A missing sphincteric component of the gastro-oesophageal junction in patients with GORD

Abstract  It was recently shown that the tonic pressure contribution to the high-pressure zone of the oesophago-gastric segment (OGS) contains the contributions from three distinct components, two of which are smooth muscle intrinsic sphincter components, a proximal and a distal component [ J Physiol 2007; 580.3 : 961 ]. The aim of this study was to compare the pressure contributions from the three sphincteric components in normal subjects with those in gastro-oesophageal reflux disease (GORD) patients. A simultaneous endoluminal ultrasound and manometry catheter was pulled through the OGS in 15 healthy volunteers and seven patients with symptomatic GORD, before and after administration of atropine. Pre-atropine (complete muscle tone), postatropine (non-muscarinic muscle tone plus residual muscarinic tone) and subtracted (pure muscarinic muscle tone) pressure contributions to the sphincter were averaged after referencing spatially to the right crural diaphragm and the pull-through start position. In the normal group, the atropine-resistant and atropine-attenuated pressures identified the crural and two smooth muscle sphincteric components respectively. The subtraction pressure curve contained proximal and distal peaks. The proximal component moved with the crural sling between full inspiration and full expiration and the distal component coincided with the gastric sling-clasp fibre muscle complex. The subtraction curve in the GORD patients contained only a single pressure peak that moved with the crural sphincter, while the distal pressure peak of the intrinsic muscle component, which was previously recognized in the normal subjects, was absent. We hypothesize that the distal muscarinic smooth muscle pressure component (gastric sling/clasp muscle fibre component) is defective in GORD patients.     

Regulation of interstitial cells of Cajal in the mouse gastric body by neuronal nitric oxide

The factors underlying the survival and maintenance of interstitial cells of Cajal (ICC) are not well understood. Loss of ICC is often associated with loss of neuronal nitric oxide synthase (nNOS) in humans, suggesting a possible link. The aim of this study was to determine the effect of neuronal NO on ICC in the mouse gastric body. The volumes of ICC were determined in nNOS(-/-) and control mice in the gastric body and in organotypic cultures using immunohistochemistry, laser scanning confocal microscopy and three-dimensional reconstruction. ICC numbers were determined in primary cell cultures after treatment with an NO donor or an NOS inhibitor. The volumes of myenteric c-Kit-immunoreactive networks of ICC from nNOS(-/-) mice were significantly reduced compared with control mice. No significant differences in the volumes of c-Kit-positive ICC were observed in the longitudinal muscle layers. ICC volumes were either decreased or unaltered in the circular muscle layer after normalization for the volume of circular smooth muscle. The number of ICC was increased after incubation with S-nitroso-N-acetylpenicillamine and decreased by N(G)-nitro-l-arginine. Neuronally derived NO modulates ICC numbers and network volume in the mouse gastric body. NO appears to be a survival factor for ICC.     

Apoptotic cell death of human interstitial cells of Cajal

Abstract  Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabelling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabelling for activated caspase-3, terminal dUTP nucleotide end labelling and by ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double-labelled tissue sections. They were identified in all layers of the colonic muscle. In the muscularis propria 1.5 ± 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 ± 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is a continuing process in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.     

Hip strength: Ankle proprioceptive threshold ratio predicts falls and injury in diabetic neuropathy

Introduction: We determined lower limb neuromuscular capacities associated with falls and fall‐related injuries in older people with declining peripheral nerve function. Methods: Thirty‐two subjects (67.4 ± 13.4 years; 19 with type 2 diabetes), representing a spectrum of peripheral neurologic function, were evaluated with frontal plane proprioceptive thresholds at the ankle, frontal plane motor function at the ankle and hip, and prospective follow‐up for 1 year. Results: Falls and fall‐related injuries were reported by 20 (62.5%) and 14 (43.8%) subjects, respectively. The ratio of hip adductor rate of torque development to ankle proprioceptive threshold (Hip^STR/Ank_PRO) predicted falls (pseudo‐R² = .726) and injury (pseudo‐R² = .382). No other variable maintained significance in the presence of Hip^STR/Ank_PRO. Conclusions: Fall and injury risk in the population studied is related inversely to Hip^STR/Ank_PRO. Increasing rapidly available hip strength in patients with neuropathic ankle sensory impairment may decrease risk of falls and related injuries. Muscle Nerve 50 : 437–442, 2014     

Distribution of interstitial cells of Cajal and nitrergic neurons in normal and diabetic human appendix

Abstract  The objective of this study was to determine the distribution of enteric nerves and interstitial cells of Cajal (ICC) in the normal human appendix and in type 1 diabetes. Appendixes were collected from patients with type 1 diabetes and from non-diabetic controls. Volumes of nerves and ICC were determined using 3-D reconstruction and neuronal nitric oxide synthase (nNOS) expressing neurons were counted. Enteric ganglia were found in the myenteric plexus region and within the longitudinal muscle. ICC were found throughout the muscle layers. In diabetes, c-Kit positive ICC volumes were significantly reduced as were nNOS expressing neurons. In conclusion, we describe the distribution of ICC and enteric nerves in health and in diabetes. The data also suggest that the human appendix, a readily available source of human tissue, may be useful model for the study of motility disorders.     

Prognostic significance of ischemic electrocardiographic changes during vasodilator stress testing in patients with normal SPECT images

BACKGROUND: Patients with ischemic electrocardiographic (ECG) findings during exercise stress testing but normal perfusion images generally have a low risk of cardiac death or myocardial infarction (<1% per year). During vasodilator stress testing, however, the prognostic significance of the combination of normal perfusion images and ischemic ECG changes is unknown. METHODS AND RESULTS: Among 5526 patients who underwent vasodilator stress single photon emission computed tomography (SPECT), 49 (0.9%) had normal images but ischemic ECG changes. A unique feature of this population was that 43 (88%) were women with a mean age of 67 +/- 10 years. Ischemic ECG changes occurred at a mean heart rate of 101 +/- 15 beats per minute and persisted for 6.8 +/- 4.7 minutes after termination of drug infusion. During follow-up of 28 +/- 20 months, cardiac death occurred in 2 patients and nonfatal myocardial infarction in 4 patients. The rate of cardiac death or nonfatal myocardial infarction was 4% at 1 year, 10% at 2 years, and 14% at 3 years. Of the 12 patients who underwent coronary angiography or autopsy during follow-up, 11 had multivessel coronary artery disease, indicating that these patients likely had false-negative SPECT image results. Eight patients required coronary revascularization. CONCLUSIONS: The finding of ischemic ECG changes with normal SPECT images during vasodilator infusion is uncommon, occurs primarily in older women, and is associated with a higher subsequent cardiac event rate than is customarily associated with normal images.