1 Department of Internal Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Centre for Chinese Medicine, Universitätsallee 3, 28359 Bremen, Germany German Society for Traditional Chinese Medicine (DGTCM), Heidelberg University, Karlsruher Straße 12, 69126 Heidelberg, Germany 4 Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, Heidelberg University, Ludolf-Krehl-Straße 7-11, 68167 Mannheim, Germany 5 Shen-Centre for Traditional Chinese Medicine, Südliche Stadtmauer Straße 25, 91054 Erlangen, Germany Department of Society, Human Development and Health, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA Abel Salazar Biomedical Sciences Institute, University of Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313 Porto, Portugal

OBJECTIVES:Phosphatidylcholine is a key component of the mucosal barrier. Treatment with modified release phosphatidylcholine aims to improve the impaired barrier function. The primary objective is to evaluate the efficacy of LT-02, a newly designed modified release phosphatidylcholine formula, in a multicenter setting. METHODS:This is a double-blinded, randomized, placebo-controlled, superiority study conducted in 24 ambulatory referral centers in Germany, Lithuania, and Romania. A total of 156 patients with an inadequate response to mesalazine, a disease activity score (Simple Clinical Colitis Activity Index (SCCAI)) of ≥ 5, and bloody diarrhea underwent treatment with 0, 0.8, 1.6, or 3.2 g LT-02. The primary end point was defined a priori as changes in SCCAI from baseline to the end of treatment. The primary statistical model was a general linear least-squares model. The study was funded by the sponsor Lipid Therapeutics, Heidelberg, Germany, and registered at http://clinicaltrials.gov/show/NCT01011322. RESULTS:Baseline characteristics and dropouts were well balanced between all groups. The primary analyses revealed an SCCAI drop of 33.3% in the placebo group (from 9.0 to 6.0 points) compared with 44.3% in the 0.8 g LT-02 (from 8.8 to 4.9, P>0.05) and 40.7% in the 1.6 g groups (from 8.6 to 5.1, P>0.05). The 3.2 g group improved 51.7% from 8.5 to 4.1 (P=0.030 in comparison with placebo). The remission rate was 15% (6/40) in the placebo group compared with 31.4% (11/35) in the highest LT-02 dose group (P=0.089). Mucosal healing was achieved in 32.5% of placebo patients compared with 47.4% of LT-02 patients (P=0.098); the rates for histologic remission were 20% compared with 40.5%, respectively (P=0.016). There were 17 (48.6%) treatment-emergent adverse events in the highest dose group (and 0 serious adverse events (SAEs)) compared with 22 (55%) in the placebo group (4 SAEs). CONCLUSIONS:The primary end point analysis showed a statistically significant improvement in disease activity during LT-02 treatment in comparison with placebo. The drug was found to be very safe.

Introduction. Acupuncture was recently shown to be effective in the treatment of knee osteoarthritis. However, controversy persists whether the observed effects are specific to acupuncture or merely nonspecific consequences of needling. Therefore, the objective of this study is to determine the efficacy of different acupuncture treatment modalities. Materials and Methods. We compared between three different forms of acupuncture in a prospective randomised trial with a novel double-blinded study design. One-hundred and sixteen patients aged from 35 to 82 with osteoarthritis of the knee were enrolled in three study centres. Interventions were individualised classical/ modern semistandardised acupuncture and non-specific needling. Blinded outcome assessment comprised knee flexibility and changes in pain according to the WOMAC score. Results and Discussion. Improvement in knee flexibility was significantly higher after classical Chinese acupuncture (10.3 degrees; 95% CI 8.9 to 11.7) as compared to modern acupuncture (4.7 degrees; 3.6 to 5.8). All methods achieved pain relief, with a patient response rate of 48 percent for non-specific needling, 64 percent for modern acupuncture, and 73 percent for classical acupuncture. Conclusion. This trial establishes a novel study design enabling double blinding in acupuncture studies. The data suggest a specific effect of acupuncture in knee mobility and both non-specific and specific effects of needling in pain relief.

The colonic mucus serves a first barrier towards invasion of commensal bacteria in stools to prevent inflammation. One essential component of intestinal mucus is phosphatidylcholine (PC) which represents more than 90% of the phospholipids in mucus indicative for a selective transport of PC into this compartment. It is arranged in lamellar structures as surfactant-like particles which provide a hydrophobic surface on top of the hydrated mucus gel to prevent the invasion of bacteria from intestinal lumen. In ulcerative colitis (UC), the mucus PC content is reduced by 70%, irrespective of the state of inflammation. Thus, it could represent an intrinsic primary pathogenetic condition predisposing to bacterial invasion and the precipitation of inflammation. Since PC was shown to be mainly secreted by the ileal mucosa from where it is assumed to move distally to the colon, the PC content along the colonic wall towards the rectum gradually thins, with the least PC content in the rectum. This explains the start of the clinical manifestation of UC in the rectum and the expansion from there to the upper parts of the colon. In three clinical trials, when missing mucus PC in UC was supplemented by an oral, delayed release PC preparation, the inflammation improved and even resolved after a 3-month treatment course. The data indicate the essential role of the mucus PC content for protection against inflammation in colon.

Health Improvement Network primary care database was used to identify 2 cohorts of patients aged 1-17 years between 2000 and 2005; patients with a recorded diagnosis of gastroesophageal reflux disease (GERD) during the study period (n = 1809) and a cohort of patients without GERD (n = 5000).Non-GERD patients were frequency matched to GERD patients by age, sex and calendar year.Among GERD patients, 2 sub-cohorts of patients were identified according to whether they had been prescribed a PPI within 1 year of GERD diagnosis; there were 487 GERD PPI users and 1322 GERD PPI non-users.All patients (GERD and non-GERD) were followed-up for up to 1 year from the start date (date of first prescription for GERD PPI users, date of GERD diagnosis for GERD PPI non-users and a random date for non-GERD patients).A total of 118 patients with a recorded diagnosis of fracture were identified; their medical records were reviewed manually to ascertain incident cases.There were a total of 45 fracture cases among GERD patients; 11 among PPI users and 34 among PPI non-users.Adjusted incidence rate ratios (IRRs) for fracture risk associated with exposure to PPIs were calculated.We also conducted a nested case-control analysis, using all 118 cases of fracture identified in both GERD and non-GERD cohorts.All remaining patients without fracture at the end of follow-up in both cohorts served as controls (n = 6656).The index date was the date of diagnosis for fracture cases and a random date for controls.Data on PPI use were obtained and odds ratios (ORs) for fracture risk associated with PPI use were calculated by multivariate adjusted logistic regression models.Results.Among GERD patients, there was no association between fracture risk and current (IRR: 0.68; 95% CI: 0.24-1.94)or recent/past use (IRR: 0.90; 95% CI: 0.40-2.05) of PPIs compared with non-use of PPIs.Similarly, among all patients (with or without GERD), neither current (OR: 0.71; 95% CI: 0.25-2.04)nor recent/past use (OR: 0.95; 95% CI: 0.41-2.18) of PPIs was associated with an increased risk of fracture compared with non-use of PPIs.However, these estimates were based on only four currently exposed cases and seven recently/past exposed cases.Conclusion.The results of our study do not support an association between PPI use and risk of fracture in children and adolescents with or without a diagnosis of GERD.However, it should be noted that only a small number of cases were exposed to a PPI.

Hintergrund: Als pathogenetischer Faktor der Colitis ulcerosa (CU) wird u.a. ein verminderter Gehalt an Phosphatidylcholin (PC) im intestinalen Mucus diskutiert. Eine orale Medikation von verzögert freigesetztem PC (modified release PC; mrPC) zeigte Wirksamkeit in drei monozentrischen Studien. Ein multizentrischer Wirksamkeitsnachweis stand aus.

Background: In 2 preceding studies, delayed release phosphatidylcholine (rPC) was found to (a) improve disease activity and (b) withdraw steroids in patients with chronic-active ulcerative colitis.Goal: Objective of the study was to determine the most effective rPC dose with least adverse events.Study: A randomized, dose-controlled, double-blinded study. Four groups of 10 patients each with nonsteroid-treated, chronic-active ulcerative pancolitis with a clinical activity index (CAI) and endoscopic activity index (EAI) >= 7. Patients were treated with oral rPC at doses of 0.5, 1, 3, and 4 g daily over 12 weeks.Results: The CAI changes from baseline to the end of the study were 2.5 (0.5 g), 7.0 (1 g), 5.5 (3 g), and 6.0 (4 g dose arm). Significant improvement of the CAI was registered between the lowest rPC dose of 0.5 g (control group) and all higher doses of 1.0, 3.0, and 4.0-g rPC (P <= 0.05). Remission (CAI <= 3) was reached in 5/10 and 6/10 patients in the 3 and 4-g dose groups compared with no patients in the 0.5-g arm (P=0.033). In the 1-g dose group only 3/10 patients reached remission (P=0.21). The rates of clinical response (>= 50% CAI improvement) were 70% in all of the effective dose groups (1 to 4 g, P=0.003). This was paralleled by the EAI improvement and by the rates of mucosal healing. Median time to clinical response was 5 (IQR 2 to 8) weeks. Bloating was registered in 40% of the patients irrespective of the treatment dose. Three of the 10 patients in the 4 g dose group reported nausea.Conclusion: We found a saturable dose response of rPC in the treatment of chronic-active ulcerative colitis with effective doses >= 1 g per day; doses of 3 and 4 g seem to be superior in achieving remission.

Importance of the field: As the pathogenesis of ulcerative colitis (UC) is unknown, a causative therapy is lacking. Therefore, some UC patients suffer from disease activity despite symptomatic anti-inflammatory treatment strategies. We claim that reduction of phosphatidylcholine (PC) in colonic mucus impairs the mucosal barrier and, thus, causes attacks of the commensal bacterial flora to induce colitis. Thus, mucus PC substitution could provide a causal therapy for UC.Areas covered in this review: A delayed released oral PC preparation (rPC) was found to substitute for the lack of PC in rectal mucus. In non-steroid-treated active UC, 53% of rPC-treated patients reached remission compared with 10% of placebo patients (p < 0.001). In a second trial with chronic-active, steroid-dependent UC patients, steroid withdrawal with a concomitant achievement of remission (CAI ≤ 3) or clinical response (≥ 50% CAI improvement) was reached in 15 rPC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002).What the reader will gain: The concept that missing PC in colonic mucus is the main pathogenetic factor for development of UC. PC can be substituted by rPC, which cures the disease in the majority of patients.Take home message: rPC is, to our knowledge, the first causative therapeutic option for patients with UC.

Colonic mucus protects against attacks from bacteria in stool. One component of mucus is phosphatidylcholine (PC) which is thought to be arranged as continuous lamellar layer in the apical mucus and to be responsible for establishing a protective hydrophobic surface. This ‘intestinal surfactant’ plays a key role in mucosal defense. Thus, a defective PC layer contributes to the development of inflammation. Analysis of rectoscopically acquired mucus aliquots revealed a 70% decrease in PC content in ulcerative colitis (UC) compared to Crohn´s disease (CD) and healthy controls – independent of disease activity. Accordingly, we propose that lack of mucus PC is a key pathogenetic factor in UC. In clinical studies a delayed-release oral PC preparation (rPC) was found to substitute the lack of PC in rectal mucus. Indeed, in non-steroid-treated active UC, 53% of rPC patients reached remission [clinical activity index (CAI) ≤3] compared to 10% of placebo patients (p ≤ 0.001). Endoscopic and histologic findings improved concomitantly. A second trial with 60 chronic-active, steroid-dependent UC patients was conducted to test for steroid-sparing effects. Complete steroid withdrawal with a concomitant achievement of remission (CAI ≤3) or clinical response (≧50% CAI improvement) was reached in 15 PC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002). In conclusion, intrinsic reduction of PC (lecithin) in colonic mucus may be a key pathogenetic feature of UC. Topical supplement of PC by a delayed-released oral PC preparation is effective in resolving inflammatory activity of UC and may develop to a first-choice therapy for this disease.

Phosphatidylcholine (PC) is an important constituent of the gastrointestinal tract. PC molecules are not only important in intestinal cell membranes but also receiving increasing attention as protective agents in the gastrointestinal barrier. They are largely responsible for establishing the hydrophobic surface of the colon. Decreased phospholipids in colonic mucus could be linked to the pathogenesis of ulcerative colitis, a chronic inflammatory bowel disease. Clinical studies revealed that therapeutic addition of PC to the colonic mucus of these patients alleviated the inflammatory activity. This positive role is still elusive, however, we hypothesized that luminal PC has two possible functions: first, it is essential for surface hydrophobicity, and second, it is integrated into the plasma membrane of enterocytes and it modulates the signaling state of the mucosa. The membrane structure and lipid composition of cells is a regulatory component of the inflammatory signaling pathways. In this perspective, we will shortly summarize what is known about the localization and protective properties of PC in the colonic mucosa before turning to its evident medical importance. We will discuss how PC contributes to our understanding of the pathogenesis of ulcerative colitis and how reinforcing the luminal phospholipid monolayer can be used as a therapeutic concept in humans.

BACKGROUND:A definition of disease activity in ulcerative colitis (UC) is difficult. The clinical activity index (CAI) is only an indirect assessment tool of bowel inflammation and the endoscopic activity index (EAI) sometimes cannot reflect the severity of disease to the full extent. Therefore, there is a need for an objective means to quantify inflammatory activity in mucosal biopsies. In our study, we wanted to examine the correlation between transcript levels of interleukin 8 (CXCL8), interferon gamma inducible protein 10 (CXCL10), myeloid-related protein 14 (calgranulin B), macrophage inflammatory protein 2 alpha (CXCL2) with CAI and EAI in UC.METHODS:Cytokine and chemokine transcripts were quantified using real-time PCR in 49 mucosal biopsies from 27 different patients with UC. Cytokine transcript levels were correlated with CAI and EAI.RESULTS:There was a statistically significant positive correlation between CXCL8 (r = 0.30; p < 0.05), CXCL10 (r = 0.40; p < 0.02), calgranulin B (r = 0.36; p < 0.03), CXCL2 (r = 0.31; p < 0.05) and CAI. Concerning EAI significant positive correlations for CXCL8 (r = 0.37; p < 0.02), CXCL10 (r = 0.33; p < 0.04), calgranulin B (r = 0.31; p < 0.05) and CXCL2 (r = 0.44; p < 0.05) were found. Low clinical and endoscopic activity was accompanied by low cytokine levels whereas high CAI and EAI were associated with high cytokine levels.CONCLUSION:From our data, we conclude that real-time PCR quantification of CXCL8, CXCL10, calgranulin B and CXCL2 in colonic biopsies is a simple and objective method for grading inflammation of intestinal mucosa in UC. CXCL8, CXCL10, calgranulin B and CXCL2 might be used as biomarkers and thus as an objective tool especially in clinical trials to evaluate anti-inflammatory and immunomodulatory regimens.

worsening UC symptoms that necessitated colectomy.Three patients in the 1.0 mg/kg and 2 patients in the 3.0 mg/kg cohorts had clinical responses; however, the clinical response of one patient in the 1.0 mg/kg cohort was confounded by the initiation of concomitant immunomodulator therapy 2 months prior to MDX-1100 administration.Three responding patients relapsed after 50, 85 and 93 days, respectively and have been administered additional MDX-1100 doses; 2 patients responded to re-treatment.Pharmacodynamic and pharmacokinetic analyses were performed.Conclusion: This pilot study demonstrated that single doses of up to 10 mg/kg of a fully human anti-CXCL10 monoclonal antibody in patients with active ulcerative colitis was safe.Clinical responses were seen at dose levels at or above 1.0 mg/kg.These data support further studies of MDX-1100 in ulcerative colitis.

Background: Inflammatory bowel disease (IBD) impairs health-related quality of life (HRQOL). Our aim was to investigate whether the improvement in the Clinical Activity Index (CAI) and Endoscopic Activity Index (EAI) is significantly correlated with the advancement of HRQOL and its dimensions in ulcerative colitis (UC) and to assess whether demographic and disease-related factors influence patients' experience of HRQOL. This examination was performed in the context of our recently published study of the anti-inflammatory effect of phosphatidylcholine in UC.Methods: Sixty patients with chronic active UC were treated with phosphatidylcholine or placebo over 3 months. They were asked to complete the Inflammatory Bowel Disease Questionnaire-Deutschland (IBDQ-D) before and after the study. The correlations between CAI and EAI and IBDQ-D scores were calculated. Demographic and disease-related factors were obtained.Results: A statistically significant lowering of CAI and EAI after treatment in the phosphatidylcholine group led to a statistically significant improvement in HRQOL (r = -0.623, P = 0.0003 for CAI; r = -0.511, P = 0.005 for EAI). Constant disease activity indexes in the placebo group accompanied constant 14RQOL (r = -0.747, P < 0.0001 for CAI; r = -0.634, P = 0.0002 for EAI). Furthermore, besides a few exceptions, significant correlations between CAI and EAI and the 4 dimensions of the IBDQ-D could be shown. Demographic parameters did not significantly influence the IBDQ-D scores.Conclusions: This study points out the strong relationship between CAI and EAI and all domains of HRQOL in patients with UC. Therefore, the IBDQ-D is a valid and reliable assessment tool that reflects changes in the health status of UC patients. It is a useful measure of therapeutic efficacy and should be used in clinical trials in IBD.