trial and review of the literature.

Nonsteroidal antiinflammatory drugs are frequently used as initial therapy in acute gout. In select cases, however, colchicine has been recommended as an alternative therapy. A review of the literature raises significant concerns regarding the cost to benefit ratio of using colchicine in this setting. A survey of alternative forms of therapies showed few studies investigating the efficacy and side effects of a short course of oral steroids, and little support for this modality in standard textbooks. Our preliminary study suggests that a short course of oral corticosteroid therapy can be used effectively for acute gout when NSAIDs are contraindicated. The use of prednisone 30 to 50 mg or its equivalent initially, and gradually tapered over 10 days, results in clinical resolution without rebound arthropathy or steroid complications in most patients. As a result, we rarely use colchicine in the management of acute gout in our practice.

Glucocorticoid receptor expression in inflammatory bowel disease: evidence for a mucosal down-regulation in steroid-unresponsive ulcerative colitis.

BACKGROUND: Glucocorticoids (GC) play a major role in the attenuation of inflammation. Glucocorticoid receptor (GR) expression is an important determinant of steroid sensitivity. AIMS: To investigate whether GR mRNA expression is altered in inflammatory bowel disease, and whether GR mRNA expression correlates with disease activity and may predict response to GC therapy. METHODS: Mucosal biopsies were taken from 33 patients with ulcerative colitis, 21 with Crohn's disease and 11 controls. Peripheral blood mononuclear cells were isolated from 24 ulcerative colitis and 18 Crohn's disease patients and 11 controls. GR mRNA was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), and correlated to endoscopic findings, clinical activity and outcome of GC therapy. In a subset of subjects GR localisation was shown by immunohistochemistry. RESULTS: In patients with inflammatory bowel disease GR expression was not different from controls. However, GR was decreased in biopsies from ulcerative colitis patients with impaired GC response. The inhibitory subtype GRbeta was expressed 100-1000 times lower than GRalpha. GR immunoreactivity was identified in immune and epithelial cells except for colonic crypts. CONCLUSION: In inflammatory bowel disease systemic and mucosal GR mRNA expression is not altered. However, in ulcerative colitis patients, low mucosal GR expression may predict the outcome of GC therapy. The low expression of GRbeta challenges its role in steroid refractoriness in inflammatory bowel disease.

99mTC-labelled antigranulocyte monoclonal antibody FAB' fragments versus echocardiography in the diagnosis of subacute infective endocarditis.

OBJECTIVE: We performed this pilot study to gain first clinical data of immunoscintigraphy with 99mTc-labelled anti-NCA-90 antigranulocyte antibody Fab' fragments (99mTc-Fab' (LeukoScan((R)))) in endocarditis. PATIENTS AND METHODS: 99mTc-Fab' and echocardiography were used in 24 consecutive patients with suspected endocarditis. Nuclear medicine imaging was performed after i.v. injection of 925 MBq 99mTc-Fab' fragments and evaluation was done by region of interest (ROI) technique and visually. RESULTS: Seven patients were found to have endocarditis on the basis of the revised Duke criteria, which served as gold standard. Initial scintigraphy was true positive in five patients and false positive in one. In the five true positives, T/B ratios in projection to the heart valve plane (with T/B>/=1.3+/-0.072) were highly suspicious for florid endocarditis. TTE and TEE were true positive in two and in six patients, whereas false positives were seen in two and in four patients. Scintigraphy was positive in four of the five patients with the false negative TTE and negative in the three false positive TEE. Vice versa, TEE was positive in the two patients with false negative scintigraphy. CONCLUSIONS: Immunoscintigraphy with 99mTc-Fab' fragments in combination with TEE improves diagnostic accuracy compared with TTE/TEE in patients with subacute infective endocarditis.

[Improved detection of gastrointestinal bleeding sites with 99mTc market autologous erythrocytes and continuous dynamic scintigraphy with cine-mode display]. / Verbesserter Nachweis gastrointestinaler Blutungsquellen mit 99mTc-markierten autologen Erythrocyten und kontinuierlicher dynamischer Szintigraphie mit Cine-mode-Befundung.

BACKGROUND: Scintigraphic studies of gastrointestinal bleeding are usually performed in static acquisition mode and without continuous imaging over a longer period. The aim of this study was to evaluate the diagnostic accuracy of continuous dynamic 99mTc red blood cell scintigraphy (BQS) and cine-mode display in the assessment of unexplained gastrointestinal bleeding. PATIENTS AND METHODS: We performed BQS in 40 patients (mean age 57 years) with gastrointestinal bleeding from an undetermined source. All these patients had negative findings of previous examinations. Blood transfusions were required in 16 patients. Continuous dynamic scintigraphic acquisition was performed up to 6 h post injection (p.i.). The scintigraphic data were reviewed without knowledge of the patient's final diagnosis. For this purpose we used a cine-mode display. RESULTS: Dynamic 99mTc red blood cell scintigraphy correctly identified the site of active bleeding in 22 of 23 patients with positive scintigraphic findings. The sensitivity of the scan was 95%, the specificity 94%, the positive and negative predictive values 95% and 94%, respectively. Forty-three percent of the scans became positive within 1.5 h and 82% within 5 h. Positive scans were more likely in patients who required blood transfusions than in patients without transfusion requirement (16 vs 7 patients), and the bleeding site was identified earlier in the former group (mean 2.83 vs 5.28 h p.i.). The scintigraphic identification of the bleeding lesions enabled the performance of a more limited surgical approach in the colon as well as in the distal small intestine, while exact scintigraphic localization was not possible if the bleeding site was located in the proximal small intestine. DISCUSSION: Continuous dynamic 99mTc red blood cell scintigraphy interpreted by cine-mode display is highly accurate in the identification of a bleeding site. When performed correctly, scintigraphy enables usually segmental resection of these lesions.

CD4+ immune response as a potential biomarker of patient reported inflammatory bowel disease (IBD) activity.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) which are characterized by dysfunctional regulation of the immune system. A number of immune modifying drugs are used to treat CD and UC. Therapy is adjusted largely on the bases of subjective reports of disease activity and non-specific laboratory tests. Identification of a single or combination of immune markers of disease activity could be useful to select and monitor therapeutic responses. However, to date no reliable quantitative associations between IBD activity and laboratory measures of immune function have been identified. This study was designed to evaluate the usefulness of a commercially available laboratory measure of CD4(+) immune function, the Cylex® ImmuKnow®, as a surrogate marker of IBD activity. METHODS: Adult IBD patients with either CD (N=55, 27 males, mean, SD age=38.5, 11.5 years) or UC (N=45, 24 males, mean, SD age=41.7, 15.4 years) were enrolled. Patients both in clinical remission and with active disease provided responses to structured, validated questionnaires (CDAI and HBI for CD patients and SCCAI for UC patients) used to monitor IBD activity. Whole blood and plasma samples were collected to quantify various markers of disease status including routine cell counts and differentials (CBCs), CRP, and albumin (Alb), as well as CD4(+) immune response (Cylex® ImmuKnow®, N=98). Results were compared between all IBD patients as well as between CD and UC subgroups. RESULTS: There was a good correlation between the results of CDAI and HBI scores (r=0.811, p<0.01, Spearman-Rho) but HBI scores correlated slightly better (r=0.575, p<0.001) than the CDAI's (r=0.449, p=0.001) with CD patients' reported perception of their general condition. CDAI and HBI scores categorized 12/55 versus 36/55 of CD patients respectively as having active disease. SCCAI scores indicated that 25/45 of UC patients had active disease. Cylex® results (in ng/mL of ATP) were increased in 74/98 IBD subjects (≥525 ng/mL) but were influenced by the use of systemic corticosteroids (SCS) and infliximab. There were weak but statistically significant Spearman-Rho correlations between Alb concentrations and both CDAI (r=0.413, p=0.002) and HBI (r=0.325, p=0.017) scores as well as between CRP values and HBI scores (r=0.331, p=0.016). Correlations between CRP and both CDAI and SCCAI scores and between Alb and SCCAI scores were not significant and there were no significant positive associations between any of the three clinical scores and Cylex® results. CONCLUSIONS: CD4(+) immune responses were significantly elevated in IBD patients whether or not they were in clinical remission but were influenced by treatment. There were some significant correlations between the clinical scores and CRP or Alb but not with the CD4(+) results. Both other clinical scoring systems, other measures of immune function, and CD4(+) immune response changes over time should be examined to see if this or other laboratory measures of immune response are predictive of actual disease activity or symptoms in CD or UC patients.

Carbohydrate metabolism and the liver: actual aspects from physiology and disease.

The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range. This is achieved by a tightly regulated system of enzymes and kinases regulating either glucose breakdown or synthesis in hepatocytes. This process is under the control of glucoregulatory mediators among which insulin plays a key role. In type 2 diabetes, as well as in liver disease, alterations in hepatic glucose metabolism like an increased post-absorptive glucose production together with diminished glucose uptake following carbohydrate ingestion occur, implying insulin resistance as a central pathological principle. Knowledge of the processes involved in maintaining glucose homeostasis as well as insulin resistance is a prerequisite to develop new therapeutic approaches in diabetes as well as in liver disease. In the recent years, genetically-altered mouse models that have helped to identify enzymes, transcription factors and mediators that are essential for maintaining glucose homeostasis in the liver and provide a valuable tool to study carbohydrate metabolism in liver disease. In this current review, genetically manipulated animals either overexpressing or lacking key gluconeogenic enzymes, hepatic transcription factors, IGF-1, hepatic insulin receptors, adipokines and hepatitis C core antigen will be discussed in the context of human disease.

Increased number of mature dendritic cells in Crohn's disease: evidence for a chemokine mediated retention mechanism.

BACKGROUND AND AIMS: Activation of T cells by dendritic cells (DC) is thought to play a pivotal role in induction and maintenance of Crohn's disease. Detailed analyses however concerning the phenotype and maturation of DC as well as the mechanisms underlying their recruitment are still lacking for Crohn's disease. METHODS: Different myeloid and plasmacytoid DC subsets were characterised by immunohistochemistry. Expression of the so-called "lymphoid" chemokines CCL19, CCL20, and CCL21 was determined by real time reverse transcription-polymerase chain reaction in Crohn's disease and normal controls. Furthermore, expression of CCL19, CCL20, and CCL21 as well as their receptors CCR6 (for CCL20) and CCR7 (for CCL19 and CCL21) was characterised by immunohistochemistry and, in addition, their cellular localisation was determined by double immunofluorescence investigations. RESULTS: Colonic tissue affected by Crohn's disease was characterised by an increased number of mature myeloid DC forming clusters with proliferating T cells. In keeping with their advanced maturation, DC possess the chemokine receptor CCR7. Increased expression of the CCR7 ligands CCL19 by DC themselves as well as CCL21 by reticular cells and lymphatic vessels was observed in Crohn's disease, thereby causing the matured DC to be trapped at the site of inflammation. CONCLUSION: Our results demonstrate that autocrine and paracrine actions of lymphoid chemokines in Crohn's disease may lead to increased numbers of mature DC away from their usual migration to lymphoid organs and result in the development of a tertiary lymphatic tissue within the bowel wall maintaining the autoimmune inflammation in Crohn's disease.

Septic bursitis: presentation, treatment and prognosis.

Forty-nine episodes of septic bursitis in 45 patients were reviewed. Our experience concurs with previous studies: (1) the most frequently involved sites were the olecranon (63%) and prepatellar (27%) bursae; (2) Staphylococcus aureus was the commonest pathogen (78%); (3) skin breakage, trauma and/or occupational risk factors were significantly associated with infections (74 and 92% of olecranon and prepatellar episodes, respectively); (4) bursal fluid white blood cell (WBC) counts varied widely (350-392,500 WBC/mm3); and (5) a significant number of patients failed to respond to initial oral antibiotics. In addition to these points, we have been impressed with several clinical observations that merit special emphasis: (1) cellulitis adjacent to the affected bursae was frequent (89%) and often extensive; (2) profound edema occurred in 11% of affected limbs; (3) clinical resolution was slow, occurring at a mean of greater than 5 weeks, but at times requiring as long as 20 weeks to return to baseline status.

Glucocorticoid receptor signaling in the intestinal epithelial cell lines IEC-6 and Caco-2: evidence of inhibition by interleukin-1beta.

BACKGROUND AND AIMS: Glucocorticoids are potent anti-inflammatory drugs widely used in the treatment of inflammatory bowel disease, but many patients do not benefit from glucocorticoid therapy (glucocorticoid resistance) or need inappropriately high doses to retain remission (glucocorticoid dependency). Because of the role of intestinal epithelial cells in inflammatory bowel disease we examined glucocorticoid receptor signaling and the effect of interleukin-1beta as one of the main proinflammatory cytokines in the intestinal epithelial cell lines IEC-6 and Caco-2. METHODS: Dexamethasone effects on transcriptional activation was measured by reporter gene assay using a construct containing glucocorticoid-responsive elements. The transrepressive effect was monitored by a nuclear factor (NF) kappaB inducible reporter construct. In addition in IEC-6 cells immuncytochemistry was used to monitor glucocorticoid receptor translocation. RESULTS: Dexamethasone induced receptor-mediated reporter gene transcription and receptor translocation, while interleukin-1beta significantly inhibited dexamethasone effects. Dexamethasone inhibited interleukin-1beta induced, NF-kappaB driven gene transcription only in IEC-6 and not in Caco-2 cells. However, in Caco-2 cells glucocorticoid receptor overexpression resulted in a marked decrease in NF-kappaB activity even in absence of dexamethasone. CONCLUSIONS: These studies demonstrate that glucocorticoid receptor driven gene regulation in intestinal epithelial cells may contribute to the anti-inflammatory effects of glucocorticoids in inflammatory bowel disease. Our data are consistent with the notion that interleukin-1beta produced during inflammatory response induces steroid resistance, which is a common clinical problem in treating patients with inflammatory bowel disease.

Subcellular distribution of glucocorticoid receptor in cultured rat and human liver-derived cells and cell lines: influence of dexamethasone.

Glucocorticoid receptor (GR) distribution in isolated rat hepatocytes and nonparenchymal hepatic stellate cells, Kupffer cells, and liver fibroblasts with and without dexamethasone treatment was investigated by immunostaining and confocal laser scanning microscopy. In addition, human liver fibroblasts, Hep3B and HepG2 cells were investigated. Subcellular distribution of GR immunostaining was assessed semiquantitatively by digital image analysis. Short-term incubation of rat liver cells with dexamethasone resulted in an increase of nuclear staining. The same was true for human liver fibroblasts. In contrast, predominant nuclear staining could be observed in untreated as well as in dexamethasone-treated Hep3B and HepG2 cells. By means of reverse-transcription polymerase chain reaction, it could be shown that messenger RNA of both known human GR isoforms, hGR alpha and nonhormone-binding hGR beta, are present in human cells. Furthermore, dexamethasone binding indicates that hGR alpha protein is expressed in all human cells investigated. The data of this study show that GR is present in all cells investigated. Rat liver cells and human liver fibroblasts contain a translocating GR, suggesting that glucocorticoid action is receptor mediated in these cells. Nuclear localization of unliganded GR in Hep3B and HepG2 indicates that factors other than glucocorticoids may direct subcellular GR distribution.

Acute polyarticular gout.

We report here on 41 male patients with acute polyarticular gout seen in 3 years. Acute polyarticular gout continues to masquerade as other commoner rheumatological disorders such as septic arthritis, rheumatoid arthritis, degenerative joint disease, and even hemiparesis. Almost all of these patients had clues to the diagnosis of acute gout in their medical history. These clues included a past history of intermittent acute gout, prior attacks of polyarticular arthritis, previous hyperuricaemia, and/or obvious tophi. The patients all responded promptly to nonsteroidal anti-inflammatory drugs. We observed serious toxic drug reactions in 8 patients.

Antigen-induced experimental septic arthritis in rabbits after intraarticular injection of Staphylococcus aureus.

With the Dumonde-Glynn model of antigen-induced arthritis, a rabbit model was developed to examine the histopathologic differences between normal and arthritic joints in the same animal infected by intraarticular injections of Staphylococcus aureus. Microscopic examination of whole joint sections and a quantitative histopathologic scale were used to compare changes in all the articular components of 17 normal and 17 arthritic joints infected for less than two weeks. The histological changes were more severe in infected arthritic joints than in infected normal joints (mean +/- SD total histology score, 13.8 +/- 2.4 and 9.3 +/- 4.0, respectively; P less than .001). In infected arthritic joints, subsynovial abscesses extended into subchondral bone via the pannus of chronic synovitis at articular margins and intraarticular attachments of cruciate ligaments, rather than by initial cartilage destruction and direct extension into subchondral bone.

HFE genotype and parameters of iron metabolism in German first-time blood donors - evidence for an increased transferrin saturation in C282Y heterozygotes.

BACKGROUND: Hemochromatosis is usually inherited in an autosomal recessive mode and associated with missense mutations in the hemochromatosis gene (HFE), an HLA class 1 related gene. However the degree of penetrance is presently matter of debate. METHODS: To elucidate the frequency of HFE mutations in a German population and the relationship between genotype and phenotype, we determined the HFE C282Y and H63D genotypes in 500 first-time blood donors using an allele-specific ligase chain reaction (LCR). Ferritin and transferrin saturation (TS) of all donors found to have at least one mutation were compared to gender- and age-matched controls. RESULTS: The C282Y allele frequency was 46 in 1000 chromosomes (4.6 %). The allele frequency of H63D was 108 in 1000 (10.8 %) chromosomes. We found three persons homozygous for H63D, nine compound heterozygotes and none homozygous for C282Y. TS was elevated in C282Y heterozygotes (p = 0.002) and C282Y/H63D compound heterozygotes (p = 0.04) compared to wild-type controls. Serum ferritin tended to be elevated in compound heterozygotes (p = 0.053). Mean corpuscular volume (MCV) and hemoglobin (MCH) were not different from controls. CONCLUSION: The frequency of HFE mutations in the tested population was comparable to those of other northern European populations. The elevated TS in subjects carrying a single copy of the C282Y mutation suggests that C282Y heterozygosity is associated with an increased intestinal iron absorption and might therefore offer a selection advantage in conditions of iron depletion.

Effect of heparin and liver heparan sulphate on interaction of HepG2-derived transcription factors and their cis-acting elements: altered potential of hepatocellular carcinoma heparan sulphate.

Proteoglycan assembly in malignant tumours is subject to profound changes. The significance of these alterations is not well understood; especially, their role in nuclear regulation is a topic for debate. The capacity of heparin and liver carcinoma heparan sulphate (HS) to alter DNA-transcription factor interactions has been studied to provide further evidence concerning the regulatory potential of glycosaminoglycan (GAG) in the nucleus. Experiments both in vitro and in vivo indicated that heparin and HS are capable of inhibiting the interaction of transcription factors with their consensus oligonucleotide elements. Among five transcription factors studied, AP-1, SP-1, ETS-1 and nuclear factor kappaB proved to be sensitive to heparin and heparan sulphate, whereas TFIID was hardly inhibited in either in vitro or in vivo systems. Interestingly, HS from peritumoral liver was five times more effective than heparin. Liver carcinoma HS was less effective than liver HS, but its activity was comparable with that of heparin. These results indicate that the structural differences of GAG chains strongly influence their biological behaviour. The loss of their recognized functional activity in malignant tumours might promote the development of uncontrolled growth and gene expression favouring the neoplastic process.