Association of Body Mass and Brain Activation during Gastric Distention: Implications for Obesity

BACKGROUND:Gastric distention (GD), as it occurs during meal ingestion, signals a full stomach and it is one of the key mechanisms controlling food intake. Previous studies on GD showed lower activation of the amygdala for subjects with higher body mass index (BMI). Since obese subjects have dopaminergic deficits that correlate negatively with BMI and the amygdala is innervated by dopamine neurons, we hypothesized that BMI would correlate negatively with activation not just in the amygdala but also in other dopaminergic brain regions (midbrain and hypothalamus). METHODOLOGY/PRINCIPAL FINDINGS:We used functional magnetic resonance imaging (fMRI) to evaluate brain activation during GD in 24 healthy subjects with BMI range of 20-39 kg/m(2). Using multiple regression and cross-correlation analyses based on a family-wise error corrected threshold P = 0.05, we show that during slow GD to maximum volumes of 500 ml and 700 ml subjects with increased BMI had increased activation in cerebellum and left posterior insula, and decreased activation of dopaminergic (amygdala, midbrain, hypothalamus, thalamus) and serotonergic (pons) brain regions and anterior insula, regions that were functionally interconnected with one another. CONCLUSIONS:The negative correlation between BMI and BOLD responses to gastric distention in dopaminergic (midbrain, hypothalamus, amygdala, thalamus) and serotonergic (pons) brain regions is consistent with disruption of dopaminergic and serotonergic signaling in obesity. In contrast the positive correlation between BMI and BOLD responses in posterior insula and cerebellum suggests an opposing mechanism that promotes food intake in obese subjects that may underlie their ability to consume at once large food volumes despite increasing gastric distention

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

BOLD signals in hypo-activated regions vs. BMI.

<p>Scatter plots exemplifying the negative correlations between BMI and the average BOLD-fMRI responses across all volumetric conditions (125, 375, 500, 600, and 700 ml) in dopaminergic brain regions (hypothalamus, midbrain, and amygdala) during gradual GD (N = 24).</p

Gradual gastric distention (GD) paradigm.

<p>The deflated balloon was inserted orally and positioned in the stomach 2-cm above the gastro-esophageal junction. The solid and dashed lines depict the emptied (0 ml) and filled (500 ml for GD1 or 700 ml for GD2) balloon conditions. The balloon was filled and emptied with constant flow (5 ml/s) of tap water (warmed at 37°C) in either 90s to 500 ml (GD1) or in 140 s to 700 ml (GD2). The vagus nerve transmits the signal of a full stomach to the solitary and parabrachial nuclei in the brain stem that project to dopaminergic and serotonergic nuclei in midbrain and pons. Other regions implicated in the control of food intake are additionally highlighted (hypothalamus, amygdala, and cerebellum).</p

Association of BOLD signals in hyper- and hypo-activated regions.

<p>Regression plots exemplifying positive and negative cross-correlations of BOLD-fMRI signals (averaged across all volumetric conditions; 125, 375, 500, 600, and 700 ml) in different ROIs (listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006847#pone-0006847-t001" target="_blank">Table 1</a>). Sample = 24 subjects.</p

Behavioral responses during gradual GD.

<p>Ratings of fullness, discomfort, hunger, and desire for food, collected during the empty and full balloon conditions for GD1 (500 ml) and GD2 (700 ml). (*) P<0.0002.</p

Functional Connectivity during gastric distention.

<p>Statistically significant cross-correlations among time-varying fMRI signals in the 27 ROIs listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006847#pone-0006847-t001" target="_blank">Table 1</a>; Sample: 24 subjects, 90 fMRI runs; t-test; statistical threshold <i>P</i>_c<0.05 (Bonferroni correction for 351 comparisons).</p

BOLD signals in hyper-activated regions vs. BMI.

<p>Scatter plots exemplifying the positive correlations between the body mass index (BMI) and the average BOLD-fMRI response across all volumetric conditions (125, 375, 500, 600, and 700 ml) in cerebellum and posterior insula during gradual GD (N = 24).</p

Brain activation during gradual gastric distention (GD).

<p>Top panel: Statistical maps showing regions with significant brain activation (red-yellow) and deactivation (blue-green) during gradual GD. Bottom panel: correlations between BMI and BOLD-fMRI responses in the brain during gradual GD. Threshold for statistical significance: <i>P</i>_corr<0.05 corrected for multiple comparisons using the family-wise error (FWE) correction. Sample: 24 healthy controls. Data from all 47 GD1 and 43 GD2 fMRI runs were included in SPM2 multiple regression analyses. Activation/correlation patterns reflecting the effect of volume were not significant in any brain region.</p