Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel

Background Advanced age is associated with a reduction in clinical visceral pain perception. However, the underlying mechanisms remain largely unknown. Previous studies have suggested that an abnormal interplay between mast cells, enterochromaffin (EC) cells, and afferent nerves contribute to nociception in gastrointestinal disorders. The aim of this study was to investigate how aging affects afferent sensitivity and neuro-immune association in the human bowel. Methods Mechanical and chemical sensitivity of human bowel afferents were examined by ex vivo afferent nerve recordings. Age-related changes in the density of mast cells, EC cells, sensory nerve terminals, and mast cell-nerve micro-anatomical association were investigated by histological and immune staining. Key Results Human afferents could be broadly classified into subpopulations displaying mechanical and chemical sensitivity, adaptation, chemo-sensitization, and recruitment. Interestingly human bowel afferent nerve sensitivity was attenuated with age. The density of substance P-immunoreactive (SP-IR) nerve varicosities was also reduced with age. In contrast, the density of ileal and colonic mucosal mast cells was increased with age, as was ileal EC cell number. An increased proportion of mast cells was found in close apposition to SP-IR nerves. Conclusions & Inferences Afferent sensitivity in human bowel was reduced with advancing age. Augmentation of mast cells and EC cell numbers and the mast cell-nerve association suggest a compensatory mechanism for sensory neurodegeneration

Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel.

BACKGROUND: Advanced age is associated with a reduction in clinical visceral pain perception. However, the underlying mechanisms remain largely unknown. Previous studies have suggested that an abnormal interplay between mast cells, enterochromaffin (EC) cells, and afferent nerves contribute to nociception in gastrointestinal disorders. The aim of this study was to investigate how aging affects afferent sensitivity and neuro-immune association in the human bowel. METHODS: Mechanical and chemical sensitivity of human bowel afferents were examined by ex vivo afferent nerve recordings. Age-related changes in the density of mast cells, EC cells, sensory nerve terminals, and mast cell-nerve micro-anatomical association were investigated by histological and immune staining. KEY RESULTS: Human afferents could be broadly classified into subpopulations displaying mechanical and chemical sensitivity, adaptation, chemo-sensitization, and recruitment. Interestingly human bowel afferent nerve sensitivity was attenuated with age. The density of substance P-immunoreactive (SP-IR) nerve varicosities was also reduced with age. In contrast, the density of ileal and colonic mucosal mast cells was increased with age, as was ileal EC cell number. An increased proportion of mast cells was found in close apposition to SP-IR nerves. CONCLUSIONS & INFERENCES: Afferent sensitivity in human bowel was reduced with advancing age. Augmentation of mast cells and EC cell numbers and the mast cell-nerve association suggest a compensatory mechanism for sensory neurodegeneration

Ageing and gastrointestinal sensory function: Altered colonic mechanosensory and chemosensory function in the aged mouse

Ageing has a profound effect upon gastrointestinal function through mechanisms that are poorly understood. Here we investigated the effect of age upon gastrointestinal sensory signalling pathways in order to address the mechanisms underlying these changes. In vitro mouse colonic and jejunal preparations with attached splanchnic and mesenteric nerves were used to study mechanosensory and chemosensory afferent function in 3-, 12- and 24-month-old C57BL/6 animals. Quantitative RT-PCR was used to investigate mRNA expression in colonic tissue and dorsal root ganglion (DRG) cells isolated from 3- and 24-month animals, and immunohistochemistry was used to quantify the number of 5-HT-expressing enterochromaffin (EC) cells. Colonic and jejunal afferent mechanosensory function was attenuated with age and these effects appeared earlier in the colon compared to the jejunum. Colonic age-related loss of mechanosensory function was more pronounced in high-threshold afferents compared to low-threshold afferents. Chemosensory function was attenuated in the 24-month colon, affecting TRPV1 and serotonergic signalling pathways. High-threshold mechanosensory afferent fibres and small-diameter DRG neurons possessed lower functional TRPV1 receptor responses, which occurred without a change in TRPV1 mRNA expression. Serotonergic signalling was attenuated at 24 months, but TPH1 and TPH2 mRNA expression was elevated in colonic tissue. In conclusion, we saw an age-associated decrease in afferent mechanosensitivity in the mouse colon affecting HT units. These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease

Gastrointestinal motor and sensory function in complicated and uncomplicated peptic ulcer disease.

Peptic ulcer disease is common. The exact pathophysiology of peptic ulcer disease is still unclear. However, major causes of peptic ulcer disease are Helicobacter pylori infection and Non-steroidal anti-inflammatory drugs (NSAIDs) used. Peptic ulcer disease usually manifests as either dyspepsia or, less commonly, with life threatening complications such as bleeding and perforation (Linder and Wilcox 2001). Over the past two decades the incidence of uncomplicated peptic ulcer disease has dropped substantially, whilst the incidence of peptic ulcer bleeding seems to have remained unchanged (Lassen, Hallas et al. 2006; Post, Kuipers et al. 2006). Approximately 30% to 50% of patients with bleeding peptic ulcer are asymptomatic until bleeding occurs (Croker 1991) even though the endoscopic assessment may reveal multiple ulcer scars suggestive of previous ulceration. Moreover, the majority of patients dying from peptic ulceration have no symptoms of ulcer disease until the presentation of their final, fatal illness (Pounder 1989). The mechanism of ulcer pain is still unclear. However, several factors have been associated with silent peptic ulceration. Older age and NSAIDs have been shown to be associated with asymptomatic peptic ulcer (Clinch, Banerjee et al. 1984; Mellem, Stave et al. 1985; Dew 1987), although this notion has been challenged (Wilcox and Clark 1997; Lu, Chang et al. 2004). While, no study has reported in relate to visceral sensory function in patients with peptic ulcer disease. Altered gastric motor function has been proposed to be associated with the pathogenesis of peptic ulcer disease, though this idea is not well acknowledged. Gastric motor function and visceral sensory function may be the key responsible for the difference between clinical manifestations of complicated and uncomplicated peptic ulcer. The incidence and proportion of patients between symptomatic and asymptomatic peptic ulcer is unknown. Few studies have shown the factors that could be associated with asymptomatic peptic ulcer such as age, NSAIDs and ulcer size. This research aims of this thesis were, therefore, to examine: (i) the effect of age on gastric sensory function using the nutrient challenge test; (ii) assess symptom profiles and compare visceral sensory thresholds in patients with bleeding peptic ulcer, uncomplicated peptic ulcer disease and healthy controls; (iii) assess gastric emptying in patients with bleeding peptic ulcer, uncomplicated peptic ulcer and healthy controls, and the relationship between symptoms and gastric emptying; (iv) study the link between immune activation and clinical manifestation of patients with peptic ulcer disease and explore the link between anxiety or depression and the release of inflammatory cytokine; (v) determine the incidence and risk factors of uncomplicated peptic ulcer disease, bleeding peptic ulcer and asymptomatic peptic ulcer, and changes of epidemiology of peptic ulcer disease over a 10-year period, between 1997 to 2007, at the Royal Adelaide Hospital; (vi) compare the symptoms reported in patients with uncomplicated peptic ulcer compared with bleeding peptic ulcer after 1 year of ulcer healing; (vi) assess the distribution of GNB3 C825T polymorphisms and the association between GNB 3 528 polymorphisms and symptoms during a nutrient challenge in healthy subjects. The current study indicates that elderly people have decreased gastric visceral sensation compared with younger people. This study also shows that patients with uncomplicated peptic ulcer have an augmented symptom response and significantly delayed gastric emptying whilst patients with bleeding peptic ulcer have a symptom response to a test meal and gastric emptying time that is not different from that in healthy control, suggesting fundamental difference in visceral sensitivity and abnormal gastric motor function suggesting a between patients with bleeding or asymptomatic ulcers and those with symptomatic or uncomplicated ulcers. Our findings also showed that there were increased levels of systemic proinflammatory cytokines in patients with uncomplicated peptic ulcer, despite the ulcer had healed, compared with patients with bleeding peptic ulcer and healthy control. The findings further support the notion that patients with uncomplicated peptic ulcer share similarities with patients with functional dyspepsia. The study in this thesis also demonstrates the epidemiology of symptomatic and asymptomatic peptic ulcer disease over the past 10 years at the Royal Adelaide Hospital, including the risk of being asymptomatic peptic ulcer. The study shows that over the last 10 years, the incidence of uncomplicated peptic ulcer has decreased whereas bleeding peptic ulcer has remained stable. The work described in Chapter 15 demonstrates that most patients with dyspeptic symptoms prior to the diagnosis of peptic ulcer disease continue to have dyspeptic symptoms 12 months after ulcer healing and Helicobacter pylori eradication. Patients with persistent dyspeptic symptoms have higher level of anxiety and depression score than patients without symptoms. The data suggest that most patients with symptomatic peptic ulcer disease have concomitant functional dyspepsia, which may have led to the diagnostic endoscopy being performed that probably prevented the development of a life threatening ulcer bleed. Based upon our data it might be speculated that mechanisms that are involved into the manifestation of symptoms in patients with functional dyspepsia may actually prevent the manifestation of ulcer complications since ulcers manifest with symptoms that trigger health care seeking and treatment before complications occur. Chapter 16 of this thesis might potentially explain one of the mechanisms of abdominal pain. The work described in this study shows that GNB3 825T-CC plays a role in the processing of visceral sensory information or the gastrointestinal motor responses to a nutrient challenge. By doing so, the research studies which were conducted as part of this thesis have significantly improved and added new knowledge in the fields of gastric motor and sensory function in peptic ulcer disease. In conclusion, the thesis has highlighted the differences in gastric motor function, gastrointestinal sensory function and immune activation between patients with uncomplicated peptic ulcer disease and bleeding peptic ulcer. This thesis also showed the epidemiologic data of patients with symptomatic and asymptomatic peptic ulcer disease, including the risk factors of being asymptomatic peptic ulcer. The results have important therapeutic implications, and suggest aggressive management of patients with peptic ulcer disease. In addition, the research study also suggests further studies in the areas of the mechanism and pathogenesis of peptic ulcer pain, and abdominal pain, which are likely to result in better strategies to manage and prevent this important clinical condition.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201

A simple deformable model for shark recognition

The great white shark is a large marine animal that is a potential threat to swimmers. There were many shark attack reports worldwide and many of the attacks happened in shallow waters. One way to reduce the incidence of shark attacks is to employ shark patrols. This is done by flying a light plane along the coast and the shark spotting is done by humans. The aim of this research is to automate this process. Gururatsakul [2] proposed a technique to recognize sharks from dolphins and shark-like objects in top-view aerial images by focusing on shape feature characteristics. This work proposes an alternate way of distinguishing sharks from dolphins and shark-like objects by considering two-dimensional deformable models. A deformable model is represented by variables and two reference tables. These variables are optimized (deforming the model to best fit a test object) by iteratively adjusting their values to reduce the error output from the objective function. The classification of sharks from dolphins and shark-like objects is based on the best matching model. A high result of 93% on identifying sharks, dolphins, and shark-like objects has been achieved by the proposed method.Suthep Gururatsakul, Danny Gibbins, David Kearne

Complicated and uncomplicated peptic ulcer disease: altered symptom response to a nutrient challenge linked to gastric motor dysfunction

Background: Bleeding peptic ulcer (BPU) frequently occurs in the absence of preceding dyspeptic symptoms. We have observed that patients with BPU had a diminished symptom response to nutrient challenge test compared to uncomplicated peptic ulcer disease (uPUD). We postulated that more symptoms are manifest in patients with uPUD than BPU because there are greater derangements in gastric motor function. Aim: To assess gastric emptying in patients with BPU, uPUD and healthy controls (HC). Methods: We studied 17 patients with BPU, 10 with uPUD, and 15 HC. After an 8-hour fast, subjects ingested 200 ml of an enteral feeding solution, containing 5 MBq ⁹⁹^mTc-rhenium sulphide colloid, every 5 min up to a cumulative volume of 800 ml. Gastric emptying was measured by scintigraphy for the total, proximal and distal stomach. Results: Patients with uPUD had significantly higher gastric retention in the proximal and total stomach at 100 min than HC and BPU, while BPU had similar percent retention to HC. Patients with uPUD had significantly higher cumulative symptom response to the nutrient challenge than did HC and BPU, while BPU had similar symptom responses to HC. Conclusions: Patients with uPUD have significantly delayed gastric emptying compared to HC and BPU. Data suggest that in addition to alterations of visceral sensory function, altered gastric motor function occurs during a nutrient challenge in uPUD but not BPU. Gastric motor function may contribute to the manifestation of dyspeptic symptoms in PUD