CON-COUR study: Interferential therapy in the treatment of chronic constipation in adults: study protocol for a randomized controlled trial

International audienceBackground: The prevalence of chronic constipation is about 15 % in Western countries with a significant impact on quality of life and health care costs. The first-line therapy, based on medical treatment combined with laxatives and dietary rules, is often disappointing. Interferential therapy is a new treatment that has demonstrated its efficiency in the treatment of chronic constipation in children and encouraging results in adults. The primary objective of this study is to assess the efficacy of interferential therapy during 8 weeks in adult patients. The secondary objectives are to assess this new and noninvasive therapy in terms of persistence of the clinical efficacy, colonic transit time, ano-rectal manometry, patient satisfaction and quality of life (QoL), and tolerance. Methods/ Design: Design: multicenter, prospective, randomized, placebo-controlled, double blind, two-parallel groups study. Setting: nine French adult gastroenterology centers. Inclusion criteria: adult patients with a history of chronic constipation refractory to medical treatment for at least 3 months. Treatment groups: (1) interferential-experimental group (effective stimulation); (2) placebo-control group (sham stimulation). Randomization: 1:1 allocation ratio. Evaluation times: inclusion (T0, randomization), baseline assessment (T1), start of stimulation (T2), intermediary assessment (T3, 4 weeks), end of stimulation (T4, 8 weeks), follow-up (T5 and T6, 1- and 6-month). Endpoints: (1) primary: short-term efficacy at T4 (treatment response defined as three or more spontaneous, complete bowel movements per week); (2) secondary: efficacy at T5 and T6, symptoms (Patient Assessment of Constipation Symptoms questionnaire), colonic transit time, anorectal manometry, patient satisfaction (analogical visual scale), patient QoL (Patient Assessment of Constipation Quality of Life Questionnaire), side/unexpected effects. Sample size: 200 individuals to obtain 80 % power to detect a 20 % difference in treatment response at T4 between the two groups (15 % of lost to follow-up patients expected). Discussion: The randomized, double-blind, placebo-controlled design is the most appropriate to demonstrate the efficacy of a new experimental therapeutic (Evidence-Based Medicine Working Group classification). National and international recommendations could be updated based on the findings of this study

Hypoxia-inducible factor (HIF1α) gene expression in human shock states.

International audienceABSTRACT: INTRODUCTION: Hypoxia-inducible factor-1 (HIF1) controls the expression of genes involved in the cellular response to hypoxia. No information is available on its expression in critically ill patients. Thus, we designed the first clinical study in order to evaluate the role of HIF1α as a prognosis marker in patients suffering from shock. METHODS: Fifty consecutive adult patients with shock and 11 healthy volunteers were prospectively enrolled in the study. RNA was extracted from whole blood samples and expression of HIF1α was assessed over the first four hours of shock. The primary objective was to assess HIF1α as a prognostic marker in shock. Secondary objectives were to evaluate the role of HIF1α as a diagnostic and follow-up marker. Patient survival was evaluated at day 28. RESULTS: The causes of shock were sepsis (78%), hemorrhage (18%), and cardiac dysfunction (4%). HIF1α expression was significantly higher in the shock patients than in the healthy volunteers (121 (range: 72-168) versus 48 (range: 38-54) normalized copies, P <0.01), whatever the measured isoforms. It was similar in non-survivors and survivors (108 (range 84-183) versus 121(range 72-185) normalized copies, P = 0.92), and did not significantly change within the study period. CONCLUSIONS: The present study is the first to demonstrate an increased expression of HIF1α in patients with shock. Further studies are needed to clarify the potential association with outcome. Our findings reinforce the value of monitoring plasma lactate levels to guide the treatment of shock

Increased serum levels of fractalkine and mobilisation of CD34+CD45− endothelial progenitor cells in systemic sclerosis

International audienceBackground: The disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity

p8 inhibits the growth of human pancreatic cancer cells and its expression is induced through pathways involved in growth inhibition and repressed by factors promoting cell growth

<p>Abstract</p> <p>Background</p> <p>p8 is a stress-induced protein with multiple functions and biochemically related to the architectural factor HMG-I/Y. We analyzed the expression and function of p8 in pancreatic cancer-derived cells.</p> <p>Methods</p> <p>Expression of p8 was silenced in the human pancreatic cancer cell lines Panc-1 and BxPc-3 by infection with a retrovirus expressing p8 RNA in the antisense orientation. Cell growth was measured in control and p8-silenced cells. Influence on p8 expression of the induction of intracellular pathways promoting cellular growth or growth arrest was monitored.</p> <p>Results</p> <p>p8-silenced cells grew more rapidly than control cells transfected with the empty retrovirus. Activation of the Ras→Raf→MEK→ERK and JNK intracellular pathways down-regulated p8 expression. In addition, the MEK1/2 inhibitor U0126 and the JNK inhibitor SP600125 up-regulates expression of p8. Conversely, p38 or TGFβ-1 induced p8 expression whereas the specific p38 inhibitor SB203580 down-regulated p8 expression. Finally, TGFβ-1 induction was in part mediated through p38.</p> <p>Conclusions</p> <p>p8 inhibits the growth of human pancreatic cancer cells. p8 expression is induced through pathways involved in growth inhibition and repressed by factors that promote cell growth. These results suggest that p8 belongs to a pathway regulating the growth of pancreatic cancer cells.</p

TWEAK-binding autoantibodies are generated during psoriatic arthritis and are not influenced by anti-TNF therapy

International audienceBACKGROUND: TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown. METHODS: We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy. RESULTS: Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients \textless0.003, p \textgreater 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p \textgreater 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p \textless 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. CONCLUSION: Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical trial.gov under the number: NCT02164214

Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets.

International audienceBACKGROUND AND OBJECTIVE: Adrenal insufficiency is caused by primary adrenal failure or by impairment of the corticotropic axis. In both situations, cortisol secretion is deficient, and hydrocortisone is a logical replacement therapy. However, no consensus guideline for dosing has been published, and clinicians adapt the dose empirically after only a clinical evaluation. Under this regimen, some patients receiving an inappropriately high dose of cortisol feel comfortable and also have an increased risk of adverse effects. We performed a pharmacokinetic study of cortisol in patients with adrenal insufficiency to evaluate plasma concentrations when the dosing was based on clinical examination and to develop a model allowing optimization of drug dosing. STUDY DESIGN: This was a prospective, open-label study in two endocrinology departments and a clinical investigation centre (Assistance Publique Hôpitaux de Marseille, Marseille, France). METHODS: Fifty patients with primary (n = 20) or secondary (n = 30) adrenal insufficiency were recruited. All patients were given their usual hydrocortisone replacement regimen. Blood samples for cortisol measurements were drawn at 0600, 0800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 and 0000 h. The observed values were compared with the known physiological range throughout the day (0800, 1600 and 0000 h). A population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling software (NONMEM). The final pharmacokinetic model was then used to simulate several hydrocortisone dosing scenarios. RESULTS: Thirteen different treatment regimens for 50 patients were observed. The cortisol plasma concentrations were compared with the physiological range and showed that 79%, 55% and 45% of patients were over- or under-treated at 0800, 1600 and 2400 h, respectively. The cortisol concentrations showed wide variability and were best described using a one-compartment model with zero-order input and first-order elimination. The pharmacokinetic parameters (intersubject variability) were the following: duration of absorption 0.54 hour, volume of distribution 38.7 L (39.7%) and clearance 12.1 L/h (23.2%). The proportional residual error was 32.3%. This final model was then used to simulate 18 different dosing regimens. The regimen with the highest proportion of simulated patients within the physiological targets was 10 + 5 + 5 mg at 0730, 1200 and 1630 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over- or under-treated at 0800, 1600 and 2400 h, respectively. CONCLUSIONS: Most patients with adrenal insufficiency are imperfectly treated with hydrocortisone relative to their plasma cortisol concentrations. Using simulation, a standard dosing regimen is suggested, which increases the proportion of patients within the physiological target concentrations. However, an individualized dose adjustment would be more accurate

Upper airway modifications in head extension during development

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Targeting tissular immune response improves diagnostic performance of anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease.

Antibodies against Saccharomyces cerevisiae (ASCA) and Escherichia coli outer membrane porin C (anti-OmpC) are known to be detectable in the serum of patients with Crohn's disease (CD) but display a very poor sensitivity for the disease especially in forms with isolated colonic involvement. In this study we aimed at evaluating performances of these markers in supernatant of cultured colonic biopsies. Patients with colonic CD (n =  67), ulcerative colitis (UC) (n = 35) and control individuals (n = 37) were prospectively recruited for colonoscopy pinch biopsies and blood sampling. Serum and supernatant of culture tissues were analyzed for ASCA and anti-OmpC. Direct immunofluorescence was also performed on colonic tissues for total IgA detection. We detected for the first time ASCA IgA/IgG and anti-OmpC IgA in cultured colonic tissue supernatants. For both markers, sensitivities for diagnosing CD were better in supernatants (ASCA: 53.7%, anti-OmpC: 28.4%) than in serum (ASCA: 31.3%, anti-OmpC: 22.4%). Combination of results from a panel of these tests gave the greatest sensitivity ever described for CD diagnosis in colonic forms (70.2%). In this study, we described, for the first time, ASCA in supernatant of colonic tissue cultures. This assaying approach in CD diagnosis should be taken into consideration in the future especially in CD forms with isolated colonic involvement

Is endoscopic sphincterotomy avoidable in patients with sphincter of Oddi dysfunction?

International audienceAIM: Endoscopic sphincterotomy is an efficient means of treating sphincter of Oddi dysfunction (SOD), but it is associated with a morbidity rate of 20%. The aim of this study was to assess how frequently endoscopic sphincterotomy was performed to treat SOD in a group of patients with a 1-year history of medical management. METHODS: A total of 59 patients, who had been cholecystectomized 9.3 years previously on average, were included in this study and they all underwent biliary scintigraphy. Medical treatment was prescribed for 1 year. Endoscopic sphincterotomy was proposed for patients whose medical treatment had been unsuccessful. RESULTS: Eleven patients were rated group 1 on the Milwaukee classification scale, 34 group 2 and 14 group 3. The hile-duodenum transit time (HDTT) was lengthened in 32 patients. The medical treatment was efficient or fairly efficient in 45% of the group 1 patients, 67% of the group 2 patients, and 71.4% of the group 3 patients (P=0.29). Only 14 patients out of the 21 whose medical treatment was unsuccessful agreed to undergo endoscopic sphincterotomy. HDTT was lengthened in 11 of the 14 patients undergoing endoscopic sphincterotomy and in 21 of the 45 non-endoscopic sphincterotomy patients (P=0.03). Twelve of the 14 patients who underwent endoscopic sphincterotomy were cured. CONCLUSION: In this prospective series of patients with a 1-year history of medical management, only 23% of the patients with suspected SOD underwent endoscopic sphincterotomy although 54% had an abnormally long HDTT