Inhibition of Neuromuscular Contractions of Human and Rat Colon by Bergamot Essential Oil and Linalool: Evidence to Support a Therapeutic Action

Bergamot essential oil (BEO) added to food and drink promotes a citrus flavour. Folklore suggests benefits on gastrointestinal functions but with little supporting evidence. BEO and major constituents (linalool, limonene, linalyl acetate) were therefore examined for any ability to influence neuromuscular contractions of human and rat colon. Circular muscle strips (macroscopically-normal human colon obtained following ethical approval at cancer surgery; Sprague–Dawley rats) were suspended in baths (Krebs solution; 37 °C; 5% CO2 in O2) for measurement of neuronally-mediated contractions (prevented by tetrodotoxin or atropine) evoked by electrical field stimulation (5 Hz, 0.5 ms pulse width, 10s/minute, maximally-effective voltage), or contractions evoked by KCl (submaximally-effective concentrations). BEO and each constituent concentration dependently inhibited neuronally-mediated and KCl-induced contractions. In human: apparent pIC50 for BEO (volume/volume Krebs), respectively, 3.8 ± 0.3 and 4.4 ± 0.3; Imax 55.8% ± 4.2% and 37.5% ± 4.2%. For the constituents, the rank order of potency differed in human (linalool > limonene >> linalyl-acetate) and rat colon (linalyl-acetate > limonene = linalool), but rank order of efficacy was similar (linalool >> (BEO) = linalyl-acetate >> limonene). Thus, linalool had high efficacy but greater potency in human colon (Imax 76.8% ± 6.9%; pIC50 6.7 ± 0.2; n = 4) compared with rat colon (Imax 75.3% ± 1.9%; pIC50 5.8 ± 0.1; n = 4). The ability of BEO and linalool to inhibit human colon neuromuscular contractility provides a mechanism for use as complementary treatments of intestinal disorders

Implantable Cardioverter Defibrillator Therapy in Patients with Cardiac Sarcoidosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93643/1/j.1540-8167.2012.02350.x.pd

Dose-limiting, adverse event-associated bradycardia with β-blocker treatment of atrial fibrillation in the GENETIC-AF trial

Background: Heart failure (HF) patients with atrial fibrillation (AF) often have conduction system disorders, which may be worsened by β-blocker therapy.Objective: In a post hoc analysis we examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF trial.Methods: Patients randomized to metoprolol (n = 125) or bucindolol (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated. Bradycardia was defined as an electrocardiogram (ECG) heart rate (HR) &lt;60 beats per minute (bpm) and severe bradycardia &lt;50 bpm.Results: Mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for bucindolol (P &lt; .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Episodes per patient for bucindolol vs metoprolol were 0.82 vs 2.08 (P &lt; .001) for bradycardia and 0.24 vs 0.57 for severe bradycardia (P &lt; .001), with 98.9% of the episodes occurring in SR. Patients experiencing bradycardia had a 4.15-fold higher prevalence of study medication dose reduction (P &lt;.0001) compared to patients without bradycardia. Fewer patients receiving metoprolol were at target dose (61.7% vs 74.9% for bucindolol, P &lt; .0001) at ECG recordings, and bradycardia AEs were more prevalent in the metoprolol group (13 vs 1 for bucindolol, P = .001). On multivariate analysis of 21 candidate bradycardia predictors including presence of a device with pacing capability, bucindolol treatment was associated with the greatest degree of prevention (Zodds ratio -4.24, P &lt; .0001).Conclusion: In AF-prone HF patients bradycardia may limit the effectiveness of β blockers, and this property is agent-dependent.</p

Automated Analysis of Craniofacial Morphology Using Magnetic Resonance Images

Quantitative analysis of craniofacial morphology is of interest to scholars working in a wide variety of disciplines, such as anthropology, developmental biology, and medicine. T1-weighted (anatomical) magnetic resonance images (MRI) provide excellent contrast between soft tissues. Given its three-dimensional nature, MRI represents an ideal imaging modality for the analysis of craniofacial structure in living individuals. Here we describe how T1-weighted MR images, acquired to examine brain anatomy, can also be used to analyze facial features. Using a sample of typically developing adolescents from the Saguenay Youth Study (N = 597; 292 male, 305 female, ages: 12 to 18 years), we quantified inter-individual variations in craniofacial structure in two ways. First, we adapted existing nonlinear registration-based morphological techniques to generate iteratively a group-wise population average of craniofacial features. The nonlinear transformations were used to map the craniofacial structure of each individual to the population average. Using voxel-wise measures of expansion and contraction, we then examined the effects of sex and age on inter-individual variations in facial features. Second, we employed a landmark-based approach to quantify variations in face surfaces. This approach involves: (a) placing 56 landmarks (forehead, nose, lips, jaw-line, cheekbones, and eyes) on a surface representation of the MRI-based group average; (b) warping the landmarks to the individual faces using the inverse nonlinear transformation estimated for each person; and (3) using a principal components analysis (PCA) of the warped landmarks to identify facial features (i.e. clusters of landmarks) that vary in our sample in a correlated fashion. As with the voxel-wise analysis of the deformation fields, we examined the effects of sex and age on the PCA-derived spatial relationships between facial features. Both methods demonstrated significant sexual dimorphism in craniofacial structure in areas such as the chin, mandible, lips, and nose

Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease

Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor β1 (TGFβ) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors. β-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFβ signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in β-catenin-positive cells. In vitro, activation of Wnt-β-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of β-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFβ increased β-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFβ up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a β-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They also highlight the importance of the cross-talk between Wnt and TGFβ signalling pathways in CD intestinal fibrosis

Distinct contributions of extrastriate body area and temporoparietal junction in perceiving one's own and others' body.

The right temporoparietal cortex plays a critical role in body representation. Here, we applied repetitive transcranial magnetic stimulation (rTMS) over right extrastriate body area (EBA) and temporoparietal junction (TPJ) to investigate their causative roles in perceptual representations of one's own and others' body. Healthy women adjusted size-distorted pictures of their own body or of the body of another person according to how they perceived the body (subjective task) or how others perceived it (intersubjective task). In keeping with previous reports, at baseline, we found an overall underestimation of body size. Crucially, EBA-rTMS increased the underestimation bias when participants adjusted the images according to how others perceived their own or the other woman's body, suggesting a specific role of EBA in allocentric body representations. Conversely, TPJ-rTMS increased the underestimation bias when participants adjusted the body of another person, either a familiar other or a close friend, in both subjective and intersubjective tasks, suggesting an involvement of TPJ in representing others' bodies. These effects were body-specific, since no TMS-induced modulation was observed when participants judged a familiar object. The results suggest that right EBA and TPJ play active and complementary roles in the complex interaction between the perceptions of one's own and other people's body