Effects of yoga in inflammatory bowel diseases and on frequent IBD-associated extraintestinal symptoms like fatigue and depression.

Quality of life (QoL) of persons with inflammatory bowel diseases (IBD) is often impaired by symptoms that do not primarily relate to intestinal inflammation. Among the most challenging extraintestinal symptoms are depression and fatigue, which are also frequent in other chronic diseases like multiple sclerosis, rheumatoid arthritis and cancer. Yoga as an ancient Indian tradition containing postures, breathing exercises and meditation may positively influence those symptoms. This review evaluates the current literature with regard to the effect of yoga-based interventions in persons with IBD and with regard to QoL, depression and fatigue in other somatic disorders. A systematic literature search yielded three trials examining the effects of yoga in patients with IBD and 37 trials addressing depressive syndromes or fatigue in somatic disorders. In summary, both in-person and video-based yoga classes are feasible, acceptable and safe as complementary treatment in patients with IBD and significantly improve anxiety and impaired quality of life. Current literature does not provide information on the effect of yoga on depression and fatigue in patients with IBD, but research from other somatic disorders or patients with depressive disorders implies the potential of yoga in this regard for persons with IBD. This should be specifically addressed in interventional trials with standardized yoga modules including patients with IBD suffering from fatigue, depression and/or impaired QoL.

[Biosimilars in inflammatory bowel disease]. / Biosimilars in der Behandlung chronisch entzündlicher Darmerkrankungen.

After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT­P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease. Thus, the introduction of the biosimilar as primary therapy seems to be justified. Tight monitoring of the safety of biosimilars with regard to efficacy and side effects has to be ensured.

Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study.

BACKGROUND: Vidofludimus (SC12267) is a novel oral immunomodulator inhibiting dihydroorotate dehydrogenase (DHODH) and the expression of proinflammatory cytokines including interleukin-17 (IL17A and IL17F) and interferon-gamma. The objective of the study was to explore the efficacy, safety and tolerability of vidofludimus in steroid-dependent inflammatory bowel disease (IBD). METHODS: The open label uncontrolled ENTRANCE study (ClinicalTrials.gov NCT00820365) has been conducted at 13 study centers in Germany, Bulgaria and Romania. Thirty-four steroid-dependent patients with a confirmed diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were treated with a once daily 35mg oral dose of vidofludimus over 12weeks. Steroids were tapered during the first 8weeks followed by a steroid-free treatment period of 4weeks. Complete response was defined as steroid-free clinical remission at week 12; partial response was defined as being in remission at steroid dose equal or lower than the individual patient's threshold dose for relapse. RESULTS: Of the thirty-four patients enrolled in this trial 26 were evaluable for primary efficacy assessment. After completion of the 12weeks treatment phase 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC were in steroid-free remission (complete responders). Another 4 (28.6%) patients in CD and 5 (41.7%) patients in UC were partial responders. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. CONCLUSIONS: This trial provides first evidence of clinical efficacy of vidofludimus in IBD. Although the safety and tolerability profile seems favorable, long-term controlled studies are needed to further investigate its potential as novel IBD therapy.

Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis.

HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here, we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small-hairpin RNA (shRNA) inhibition, proteomic and metabolomic technology, we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, HAMLET sensitivity was modified by the glycolytic state of tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen, hexokinase 1 (HK1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 and hypoxia-inducible factor 1α modified HAMLET sensitivity. HK1 was shown to bind HAMLET in a protein array containing ∼8000 targets, and HK activity decreased within 15 min of HAMLET treatment, before morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 min. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene addiction or the Warburg effect.

[Life-threatening complications of Crohn's disease and ulcerative colitis: a systematic analysis of admissions to an ICU during 18 years]. / Lebensbedrohliche Komplikationen von Morbus Crohn und Colitis ulcerosa. Eine systematische Auswertung von Intensiv-Aufnahmen über 18 Jahre.

BACKGROUND AND OBJECTIVE: Despite numerous publications on the epidemiology of inflammatory bowel diseases (IBD) there is a lack of systematic investigations on live-threatening complications of IBD and their causes. This study evaluates risk factors, course and outcome in intensive-care patients which were related to complications of IBD. PATIENTS AND METHODS: Among 6071 admissions to the intensive-care unit (ICU) of a gastroenterological department (university hospital with IBD-outpatient unit) between 1.1.1991 and 31.1.2008 36 ICU admissions of 28 patients with IBD were documented and prospectively analysed from 1996 onwards, using a structured questionnaire on causes for ICU admission as well as risk factors regarding death, organ failure and length of ICU stay. RESULTS: ICU admissions of IBD patients mainly resulted from three causes: complications specific to IBD (44 %), including acute flare-up, perforation and electrolyte imbalance, septic complications (22 %) and thromboembolic complications (17 %). Five patients died, all from septic complications related to immunosuppression including candida sepsis, varicella pneumonia during treatment with infliximab, and pneumocystis pneumonia related to treatment with azathioprine. The most important risk factors according to uni- and multivariate analyses were old age on ICU-admission and first diagnosis of IBD, previous surgery related to IBD and Crohn's disease. CONCLUSIONS: Complications of both IBD and immunosuppressive therapy may be live-threatening in patients with IBD. Better characterization of patients with a high probability of improved outcome by immunosuppressive and/or antibody-therapy seems to be preferable to noncritical early use of these drugs.

Failure of current antibiotic first-line regimens and mortality in hospitalized patients with spontaneous bacterial peritonitis.

BACKGROUND: Increases in Gram-positive infections and infections with Enterobacteriaceae with antimicrobial resistance have been reported in patients with spontaneous bacterial peritonitis (SBP). This study was performed to investigate the rate of treatment failures of recommended empirical therapies and the impact on mortality. PATIENTS AND METHODS: A prospectively collected database comprising 101 patients with SBP (70 nosocomial, 31 community acquired) treated at a university hospital between 2002 and 2006 in Munich, Germany, was analyzed. RESULTS: 17 patients initially received a broader than recommended antibiotic regimen. Most of these were treated in the intensive care unit because of severe sepsis/septic shock. Hospital mortality in this group was 82%. A modification of therapy was necessary in 24 of the 84 patients receiving one of the published first-line therapies (cefotaxime, ampicillin/clavulanate, or ciprofloxacin). Mortality was significantly higher in these patients than in those with no change in treatment (66.7% vs 30%, p = 0.002). In 29 patients with positive cultures, mortality was also higher in those with an ineffective first-line treatment (90% vs 45%, p = 0.032). In the multivariable analysis, a modification of antibiotic treatment was an independent risk factor for mortality (odds ratio 5.876, 95% confidence interval 1.826-18.910, p = 0.003). In 41 culture-positive cases, the most commonly cultured pathogens were Escherichia coli (n = 17) and Enterococcus faecium (n = 10). Of the encountered bacterial microorganisms, 14 (33.3%) were resistant to cefotaxime, 17 (38.6%) were resistant to amoxicillin/clavulanate, and 19 (45.2%) were resistant to ciprofloxacin. 29 (64.4%) of the isolates were resistant to one of the recommended firstline antibiotic regimens, and 11 (24.4%) of the isolates were resistant to all three. CONCLUSION: Recommended empirical antibiotic regimens fail to achieve the desired effect in a substantial number of hospitalized patients with SBP. This has a negative impact on mortality.

Coma as a presenting symptom of primary HIV infection.

Primary HIV infection (PHI) is symptomatic in 50-90% of patients. The diagnosis, however, is seldom made at first presentation. This is probably because of the multifaceted and unspecific manifestations, the omission to perform adequate diagnostic testing and the failure to assess risks for PHI. Meningoencephalitis has been described as a fairly common presenting condition in PHI, with nuchal rigidity, fatigue, photophobia and headache; therefore, PHI should be considered in the differential diagnosis of aseptic meningitis. We present the case of a man with acute coma and a presumptive diagnosis of viral encephalitis in whom serological testing showed HIV encephalitis during PHI.

Differential expression of CD95, Bcl-2, and Bax in rat gastric chief and parietal cells.

Apoptotic cell death is common in the inflamed gastric mucosa, but its role in the regulation of cell homeostasis in normal gastric mucosa is unknown. We investigated the expression of CD95, Bcl-2, and Bax and their roles in the regulation of apoptosis in normal rat gastric mucosa and in cultures of highly enriched rat chief and parietal cells by immunostaining, Western blotting, and FACS. In intact tissue CD95, Bcl-2, and Bax were localized predominantly in the glandular base region in chief cells. In freshly isolated cells, expression of CD95, Bcl-2, and Bax was much more pronounced in chief cells than in parietal cells. A lower intracellular Bcl-2/Bax ratio suggesting a higher susceptibility to apoptosis was noticed in chief rather than in parietal cells. In extended cultures of parietal and chief cells, Bax expression was upregulated and Bcl-2 expression was downregulated. These regulatory changes, presumably caused by in vitro effects, were not associated with an increase in spontaneous apoptosis. Treatment of chief and parietal cells with Fas-ligand induced apoptosis of all CD95 expressing cells. Expression of CD95, Bcl-2, and Bax predominantly in chief cells suggests that in this cell type regulation of apoptosis may differ from that in parietal cells. Binding of FasL with functionally active CD95 receptors on chief and parietal cells may be relevant for induction of apoptosis in inflamed gastric mucosa.

Effects of oral casokefamide on plasma levels, tolerance, and intestinal transit in man.

Food-derived opioid peptides such as beta-casomorphins are of interest for treatment of chronic diarrhea. The beta-casomorphin analog casokefamide was administered orally at doses of 5.5, 8.0, and 16.0 mg to 10 healthy male volunteers, respectively. Dose-dependent increases of plasma levels with a maximum of 350 fmol/l were determined. No side-effects due to casokefamide has been observed. In comparison to placebo, casokefamide showed a trend toward prolongation of oro-caecal transit time. Orally applied casokefamide is well tolerated and may represent a useful tool for treatment of diarrhea in the future.

Significance of antibodies to the recombinant E2 protein of hepatitis G virus in haemodialysis patients.

Patients on maintenance haemodialysis represent a high-risk group for parenterally transmitted viral infections, such as hepatitis B, C and G. In addition to hepatitis G virus (HGV) (GBV-C) RNA, analysed in previous studies, we characterized the seroprevalence rates of antibodies to the putative E2 protein (anti-E2) of HGV in a German cohort of patients on maintenance dialysis (n = 72) in comparison to healthy blood donors (n = 100). The presence of anti-E2 and/or HGV RNA as indicators of present or past HGV infection could be demonstrated in 34.7% of patients and in 16% of the blood donors (P < 0.01). The infection rates with HGV seem to increase only during the first 6 years of haemodialysis. The simultaneous presence of viraemia and anti-E2 was found very rarely in patients and controls. Therefore, the emergence of anti-E2 indicates clearance of HGV viraemia. In conclusion, patients on haemodialysis are at high risk of acquiring HGV infection, but a chronic carrier state with viraemia is rare. The risk of infection is not strictly correlated with the duration of dialysis.