Summary
Background
Crohn's disease recurs in the majority of patients after intestinal resection.
Aim
To compare the relative efficacy of thiopurines and anti‐TNF therapy in patients at high risk of ...disease recurrence.
Methods
As part of a larger study comparing post‐operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine‐intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment.
Results
A total of 101 patients 50% male; median (IQR) age 36 (25–46) years were included. There were no differences in disease history between thiopurine‐ and adalimumab‐treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2–i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab‐treated patients intention‐to‐treat (ITT); P = 0.028 or 24 of 62 (39%) vs. 3 of 24 (13%) respectively per‐protocol analysis (PPA); P = 0.020. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab).
Conclusions
In Crohn's disease patients at high risk of post‐operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.
This book presents a new argument attacking the view that if the foetus has the moral standing of a person it has a right to life and abortion is impermissible. Most discussion of abortion has ...assumed that this premise is correct, and so has focused on the question of the personhood of the foetus. Frances Kamm, however, argues that abortion can be moral even if the foetus is indeed a person.
The American Gastroenterological Association (AGA) convened a panel of gastroenterologists expert in the area of inflammatory bowel disease (IBD) that developed this consensus statement based on ...expert presentations of current scientific knowledge about IBD and through subsequent group discussion. This statement reflects the panel’s assessment of medical knowledge available when written. Thus, readers should view this statement in the context of data that will accumulate after its creation. The opinions, conclusions, and recommendations expressed in this report are those of the consensus panel members and may or may not reflect the official opinion of the American Gastroenterological Association Institute. The conference upon which this report is based was funded through an unrestricted educational grant from Abbott Laboratories. Abbott Laboratories representatives did not attend the conference, nor did they participate in any way in the development of this report.
Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage- and Ca2+-activated K+channel (BK ...channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels ( BK-/-) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK-/-mice showed a dramatic reduction in spontaneous activity of the BK-/-cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia.
Aqueous fluorophotometric, tracer localization and modeling methods were combined to document the existence of a pathway in the normal rabbit for the diffusion of proteins from the ciliary and ...iridial process stromas through the iris stroma into the aqueous humor of the anterior chamber. A new custom-conjugated tracer, fluoresceinated horseradish peroxidase (F-HRP), was used. Anesthetized rabbits were injected intravenously with F-HRP (250 mg/kg). In some animals, aqueous fluorophotometric and tracer localization studies were performed on the same eyes. Anterior chamber fluorescence was detected 2-10 min post-injection and rose to concentrations of 0.01-0.05 mg/ml 60 min post-injection. Subsequent tracer localization studies of these eyes revealed that the morphologic components of the blood-aqueous barrier were intact, that is, no leakage of F-HRP from the iris vasculature or across the ciliary epithelium was observed. Separate tracer localization studies were performed to examine the time course of the route(s) by which tracer entered the anterior chamber. These studies revealed a "wave" of tracer that migrated from the ciliary and iridial process stromas, through the iris, and arrived at the anterior iris surface approximately 8 min post-injection. A pharmacokinetic model based on the diffusional pathway was developed to describe the time course of the concentration of plasma macromolecules in the ciliary body, iris and anterior chamber. Model predictions were consistent with aqueous fluorophotometric and tracer localization results. The diffusion model can account for a major fraction of protein entering the aqueous humor of normal rabbit eyes.
Aliment Pharmacol Ther 2011; 34: 306–317
Summary
Background Treatments that achieve sustainable steroid‐free clinical remission in Crohn’s disease are needed; however, long‐term steroid‐sparing ...efficacy data are limited.
Aim To evaluate steroid‐sparing efficacy and the impact of steroid discontinuation on adverse events during treatment of Crohn's disease with adalimumab in the phase III randomised, double‐blind 1‐year CHARM trial and for an additional 2 years in its open‐label extension ADHERE.
Methods Steroid‐free remission and response and steroid‐sparing (≥50% steroid dose reduction) remission rates were evaluated over 3 years in patients who were taking corticosteroids at CHARM baseline.
Results Of 778 patients randomised in CHARM (including those who did not achieve clinical response to open‐label induction therapy), 313 patients (40%) were on corticosteroids at baseline. In the 206 patients randomised to adalimumab, rates of steroid‐free remission at 1 year and 3 years were 26% and 23% respectively; corresponding rates were 29% and 25% for steroid‐sparing remission and 32% and 28% for steroid‐free response. Although the incidence of serious infections with adalimumab treatment during CHARM was higher in patients taking steroids at baseline than those who were not, the rates of overall adverse events, serious infections and opportunistic infections were lower in patients who were able to discontinue corticosteroids than those who remained on steroids.
Conclusion Adalimumab therapy resulted in modest but clinically meaningful rates of steroid‐free remission, sustained over 3 years of treatment, in a heavily pretreated population of patients with Crohn's disease receiving steroids at the start of therapy (http://www.clinicaltrials.gov number: NCT00077779).
The study of human neuromuscular diseases has traditionally been performed in animal models, due to the difficulty of performing studies in human subjects. Despite the unquestioned value of animal ...models, inter-species differences hamper the translation of these findings to clinical trials. Tissue-engineered models of the neuromuscular junction (NMJ) allow for the recapitulation of the human physiology in tightly controlled
settings.
: Here we report the first human patient-specific tissue-engineered model of the neuromuscular junction (NMJ) that combines stem cell technology with tissue engineering, optogenetics, microfabrication and image processing. The combination of custom-made hardware and software allows for repeated, quantitative measurements of NMJ function in a user-independent manner.
: We demonstrate the utility of this model for basic and translational research by characterizing in real time the functional changes during physiological and pathological processes.
: This system holds great potential for the study of neuromuscular diseases and drug screening, allowing for the extraction of quantitative functional data from a human, patient-specific system.
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