Interstitial cell network volume is reduced in the terminal bowel of ageing mice

Ageing is associated with impaired neuromuscular function of the terminal gastrointestinal (GI) tract, which can result in chronic constipation, faecal impaction and incontinence. Interstitial cells of cajal (ICC) play an important role in regulation of intestinal smooth muscle contraction. However, changes in ICC volume with age in the terminal GI tract (the anal canal including the anal sphincter region and rectum)have not been studied. Here, the distribution, morphology and network volume of ICC in the terminal GI tract of 3‐to 4‐month‐old and 26‐to 28‐month‐old C57BL/6mice were investigated. ICC were identified by immunofluorescence labelling of wholemount preparations with an antibody against c‐Kit. ICC network volume was measured by software‐based 3D volume rendering of confocal Z stacks. A significant reduction in ICC network volume per unit volume of muscle was measured in aged animals. No age‐associated change in ICC morphology was detected. The thickness of the circular muscle layer of the anal sphincter region and rectum increased with age, while that in the distal colon decreased. These results suggest that ageing is associated with a reduction in the network volume of ICC in the terminal GI tract, which may influence the normal function of these regions

Finite element investigation of the effect of spina bifida on loading of the vertebral isthmus

Background: Spondylolysis (SL) of the lower lumbar spine is frequently associated with spina bifida occulta (SBO). There has not been any study that has demonstrated biomechanical or genetic predispositions to explain the coexistence of these two pathologies. In axial rotation, the intact vertebral arch allows torsional load to be shared between the facet joints. In SBO, the load cannot be shared across the arch, theoretically increasing the mechanical demand of the vertebral isthmus during combined axial loading and rotation when compared to the normal state. Purpose: To test the hypothesis that fatigue failure limits will be exceeded in the case of a bifid arch, but not in the intact case, when the segment is subjected to complex loading corresponding to normal sporting activities. Study Design: Descriptive Laboratory Study. Methods: Finite element models of natural and SBO (L4-S1) including ligaments were loaded axially to 1kN and were combined with axial rotation of 3°. Bilateral stresses, alternating stresses and shear fatigue failure on intact and SBO L5 isthmus were assessed and compared. Results: Under 1kN axial load, the von Mises stresses observed in SBO and in the intact cases were very similar (differences <5MPa) having a maximum at the ventral end of the isthmus that decreases monotonically to the dorsal end. However, under 1kN axial load and rotation, the maximum von Mises stresses observed in the ipsilateral L5 isthmus in the SBO case (31MPa) was much higher than the intact case (24.2MPa) indicating a lack of load sharing across the vertebral arch in SBO. When assessing the equivalent alternating shear stress amplitude, this was found to be 22.6 MPa for the SBO case and 13.6 MPa for the intact case. From this it is estimated that shear fatigue failure will occur in less than 70,000 cycles, under repetitive axial load & rotation conditions in the SBO case, while for the intact case, fatigue failure will occur only over 10 million cycles. Conclusion: SBO predisposes spondylolysis by generating increased stresses across the inferior isthmus of the inferior articular process, specifically in combined axial rotation and anteroposterior shear. Clinical Relevance: Athletes with SBO who participate in sports that require repetitive lumbar rotation, hyperextension and/or axial loading are at a higher risk of developing spondylolysis compared to athletes with an intact spine

Amperometry approach curve profiling to understand the regulatory mechanisms governing the concentration of intestinal extracellular serotonin

Enterochromaffin (EC) cells located within the intestinal mucosal epithelium release serotonin (5-HT) to regulate motility tones, barrier function and the immune system. Electroanalytical methodologies have been able to monitor steady state basal extracellular 5-HT levels but are unable to provide insight into how these levels are influenced by key regulatory processes such as release and uptake. We established a new measurement approach, amperometry approach curve profiling, which monitors the extracellular 5-HT level at different electrode–tissue (E–T) distances. Analysis of the current profile can provide information on contributions of regulatory components on the observed extracellular 5-HT level. Measurements were conducted from ex vivo murine ileum and colon using a boron-doped diamond (BDD) microelectrode. Amperometry approach curve profiling coupled with classical pharmacology demonstrated that extracellular 5-HT levels were significantly lower in the colon when compared to the ileum. This difference was due to a greater degree of activity of the 5-HT transporter (SERT) and a reduced amount of 5-HT released from colonic EC cells. The presence of an inhibitory 5-HT4 autoreceptor was observed in the colon, where a 40% increase in extracellular 5-HT was the half maximal inhibitory concentration for activation of the autoreceptor. This novel electroanalytical approach allows estimates of release and re-uptake and their contribution to 5-HT extracellular concentration from intestinal tissue be obtained from a single series of measurements

Multi-instrument observations of the effects of a solar wind pressure pulse on the high latitude ionosphere : a detailed case study of a geomagnetic sudden impulse

Funding: ARF was supported by an STFC studentship, Science Foundation Ireland Grant 18/FRL/6199, and an Irish Research Council Government of Ireland Postdoctoral Fellowship GOIPD/2022/782. ML, TKY, and SEM acknowledge support from the Science and Technology Facilities Council, UKRI, grant no. ST/W00089X/1. JAC is supported by Royal Society grant DHF\R1\211068. HKS was supported by an STFC studentship. TE was supported by a Leverhulme Trust Early Career Fellowship (ECF-2019-155), the University of Leicester and the University of Glasgow. SJW was supported by NERC studentship NE/L002493/1. MKJ was supported by STFC Grant ST/W00089X/1. JML was supported by the Irish Research Council. LJP was supported by AFOSR MURI Award 26-0201-51-62.The effects of a solar wind pressure pulse on the terrestrial magnetosphere have been observed in detail across multiple datasets. The communication of these effects into the magnetosphere is known as a positive geomagnetic sudden impulse (+SI), and are observed across latitudes and different phenomena to characterise the propagation of +SI effects through the magnetosphere. A superposition of Alfvén and compressional propagation modes are observed in magnetometer signatures, with the dominance of these signatures varying with latitude. For the first time, collocated lobe reconnection convection vortices and region 0 field aligned currents are observed preceding the +SI onset, and an enhancement of these signatures is observed as a result of +SI effects. Finally, cusp auroral emission is observed collocated with the convection and current signatures. For the first time, simultaneous observations across multiple phenomena are presented to confirm models of +SI propagation presented previously.Publisher PDFPeer reviewe

Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics

Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps. Methods and Findings We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes. Conclusion A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.Daniel D. Buchanan, Kevin Sweet, Musa Drini, Mark A. Jenkins, Aung Ko Win, Dallas R. English, Michael D. Walsh, Mark Clendenning, Diane M. McKeone, Rhiannon J. Walters, Aedan Roberts, Sally-Ann Pearson, Erika Pavluk, John L. Hopper, Michael R. Gattas, Jack Goldblatt, Jill George, Graeme K. Suthers, Kerry D. Phillips, Sonja Woodal, Julie Arnold, Kathy Tucker, Amanda Muir, Michael Field, Sian Greening, Steven Gallinger, Renee Perrier, John A. Baron, John D. Potter, Robert Haile, Wendy Franke, Albert de la Chapelle, Finlay Macrae, Christophe Rosty, Neal I. Walker, Susan Parry and Joanne P. Youn

Microelectrode investigation of neuroneal ageing from a single identified neurone

Microelectrode amperometry is uniquely suited for characterising the dynamics of neurotransmitter release, as it offers unparalleled spatial and temporal resolution. We have used carbon fibre microelectrodes to study release of the monoamine neurotransmitter serotonin (5-HT) and the gaseous transmitter nitric oxide (NO) in intact central nervous system of the water snail, Lymnaea stagnalis. Analysis of spontaneous vesicular release of 5-HT and depolarisation-induced release of NO reveals significant differences with ageing that may be associated with changes in protein structure and function

Simple and rapid determination of serotonin and catecholamines in biological tissue using high-performance liquid chromatography with electrochemical detection

Using the CNS of Lymnaea stagnalis a method is described for the rapid analysis of neurotransmitters and their metabolites using high performance liquid chromatography coupled with electrochemical detection. Tissue samples were homogenised in ice-cold 0.1 M perchloric acid and centrifuged. Using a C18 microbore column the mobile phase was maintained at a flow rate of 100 ?l/min and consisted of sodium citrate buffer (pH 3.2)–acetonitrile (82.5:17.5, v/v) with 2 mM decane-sulfonic acid sodium salt. The potential was set at +750 mV versus Ag|AgCl reference electrode at a sensitivity of 50 nA full scale deflection. The detection limit for serotonin was 11.86 ng ml?1 for a 5 ?l injection. Preparation of tissue samples in mobile phase reduced the response to dopamine and serotonin compared with perchloric acid. In addition it was found that the storage of tissue samples at ?20 °C caused losses of dopamine and serotonin. As a result of optimising the sample preparation and mobile phase the total time of analysis was substantially reduced resulting in a sample preparation and assay time of 15–20 min