Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse-all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management ("mind-body") interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS.

Systematic review and meta-analysis: Gastric electrical stimulation for gastroparesis.

BACKGROUND: Controlled trials of gastric electrical stimulation (GES) for gastroparesis reported no significant improvement in symptoms, while open label studies suggested substantial clinical benefits. AIM: To determine if GES is effective in reducing symptoms in patients with gastroparesis. METHODS: We searched PubMed and Embase for articles published in English (1990-2014) using "gastroparesis" as a search term restricted to "clinical trial". We included studies describing repeated patient-based symptom ratings before and during standardized treatments of at least one week duration. RESULTS: Five studies randomly allocated patients to periods with or without GES. Total symptom severity (TSS) scores did not differ between these periods (0.17 [95% confidence interval: -0.06 to 0.4]; P=0.15). However, sixteen open label studies of GES showed a significant TSS decrease (2.68 [2.04-3.32]; Q=39.0; P<0.001). Other treatment modalities similarly improved TSS by 1.97 [1.5-2.44] for medical therapy (MED), by 1.52 [0.9-2.15] for placebo arms (PLA), and by 2.32 [1.56-3.06] for botulinum toxin (BTx). There were significant differences in baseline TSS ratings among these studies (GES: 6.28 [6.28-7.42]; MED: 4.76 [4.09-5.42]; PLA: 4.59 [3.77-5.42]; BTx: 6.02 [5.3-6.74]; Q=35.1; P<0.001). Meta-regression analysis showed these baseline differences to significantly impact TSS ratings during treatment (Q=71.8; P<0.001). CONCLUSION: Independent of the treatment modality, baseline symptom severity impacts treatment results in gastroparesis. Considering the skewed population with refractory symptoms, regression to the mean likely contributes to the substantial discrepancies between the reported results of controlled and open label GES studies, raising questions about the use of GES outside of defined clinical trials.

Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid.

The pleiotropic effects of retinoic acid (RA) in mammalian cells are mediated by two classes of proteins: the retinoic acid receptors (RAR) and cellular retinoic acid-binding proteins (CRABP-I and CRABP-II). Here we show that expression of CRABP-II, but not CRABP-I, markedly enhanced RAR-mediated transcriptional activation of a reporter gene in COS-7 cells. The equilibrium dissociation constants of complexes of CRABP-I or CRABP-II with RA were found to differ by 2-fold. It is thus unlikely that the distinct effects of the two proteins on transactivation stem from differential ligand-binding affinities. The mechanisms by which RA transfers from the CRABPs to RAR were thus investigated directly. The rate constant for movement of RA from CRABP-II, but not from CRABP-I, to RAR strongly depended on the concentration of the acceptor. The data suggest that transfer of RA from CRABP-I to RAR involves dissociation of the ligand from the binding protein, followed by association with the receptor. In contrast, movement of RA from CRABP-II to the receptor is facilitated by a mechanism that involves direct interactions between CRABP-II and RAR. These findings reveal a striking functional difference between CRABP-I and CRABP-II, and point at a novel mechanism by which the transcriptional activity of RA can be regulated by CRABP-II.