Glucocorticoid resistance is a serious clinical problem in chronic inflammatory diseases, because many patients with rheumatoid arthritis, asthma, or Crohn's disease fail to respond to steroid treatment. The molecular mechanisms underlying this unresponsiveness, however, are completely unknown. The effects of steroids are largely mediated by the interference of the glucocorticoid receptor (GR) with proinflammatory transcription factors. In the present study, we therefore investigated the activation of the transcription factors nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and the upstream kinases p38 and c-Jun N-terminal kinase (JNK) in steroid-sensitive and steroid-resistant patients with Crohn's disease. We demonstrated that steroid-sensitive and steroid-resistant patients reveal a remarkably different cellular activation pattern of these proinflammatory mediators. In steroid-sensitive patients, activation of NF-kappaB, AP-1, p38, and JNK was mainly found in lamina propria macrophages. In contrast, steroid-resistant patients revealed activation of all these mediators mostly in epithelial cells. The functional interference of the proinflammatory mediators with the glucocorticoid response was supported by reporter gene assays. Expression of NF-kappaB and, interestingly, also JNK1 and p38 inhibited the activity of the GR. Thus, our results suggest that steroid resistance is associated with increased epithelial activation of stress-activated protein kinases and NF-kappaB, which might inhibit the anti-inflammatory action of a limited number of GRs.

Both health-related and general life satisfaction is compromised in IBD outpatients, and health-related topics have major impact. Not surprisingly, inflammatory activity compromises QOL, which underlines the importance of anti-inflammatory strategies. The importance attributed to health-related features is higher in IBD patients than in the normal population.

Camptocormia is characterized by an abnormal posture of the trunk with pronounced flexion of the thoraco-lumbar spine during standing and walking, which abates in a supine position. Treatment options for camptocormia are limited and mostly futile. Here, we report on the ultrasound-guided ventral injection of botulinum toxin A (BTX) into deep portions of the iliopsoas muscle in four parkinsonian patients with camptocormia as chief complaint. Using this novel and safe application technique, all patients received 500-1,500 MU of BTX per side in 4-6 month intervals. Treatment was generally well tolerated. At the highest dose, all patients complained of mild weakness of hip flexion. Standardized physical exam at follow-up visits, as well as self-assessment of patients, failed to show a relevant and lasting improvement of posture. In conclusion, injection of BTX into the iliopsoas does not appear to be a promising approach for the treatment of parkinsonism-associated camptocormia.

Cutaneous leishmaniasis (CL) caused by Leishmania aethiopica is rarely encountered outside disease-endemic areas and there have been no clinical trials evaluating its pharmacotherapy. Under resource limited conditions, antiparasitic treatment of L. aethiopica infection relies largely on pentavalent antimonials. However, treatment failure is frequent and systemic application of these drugs is potentially harmful. [1][2][3][4] Evidence for the efficacy of less adverse chemotherapeutics is needed. We report treatment of CL caused by L. aethiopica using liposomal amphothericin B (LAmB) outside a diseaseendemic region.A 38-year-old man from Eritrea and a permanent resident in Germany over the past 22 years had a 6 × 5 cm skin lesion over his left zygomatic bone. Eleven months earlier, he had returned from a one-year stay in Eritrea where he had visited the coastal area of Asmara and the highlands of the Debub Region. Without an obvious reason, he had stopped taking methotrexate and leflunomid for treatment of rheumatoid arthritis during his stay abroad. Because of increasing inflammation of his left ankle and wrist after returning to Germany, the patient had been treated with infliximab, methotrexate, and prednisolone over the past six months. Two weeks after initiation of this regimen, he recognized a small papule on his left cheek that had gradually progressed to a large lesion seen at the time of hospitalization ( Figure 1A ).Skin biopsy specimens for histologic anlaysis and culture were obtained. Microscopically, a chronic lympho-plasmacellular infiltration with increased content of eosinophilic granulocytes was dominant. Amastigote Leishmania or granulomata were not present. Specific staining results for fungi and mycobacteria were negative, and cultures did not demonstrate Leishmania .However, sequences specific for Old World species could be detected in extracted DNA.5 For species differentiation, we amplified and sequenced the ribosomal internal transcribed spacer region 1 separating the 18S and 5.8S ribosomal RNA genes, which showed infection with L. aethiopica (GenBank accession no. FN252411).6, 7 IgG against recombinant rK39 antigen (immunochromatographic test) and a low positive IgG titer of 1:80 against L. donovani promastigote antigens (indirect immunofluorescence test, cutoff value = 1:40) were detected. An abdominal ultrasound scan, a full blood count, and a polymerase chain reaction for Leishmania spp. from the buffy coat did not suggest visceral disease.We stopped treatment with infliximab and administered 4.4 g LAmB (60 mg/kg body weight) in doses of 200 mg/day for 22 days through a peripheral venous line. Other than mild and transient renal impairment, this therapy was well tolerated. The lesion started to resolve during the third week of LAmB therapy. At discharge, treatment with hydroxychloroquine and sulfasalazine was initiated. However, one month later, this regimen was changed to etanercept, prednisolone, and methotrexate because of increasing rheumatic disease activity. Despite restarting th...

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Glutamine has received considerable interest as a gut-targeted nutrient due to its proposed key role in the maintenance of intestinal structure and function. We used a preparation of isolated vascularly perfused rat small intestine to investigate whether glutamine is essential for the maintenance of intestinal function. When glutamine was available, arterial glutamine was extracted at 15 +/- 2%, and net uptake was -89 +/- 5 nmol min-1 g-1. Nitrogenous metabolites ammonia, alanine, and citrulline (41 +/- 7, 41 +/- 4, and 11 +/- 2 nmol min-1 g-1, respectively) were released into the venous perfusate, but only ammonia was also excreted into the lumen (36 +/- 3 nmol min-1 g-1). In the absence of exogenous glutamine alanine release was halved and that of citrulline and ammonia nullified. Additional inhibition of glutamine synthetase yielded the same results. In all cases variables of tissue function were fully maintained also in the absence of exogenous and/or endogenous glutamine. The inhibition of glutaminase/amidotransferase reactions, however, was accompanied by a reduction in glutamine consumption and a graded deterioration in tissue function. In conclusion, glutamine seems to be dispensable as a metabolic fuel to be fully oxidized by the mucosa. However, the inhibition of major glutamine consuming pathways was associated with impaired tissue function and viability. Therefore the role of intestinal glutamine metabolism seems to be threefold: (a) providing affluent amounts of nitrogen precursors for mucosal anabolic pathways to maintain intestinal structure and function, (b) feeding the liver with an optimal substrate mix, and (c) providing citrulline and thereby arginine for the whole organism.

The aim of the study was to investigate whether quantitative magnetic resonance (

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