International validation of a health-related quality of life questionnaire in patients with erosive gastro-oesophageal reflux disease

Background  Although erosive gastro-oesophageal reflux disease (GERD) is a highly prevalent condition, there is no specific, valid, reliable and sensitive questionnaire that allows evaluating treatment-induced changes in health-related quality of life (HRQoL).
Aim  To design a self-administered questionnaire, the GERD Anal yzer (GERDyzer), for use in clinical studies.
Methods  The GERDyzer comprises 10 dimensions each illustrated by pictogram-like drawings, simplifying communication with the patients. Self-assessment is performed by 100 mm Visual Analogue Scales. For validation, a 5-week clinical trial involving 395 patients (per-protocol) with oesophagitis was conducted. Patients were treated with pantoprazole (40 mg o.d.) for 28 days. Psychometric analyses included internal consistency, test–retest reliability, responsiveness and construct validity.
Results  Factor analysis showed consistency of the dimensions and no reduction was necessary. Validation of GERDyzer indicated high internal consistency (Cronbach's α = 0.95) and test–retest reliability (intraclass correlation coefficient =0.91). Responsiveness of the total score expressed by nonparametric effect size was 1.38. Comparison of scores with other questionnaires resulted in logical correlation levels depending on the respected concepts measured.
Conclusions  GERDyzer proved to be highly valid, reproducible and responsive. It allows reliably assessing treatment-induced changes in HRQoL in erosive GERD.     

Effects of neurokinins on human colonic motility

Abstract Neurokinins have been implicated as excitatory neuromessengers involved in the mediation of different reflexes in the mammalian gastrointestinal tract. However, marked interspecies variations in reported receptor distribution and in regional peptide content do not allow the extrapolation of results obtained in animals to the human gastrointestinal tract. To characterize the myogenic and neurogenic mechanical response of human colonic muscle to neurokinins, we studied the inotropic response of muscle strips from the proximal and distal human colon, and the rectum to the NK-1 receptor agonists substance P (SP) and substance P methylester (SPME), to the NK-2 receptor agonists neurokinin A (NKA) and neurokinin A 4–10 (NKA4–10) and to the NK-3 receptor agonist neurokinin B (NKB). Even though all neurokinins caused a dose-dependent inotropic response, NKA was 15–20 times more potent than SP or SPME in all areas of the colon. The efficacy and potency of NKA was highest in distal circular colon. The response to exogenous SP and NKA was partially mediated by actions of these peptides on myenteric nerves, as indicated by the sensitivity of the mechanical response to atropine, tetrodotoxin and hexamethonium. Densensitization to NKA, but not to SP significantly increased the atropine-resistant part of the off response to electrical field simulation. These results suggest the following: (a) NKA is a potent agonist in human colon with a proximal to distal gradient in potency and in efficacy; (b) the response to NK-I, NK-2 and NK-3 agonists involves cholinergic and nicotinic mechanisms; (c) the increase in the atropine resistant off-response after desensitization with NKA is consistent with the existence of inhibitory NK-2 receptors on non-cholinergic myenteric neurons.     

Involvement of chloride channels in the receptormediated activation of longitudinal colonic muscle

In gastrointestinal smooth muscle, intracellular Cl- is maintained at levels higher than its electrochemical equilibrium. Therefore, Cl- efflux through receptor-mediated opening of Cl- channels should result in membrane depolarization and may be sufficient to activate voltage-sensitive calcium channels (VSCCs). To determine the contribution of Cl- channels to receptor-mediated contraction of the longitudinal muscle layer of the rabbit distal colon, we studied the mechanical response of muscle strips to substance P, carbachol and potassium depolarization following the depletion of Cl- i, and in the presence of the Cl- channel blocker 5-nitro-2-(3-phenylpropyl-amino)-benzoate (NPPB). A 60-min incubation of tissues in a HEPES-buffered solution in which NaCl had been replaced by Na isethionate (or Na gluconate) in equimolar amounts resulted in disappearance of phasic contractions, and in a partially reversible reduction of the tonic response to substance P and carbachol, but not to KCl depolarization. When the agonist was applied to tissues in control solution, or to Cl-(-)depleted tissues in a solution in which Na+ was acutely replaced in equimolar amounts by N-methyl-D-glucosamine, the mechanical response to substance P and carbachol was almost abolished. Acute Na+ replacement alone without prior Cl- depletion did not abolish phasic contractions, but reduced the tonic response to substance P and carbachol. Similar to the effect of Cl- depletion, incubation of tissues in NPPB (6.6 x 10(-5) M) reduced the tonic response to substance P and carbachol, and abolished phasic contractions. These findings are consistent with a contribution of a Cl- channel to the receptor-mediated activation of colonic smooth muscle. In addition, the data suggest that transient Cl- channel mediated depolarizations may play a role in the generation of phasic contractions.     

Stress and gastrointestinal motility in animals: a review of the literature

In the last decade an increasing number of studies have been published dealing with the effects of experimental stress on gastrointestinal functions in animals and humans. Initial interest in gastrointestinal stress responses in the late 1940s and early 1950s¹ was followed by continued interest only in experimental ulcer research.² The recent ‘revival’ of interest in stress is due to some methodological progress: first, our understanding of gastrointestinal functions, specifically gastrointestinal motility has grown after new measurement techniques became widely available to enable gastrointestinal stress effects to be determined directly-instead of its indirect outcome such as stool frequency or gastrointestinal symptoms. Second, interest has grown in functional abdominal disorders such as the irritable bowel syndrome or non-ulcer dyspepsia, which are often believed to be, at least in part, stress related.³ Finally, stress has become a major paradigm by which to investigate brain-gut interactions, specifically with respect to the yet unanswered question of the extent of autonomy or CNS control to regulate gastrointestinal functions.⁴ Our review is split into two parts. The first part focused on clinical aspects in human studies.¹ This part will deal with animal studies and discusses their relevance with respect to basic research questions.