Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn's disease

Background: Adalimumab is an effective treatment in patients with Crohn's disease; as it is a humanized anti-tumour necrosis factor monoclonal antibody, immunogenicity is thought not to be of any significance. Aim: To assess whether antibodies to adalimumab (ATAs) affect adalimumab treatment outcome in patients with Crohn's disease previously treated with infliximab. Methods: A retrospective study was p

Interobserver and intraobserver reliabilities of determining the ventilatory thresholds in subjects with a lower limb amputation and able-bodied subjects during a peak exercise test on the combined arm-leg (Cruiser) ergometer

The first (VT1) and second ventilator (VT2) (anaerobic) thresholds are used to individually prescribe exercise training programs. The purpose of this research was to analyze inter- and intraobserver reliabilities of determining VT1 and VT2 in subjects with lower limb amputation (LLA) and able-bodied (AB) subjects during a peak exercise test on the arm-leg (Cruiser) ergometer. Previously published data of exercise tests on the Cruiser ergometer of subjects with LLA (n = 17) and AB subjects (n = 30) were analyzed twice by two observers. The VT1 and VT2 were determined based on ventilation plots. Differences in determining the VT1 and VT2 between the observers for the first and second analyses were analyzed. To quantify variation in measurement a variance component analysis was performed. Bland-Altmann plots were made, and limits of agreement were calculated. The number of observations in which thresholds could not be determined differed significantly between observers and analysis. Variation in VT1 between and within observers was small (0-1.6%) compared with the total variation, for both the subjects with an LLA and AB subjects. The reliability coefficient for VT1 was more than 0.75, and the limits of agreement were good. In conclusion, based on the results of this study on a population level, VT1 can be used to prescribe exercise training programs after an LLA. In the current study, the determination of VT2 was less reliable than VT1. More research is needed into the clinical application of VT1 and VT2 during a peak exercise test on the Cruiser ergometer

Regulatory control and the costs and benefits of biochemical noise

Experiments in recent years have vividly demonstrated that gene expression can be highly stochastic. How protein concentration fluctuations affect the growth rate of a population of cells, is, however, a wide open question. We present a mathematical model that makes it possible to quantify the effect of protein concentration fluctuations on the growth rate of a population of genetically identical cells. The model predicts that the population's growth rate depends on how the growth rate of a single cell varies with protein concentration, the variance of the protein concentration fluctuations, and the correlation time of these fluctuations. The model also predicts that when the average concentration of a protein is close to the value that maximizes the growth rate, fluctuations in its concentration always reduce the growth rate. However, when the average protein concentration deviates sufficiently from the optimal level, fluctuations can enhance the growth rate of the population, even when the growth rate of a cell depends linearly on the protein concentration. The model also shows that the ensemble or population average of a quantity, such as the average protein expression level or its variance, is in general not equal to its time average as obtained from tracing a single cell and its descendants. We apply our model to perform a cost-benefit analysis of gene regulatory control. Our analysis predicts that the optimal expression level of a gene regulatory protein is determined by the trade-off between the cost of synthesizing the regulatory protein and the benefit of minimizing the fluctuations in the expression of its target gene. We discuss possible experiments that could test our predictions.Comment: Revised manuscript;35 pages, 4 figures, REVTeX4; to appear in PLoS Computational Biolog

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial)

Contains fulltext : 69534.pdf (publisher's version ) (Open Access)BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction.The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150

Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

Contains fulltext : 96924.pdf (publisher's version ) (Open Access)BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients

Safety of blood reinfusion after local infiltration analgesia with ropivacaine in total knee arthroplasty

Objective: The authors hypothesized that it is safe to combine local infiltration analgesia (LIA) in total knee arthroplasty (TKA) with a retransfusion drain since ropivacaine concentrations would not exceed the arterial toxicity threshold concentrations of 4.3 mg/L for total and 0.56 mg/L for unbound ropivacaine. Materials and methods: 22 patients scheduled for primary TKA were included. During surgery three peri-articular injections with ropivacaine (300 mg) were given. Plasma and shed blood samples were taken at 0, 1, 3, 6, 7, and 24 hours postoperatively. Results: At 6 hours postoperatively, the total ropivacaine plasma concentration ranged from 0.26 to 1.53 mg/L and unbound ropivacaine from 0.03 to 0.12 mg/L. At 7 hours, the total ropivacaine plasma concentration ranged from 0.19 to 1.71 mg/L and unbound ropivacaine from 0.02 to 0.09 mg/L. In the collected shed blood, a total of 0.27 to 12.8 mg (median 3.73 mg) unbound ropivacaine was present. Reinfusion would lead to an addition of 3.73 mg (median) unbound ropivacaine that would be reinfused into the patient. The calculated (modeled) estimation regarding the maximum unbound ropivacaine plasma concentration showed a median value of 0.114 mg/L (IQR: 0.09, 0.12 mg/L). All concentrations were well below reported toxicity thresholds. Conclusions: The combination of LIA and reinfusion presented herein are considered safe. However, differences in pain protocol lead to changes in the safety evaluation. Compared with previous studies, the technique of administration is of greater importance for the effect on unbound ropivacaine because of unknown mechanisms. © 2014 Dustri-Verlag Dr. K. Feistle