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Radenkovic G, Petrovic V, Zivanovic D, Stoiljkovic N, Sokolovic D, Zivkovic N, Radenkovic D, Velickov A, Jovanovic J. Interstitial Cells of Cajal and Neural Structures in the Human Fetal Appendix. J Neurogastroenterol Motil 2021; 27:127-133. [PMID: 33380557 PMCID: PMC7786081 DOI: 10.5056/jnm20100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/11/2020] [Accepted: 08/24/2020] [Indexed: 11/20/2022] Open
Abstract
Background/Aims The interstitial cells of Cajal (ICC) are located within and around the digestive tract's muscle layers. They function as intestinal muscle pacemakers and aid in the modification of enteric neurotransmission. The appendix's unique position requires an appropriate contraction pattern of its muscular wall to adequately evacuate its contents. We investigated the development and distribution of nervous structures and ICC in the human fetal appendix. Methods Specimens were exposed to anti-c-kit (CD117) antibodies to investigate ICC differentiation. Enteric plexuses were examined using anti-neuron-specific enolase, and the differentiation of smooth muscle cells was studied with anti-desmin antibodies. Results During weeks 13-14, numerous myenteric plexus ganglia form an almost uninterrupted sequence throughout the body and apex of the appendix. Fewer ganglia were present at the submucosal border of the circular muscle layer and within this layer. A large number of ganglia appear within the circular and longitudinal muscle layers in a later fetal period. The first ICC subtypes noted were of the myenteric plexus and the submucous plexus. In the later fetal period, the number of intramuscular ICC markedly rises, and this subtype becomes predominant. Conclusions The ICC and nervous structure distribution in the human fetal appendix are significantly different from all other parts of the small and large intestine. The organization of ICC and the enteric nervous system provides the basis for the specific contraction pattern of the muscular wall of the appendix.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Serbia
| | - Vladimir Petrovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Serbia
| | | | - Nenad Stoiljkovic
- Department of Physiology, Faculty of Medicine, University of Nis, Serbia
| | - Dusan Sokolovic
- Department of Biochemistry, Faculty of Medicine, University of Nis, Serbia
| | - Nikola Zivkovic
- Department of Pathology, Faculty of Medicine, University of Nis, Serbia
| | - Dina Radenkovic
- Guy's and St Thomas' Hospital and King's College London, London, UK
| | - Aleksandra Velickov
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Serbia
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Bódi N, Szalai Z, Bagyánszki M. Nitrergic Enteric Neurons in Health and Disease-Focus on Animal Models. Int J Mol Sci 2019; 20:ijms20082003. [PMID: 31022832 PMCID: PMC6515552 DOI: 10.3390/ijms20082003] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/17/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
Nitrergic enteric neurons are key players of the descending inhibitory reflex of intestinal peristalsis, therefore loss or damage of these neurons can contribute to developing gastrointestinal motility disturbances suffered by patients worldwide. There is accumulating evidence that the vulnerability of nitrergic enteric neurons to neuropathy is strictly region-specific and that the two main enteric plexuses display different nitrergic neuronal damage. Alterations both in the proportion of the nitrergic subpopulation and in the total number of enteric neurons suggest that modification of the neurochemical character or neuronal death occurs in the investigated gut segments. This review aims to summarize the gastrointestinal region and/or plexus-dependent pathological changes in the number of nitric oxide synthase (NOS)-containing neurons, the NO release and the cellular and subcellular expression of different NOS isoforms. Additionally, some of the underlying mechanisms associated with the nitrergic pathway in the background of different diseases, e.g., type 1 diabetes, chronic alcoholism, intestinal inflammation or ischaemia, will be discussed.
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Affiliation(s)
- Nikolett Bódi
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary.
| | - Zita Szalai
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary.
| | - Mária Bagyánszki
- Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary.
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Zhao J, Yang J, Liao D, Gregersen H. Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine. Clin Exp Gastroenterol 2017; 10:303-314. [PMID: 29238211 PMCID: PMC5716675 DOI: 10.2147/ceg.s145016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jian Yang
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Donghua Liao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Hans Gregersen
- Giome Center, Department of Surgery, Chinese University of Hong Kong and Prince of Wales Hospital, Shatin, Hong Kong
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Sun Y, Yang PP, Song ZY, Feng Y, Hu DM, Hu J, Xu GY, Zhang HH. α-lipoic acid suppresses neuronal excitability and attenuates colonic hypersensitivity to colorectal distention in diabetic rats. J Pain Res 2017; 10:1645-1655. [PMID: 28769585 PMCID: PMC5529097 DOI: 10.2147/jpr.s135017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
AIM Patients with long-standing diabetes often demonstrate intestinal dysfunction, characterized as constipation or colonic hypersensitivity. Our previous studies have demonstrated the roles of voltage-gated sodium channels NaV1.7 and NaV1.8 in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. This study was designed to determine roles of antioxidant α-lipoic acid (ALA) on sodium channel activities and colonic hypersensitivity of rats with diabetes. METHODS Streptozotocin was used to induce diabetes in adult female rats. Colonic sensitivity was measured by behavioral responses to colorectal distention in rats. The excitability and sodium channel currents of colon projection DRG neurons labeled with DiI were measured by whole-cell patch-clamp recordings. The expressions of NaV1.7 and NaV1.8 of colon DRGs were measured by western blot analysis. RESULTS ALA treatment significantly increased distention threshold in responding to colorectal distension in diabetic rats compared with normal saline treatment. ALA treatment also hyper-polarized the resting membrane potentials, depolarized action potential threshold, increased rheobase, and decreased frequency of action potentials evoked by ramp current stimulation. Furthermore, ALA treatment also reduced neuronal sodium current densities of DRG neurons innervating the colon from rats with diabetes. In addition, ALA treatment significantly downregulated NaV1.7 and NaV1.8 expression in colon DRGs from rats with diabetes. CONCLUSION Our results suggest that ALA plays an analgesic role, which was likely mediated by downregulation of NaV1.7 and NaV1.8 expressions and functions, thus providing experimental evidence for using ALA to treat colonic hypersensitivity in patients with diabetic visceral pain.
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Affiliation(s)
- Yan Sun
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Pan-Pan Yang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Zhen-Yuan Song
- Department of Endocrinology, The East District of Suzhou Municipal Hospital, Suzhou, People's Republic of China
| | - Yu Feng
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Duan-Min Hu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, People's Republic of China
| | - Hong-Hong Zhang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, People's Republic of China
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Sanders KM, Kito Y, Hwang SJ, Ward SM. Regulation of Gastrointestinal Smooth Muscle Function by Interstitial Cells. Physiology (Bethesda) 2017; 31:316-26. [PMID: 27488743 DOI: 10.1152/physiol.00006.2016] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Interstitial cells of mesenchymal origin form gap junctions with smooth muscle cells in visceral smooth muscles and provide important regulatory functions. In gastrointestinal (GI) muscles, there are two distinct classes of interstitial cells, c-Kit(+) interstitial cells of Cajal and PDGFRα(+) cells, that regulate motility patterns. Loss of these cells may contribute to symptoms in GI motility disorders.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, Reno, Nevada; and
| | - Yoshihiko Kito
- Department of Pharmacology, Faculty of Medicine, Saga University, Nabeshima, Japan
| | - Sung Jin Hwang
- Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, Reno, Nevada; and
| | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine, Reno, Nevada; and
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Wei R, Parsons SP, Huizinga JD. Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators. Exp Physiol 2017; 102:329-346. [DOI: 10.1113/ep086077] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Accepted: 12/15/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Ruihan Wei
- McMaster University, Department of Medicine; Farncombe Family Digestive Health Research Institute; Hamilton ON Canada
| | - Sean P. Parsons
- McMaster University, Department of Medicine; Farncombe Family Digestive Health Research Institute; Hamilton ON Canada
| | - Jan D. Huizinga
- McMaster University, Department of Medicine; Farncombe Family Digestive Health Research Institute; Hamilton ON Canada
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Giancola F, Fracassi F, Gallucci A, Sadeghinezhad J, Polidoro G, Zini E, Asti M, Chiocchetti R. Quantification of nitrergic neurons in the myenteric plexus of gastric antrum and ileum of healthy and diabetic dogs. Auton Neurosci 2016; 197:25-33. [PMID: 27189100 DOI: 10.1016/j.autneu.2016.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/25/2016] [Accepted: 04/29/2016] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM) determines a wide array of severe clinical complications including gastrointestinal motility disorders. The present study investigates the effects of spontaneous DM on the intramural innervation and in particular on nitrergic neurons of the myenteric plexus (MP) of the canine gastric antrum and ileum. Specimens of antrum and ileum from eight control-dogs and five insulin-dependent DM-dogs were collected. MP neurons were immunohistochemically identified with the anti-HuC/HuD antibody, while nitrergic neurons were identified with the antibody anti-neuronal nitric oxide synthase (nNOS). The density of HuC/HuD-immunoreactive (IR) neurons was determined and the nitrergic neurons were quantified as a relative percentage, in consideration of the total number of HuC/HuD-IR neurons. Furthermore, the density of nitrergic fibers in the muscular layers was calculated. Data were expressed as mean±standard deviation. Compared to control-dogs, no significant differences resulted in the density of HuC/HuD-IR neurons in the antrum and ileum of DM-dogs; however, HuC/HuD-immunolabeling showed nuclear localization and fragmentation in DM-dogs. In the stomachs of control- and DM-dogs, the percentages of nitrergic neurons were 30±6% and 25±2%, respectively (P=0.112). In the ileum of the control-dogs, the percentage of nitrergic neurons was 29±5%, while in the DM-dogs, it was significantly reduced 19±5% (P=0.006). The density of nNOS-IR nervous fibers was meaningful reduced in either the tracts considered. Notably, the ganglia of DM-dogs showed also a thickening of the periganglionic connective tissue. These findings indicate that DM in dogs induce modification of the myenteric neurons and, in particular, of the nitrergic neuronal subpopulation.
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Affiliation(s)
- F Giancola
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), University of Bologna, Italy
| | - F Fracassi
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), University of Bologna, Italy
| | - A Gallucci
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), University of Bologna, Italy
| | - J Sadeghinezhad
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - G Polidoro
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), University of Bologna, Italy
| | - E Zini
- Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland; Department of Animal Medicine, Production and Health, University of Padua, Padua, Italy; Istituto Veterinario di Novara, Novara, Italy
| | - M Asti
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), University of Bologna, Italy
| | - R Chiocchetti
- Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008), University of Bologna, Italy.
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Lane VA, Levitt MA, Baker P, Minneci P, Deans K. The Appendix and Aganglionosis. A Note of Caution-How the Histology Can Mislead the Surgeon in Total Colonic Hirschsprung Disease. European J Pediatr Surg Rep 2015; 3:3-6. [PMID: 26171305 PMCID: PMC4487127 DOI: 10.1055/s-0035-1552559] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 03/30/2015] [Indexed: 11/07/2022] Open
Abstract
We present the case of a child with presumed total colonic Hirschsprung disease (HD) to highlight the problems the surgeon is likely to encounter if he/she relies on the appendix alone for histopathologic diagnosis. A newborn male infant, who was presumed to have total colonic aganglionosis when the appendix was found to be aganglionic at the time of initial exploratory laparoscopy, was managed with an ileostomy in the newborn period; however, at the time of his planned pull-through procedure, the rectal biopsy revealed normal ganglion cells. The child was subsequently managed with ileostomy closure and observed for normal feeding and stooling prior to discharge home. We discuss the histopathologic findings of the appendix in separate cases of confirmed total colonic HD seen in our center, and review the normal histopathologic findings of the appendix.
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Affiliation(s)
- Victoria Alison Lane
- Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Columbus, Ohio, United States ; Center for Surgical Outcomes Research, Nationwide Children's Hospital, Columbus, Ohio, United States
| | - Marc A Levitt
- Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Columbus, Ohio, United States
| | - Peter Baker
- Department of Pathology, Nationwide Children's Hospital, Columbus, Ohio, United States
| | - Peter Minneci
- Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Columbus, Ohio, United States ; Center for Surgical Outcomes Research, Nationwide Children's Hospital, Columbus, Ohio, United States
| | - Katherine Deans
- Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Columbus, Ohio, United States ; Center for Surgical Outcomes Research, Nationwide Children's Hospital, Columbus, Ohio, United States
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Phillips LK, Deane AM, Jones KL, Rayner CK, Horowitz M. Gastric emptying and glycaemia in health and diabetes mellitus. Nat Rev Endocrinol 2015; 11:112-128. [PMID: 25421372 DOI: 10.1038/nrendo.2014.202] [Citation(s) in RCA: 194] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia--gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.
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Affiliation(s)
- Liza K Phillips
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Discipline of Medicine, The University of Adelaide, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, Frome Road, Adelaide, SA 5005, Australia
| | - Adam M Deane
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Discipline of Medicine, The University of Adelaide, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, Frome Road, Adelaide, SA 5005, Australia
| | - Karen L Jones
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Discipline of Medicine, The University of Adelaide, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, Frome Road, Adelaide, SA 5005, Australia
| | - Chris K Rayner
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Discipline of Medicine, The University of Adelaide, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, Frome Road, Adelaide, SA 5005, Australia
| | - Michael Horowitz
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Discipline of Medicine, The University of Adelaide, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, Frome Road, Adelaide, SA 5005, Australia
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Sun M, Wang F, Feng P. Insulin-like growth factor-1 inhibits colonic smooth muscle cell apoptosis in diabetic rats with colonic dysmotility. ACTA ACUST UNITED AC 2014; 194-195:41-8. [PMID: 25450576 DOI: 10.1016/j.regpep.2014.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 11/04/2014] [Accepted: 11/11/2014] [Indexed: 02/08/2023]
Abstract
Cellular apoptosis and colonic dysmotility are involved in diabetes mellitus (DM) complications. Insulin-like growth factor-1 (IGF-1) is known to affect apoptosis and proliferation. Here, we demonstrated that the treatment of 1500 ng/kg IGF-1 partly recovers the decrease of the muscle thickness, body weight and gastrointestinal transit rate in DM rats. The gastrointestinal transit rate is positively correlated with the IGF-I level, but negatively correlated with the level of colonic cellular apoptosis. The DM-induced colonic apoptosis is also attenuated by the IGF-1 stimulation. Moreover, IGF-1 inhibits the apoptosis of the isolated colonic SMCs in vitro via the activation of PI3K/Akt and ERK1/2 signaling pathways. Taken together, our data indicated that IGF-1 inhibits the DM-induced colonic SMC apoptosis and might be involved in the alleviation of colonic dysmotility in diabetic rats.
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Affiliation(s)
- Manyi Sun
- Department of Metabolic Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Gastroenterology, Tianjin Union Medicine Center, Tianjin 300121, China
| | - Feng Wang
- Department of Gastroenterology and Digestive Endoscopy, Tianjin Union Medicine Center & Tianjin People's Hospital, Tianjin 300121, China
| | - Ping Feng
- Department of Metabolic Diseases, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions. Neurogastroenterol Motil 2014; 26:611-24. [PMID: 24661628 PMCID: PMC4104990 DOI: 10.1111/nmo.12330] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/18/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Gastrointestinal manifestations of diabetes are common and a source of significant discomfort and disability. Diabetes affects almost every part of gastrointestinal tract from the esophagus to the rectum and causes a variety of symptoms including heartburn, nausea, vomiting, abdominal pain, diarrhea and constipation. Understanding the underlying mechanisms of diabetic gastroenteropathy is important to guide development of therapies for this common problem. Over recent years, the data regarding the pathophysiology of diabetic gastroenteropathy is expanding. In addition to autonomic neuropathy causing gastrointestinal disturbances the role of enteric nervous system is becoming more evident. PURPOSE In this review, we summarize the reported alterations in enteric nervous system including enteric neurons, interstitial cells of Cajal and neurotransmission in diabetic animal models and patients. We also review the possible underlying mechanisms of these alterations, with focus on oxidative stress, growth factors and diabetes induced changes in gastrointestinal smooth muscle. Finally, we will discuss recent advances and potential areas for future research related to diabetes and the ENS such as gut microbiota, micro-RNAs and changes in the microvasculature and endothelial dysfunction.
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Affiliation(s)
- S. S. Yarandi
- Division of Digestive Diseases; Emory University; Atlanta GA
- Atlanta VA Medical Center; Decatur Georgia USA
| | - S. Srinivasan
- Division of Digestive Diseases; Emory University; Atlanta GA
- Atlanta VA Medical Center; Decatur Georgia USA
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13
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Winston JH, Chen J, Shi XZ, Sarna SK. Inflammation induced by mast cell deficiency rather than the loss of interstitial cells of Cajal causes smooth muscle dysfunction in W/W(v) mice. Front Physiol 2014; 5:22. [PMID: 24550836 PMCID: PMC3912454 DOI: 10.3389/fphys.2014.00022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 01/09/2014] [Indexed: 01/19/2023] Open
Abstract
The initial hypothesis suggested that the interstitial cells of Cajal (ICC) played an essential role in mediating enteric neuronal input to smooth muscle cells. Much information for this hypothesis came from studies in W/Wv mice lacking ICC. However, mast cells, which play critical roles in regulating inflammation in their microenvironment, are also absent in W/Wv mice. We tested the hypothesis that the depletion of mast cells in W/Wv mice generates inflammation in fundus muscularis externa (ME) that impairs smooth muscle reactivity to Ach, independent of the depletion of ICC. We performed experiments on the fundus ME from wild type (WT) and W/Wv mice before and after reconstitution of mast cells by bone marrow transplant. We found that mast cell deficiency in W/Wv mice significantly increased COX-2 and iNOS expression and decreased smooth muscle reactivity to Ach. Mast cell reconstitution or concurrent blockade of COX-2 and iNOS restored smooth muscle contractility without affecting the suppression of c-kit in W/Wv mice. The expression of nNOS and ChAT were suppressed in W/Wv mice; mast cell reconstitution did not restore them. We conclude that innate inflammation induced by mast cell deficiency in W/Wv mice impairs smooth muscle contractility independent of ICC deficiency. The impairment of smooth muscle contractility and the suppression of the enzymes regulating the synthesis of Ach and NO in W/Wv mice need to be considered in evaluating the role of ICC in regulating smooth muscle and enteric neuronal function in W/Wv mice.
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Affiliation(s)
- John H Winston
- Division of Gastroenterology, Department of Internal Medicine, Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston Galveston, TX, USA
| | - Jinghong Chen
- Division of Gastroenterology, Department of Internal Medicine, Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston Galveston, TX, USA
| | - Xuan-Zheng Shi
- Division of Gastroenterology, Department of Internal Medicine, Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston Galveston, TX, USA
| | - Sushil K Sarna
- Division of Gastroenterology, Department of Internal Medicine, Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston Galveston, TX, USA
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Cheng LK, Farrugia G. New Advances in Gastrointestinal Motility Research. LECTURE NOTES IN COMPUTATIONAL VISION AND BIOMECHANICS 2013. [DOI: 10.1007/978-94-007-6561-0_1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Faussone-Pellegrini MS, Grover M, Pasricha PJ, Bernard CE, Lurken MS, Smyrk TC, Parkman HP, Abell TL, Snape WJ, Hasler WL, Unalp-Arida A, Nguyen L, Koch KL, Calles J, Lee L, Tonascia J, Hamilton FA, Farrugia G. Ultrastructural differences between diabetic and idiopathic gastroparesis. J Cell Mol Med 2012; 16:1573-81. [PMID: 21914127 PMCID: PMC3250562 DOI: 10.1111/j.1582-4934.2011.01451.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The ultrastructural changes in diabetic and idiopathic gastroparesis are not well studied and it is not known whether there are different defects in the two disorders. As part of the Gastroparesis Clinical Research Consortium, full thickness gastric body biopsies from 20 diabetic and 20 idiopathic gastroparetics were studied by light microscopy. Abnormalities were found in many (83%) but not all patients. Among the common defects were loss of interstitial cells of Cajal (ICC) and neural abnormalities. No distinguishing features were seen between diabetic and idiopathic gastroparesis. Our aim was to provide a detailed description of the ultrastructural abnormalities, compare findings between diabetic and idiopathic gastroparesis and determine if patients with apparently normal immunohistological features have ultrastructural abnormalities. Tissues from 40 gastroparetic patients and 24 age- and sex-matched controls were examined by transmission electron microscopy (TEM). Interstitial cells of Cajal showing changes suggestive of injury, large and empty nerve endings, presence of lipofuscin and lamellar bodies in the smooth muscle cells were found in all patients. However, the ultrastructural changes in ICC and nerves differed between diabetic and idiopathic gastroparesis and were more severe in idiopathic gastroparesis. A thickened basal lamina around smooth muscle cells and nerves was characteristic of diabetic gastroparesis whereas idiopathic gastroparetics had fibrosis, especially around the nerves. In conclusion, in all the patients TEM showed abnormalities in ICC, nerves and smooth muscle consistent with the delay in gastric emptying. The significant differences found between diabetic and idiopathic gastroparesis offers insight into pathophysiology as well as into potential targeted therapies.
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16
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Bettolli M, De Carli C, Cornejo-Palma D, Jolin-Dahel K, Wang XY, Huizinga J, Krantis A, Rubin S, Staines WA. Interstitial cell of Cajal loss correlates with the degree of inflammation in the human appendix and reverses after inflammation. J Pediatr Surg 2012; 47:1891-9. [PMID: 23084203 DOI: 10.1016/j.jpedsurg.2012.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 05/02/2012] [Accepted: 05/06/2012] [Indexed: 01/15/2023]
Abstract
BACKGROUND Normal gut motility relies on the complex interaction between the interstitial cell of Cajal (ICC) and the enteric nerve networks. Inflammation of the gastrointestinal tract adversely affects both ICC and enteric nerves. We aimed to determine the distribution of ICC and nerve networks in patients with appendicitis. METHODS Specimens from controls and patients with appendicitis were examined with immunohistochemistry (c-Kit for ICC, beta III tubulin [Tuj-1] and neuronal nitric oxide synthase [histochemical diaphorase] for nitrergic neurons) and electron microscopy (EM). Data were quantified using image analysis. RESULTS We found a profound decrease in c-Kit immunoreactivity (c-Kit IR) in the advanced inflammatory stages of appendicitis, which correlated with the severity of inflammation. Electron microscopy confirmed ultrastructural injury in both ICC and nerve fiber networks during acute inflammation. After the inflammation resolved, interval appendices displayed a recovery in ICC c-Kit IR to control levels and normal ultrastructure. The neuronal network also displayed ultrastructural recovery; however, neuronal nitric oxide synthase activity did not recover. CONCLUSIONS Severe inflammation results in significant ultrastructural damage of nerves and ICC networks in appendicitis. The loss of c-Kit IR is likely due to impaired ICC cytophysiology because ICC was still present under EM. After resolution of acute inflammation, ICC recovers their normal ultrastructure and c-Kit IR.
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Affiliation(s)
- Marcos Bettolli
- Department of General Surgery, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada.
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Grover M, Bernard CE, Pasricha PJ, Lurken MS, Faussone-Pellegrini MS, Smyrk TC, Parkman HP, Abell TL, Snape WJ, Hasler WL, McCallum RW, Nguyen L, Koch KL, Calles J, Lee L, Tonascia J, Ünalp-Arida A, Hamilton FA, Farrugia G. Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. Neurogastroenterol Motil 2012; 24:531-9, e249. [PMID: 22339929 PMCID: PMC3353102 DOI: 10.1111/j.1365-2982.2012.01894.x] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis. METHODS Earlier, using full thickness gastric body biopsies from 20 DG, 20 IG, and 20 matched controls, we found decreased interstitial cells of Cajal (ICC) and enteric nerves and an increase in immune cells in both DG and IG. Here, demographic, symptoms [gastroparesis cardinal symptom index score (GCSI)], and gastric emptying were related to cellular alterations using Pearson's correlation coefficients. KEY RESULTS Interstitial cells of Cajal counts inversely correlated with 4 h gastric retention in DG but not in IG (r = -0.6, P = 0.008, DG, r = 0.2, P = 0.4, IG). There was also a significant correlation between loss of ICC and enteric nerves in DG but not in IG (r = 0.5, P = 0.03 for DG, r = 0.3, P = 0.16, IG). Idiopathic gastroparesis with a myenteric immune infiltrate scored higher on the average GCSI (3.6 ± 0.7 vs 2.7 ± 0.9, P = 0.05) and nausea score (3.8 ± 0.9 vs 2.6 ± 1.0, P = 0.02) as compared to those without an infiltrate. CONCLUSIONS & INFERENCES In DG, loss of ICC is associated with delayed gastric emptying. Interstitial cells of Cajal or enteric nerve loss did not correlate with symptom severity. Overall clinical severity and nausea in IG is associated with a myenteric immune infiltrate. Thus, full thickness gastric biopsies can help define specific cellular abnormalities in gastroparesis, some of which are associated with physiological and clinical characteristics of gastroparesis.
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Affiliation(s)
- M Grover
- Mayo Clinic, Rochester, MN 55905, USA
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Ohya TR, Sumiyama K, Takahashi-Fujigasaki J, Dobashi A, Saito S, Tajiri H. In vivo histologic imaging of the muscularis propria and myenteric neurons with probe-based confocal laser endomicroscopy in porcine models (with videos). Gastrointest Endosc 2012; 75:405-10. [PMID: 22248608 DOI: 10.1016/j.gie.2011.09.045] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Accepted: 09/23/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND The submucosal tunneling technique enables us to endoscopically access deeper tissue layers. Use of probe-based confocal laser endomicroscopy (pCLE) provides optical histologic imaging on the site. OBJECTIVE To determine the technical feasibility of ex vivo and in vivo pCLE imaging of the muscularis propria and myenteric neurons by using submucosal endoscopy with a mucosal flap safety valve (SEMF). DESIGN Acute porcine model study. SETTING Animal laboratory. INTERVENTION Two ex vivo and 6 in vivo porcine models were used. A submucosal space was created with SEMF, and a neuronal molecular probe was topically applied onto the muscularis. Confocal imaging of the stained muscularis was performed by using pCLE. The selected sites were sampled, and the histopathology of the sites was analyzed. MAIN OUTCOME MEASUREMENTS The two main outcome measures were the procedural success rate of submucosal access and the correlation between pCLE and histologic images. RESULTS Submucosal access to the pCLE study site was successful in all attempts (100%; 17/17 sites). The muscularis propria was visualized with pCLE in the ex vivo and in vivo porcine models in 83.3% of sites (20/24), and the neuron-like cells were identified in 41.7% of sites (10/24). LIMITATIONS Animal experiment. CONCLUSION The muscularis propria and myenteric neurons could be selectively visualized with pCLE in vivo.
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Affiliation(s)
- Tomohiko R Ohya
- Department of Endoscopy, The Jikei University School of Medicine, Tokyo, Japan
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19
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Liu YA, Chen Y, Chiang AS, Peng SJ, Pasricha PJ, Tang SC. Optical clearing improves the imaging depth and signal-to-noise ratio for digital analysis and three-dimensional projection of the human enteric nervous system. Neurogastroenterol Motil 2011; 23:e446-57. [PMID: 21895876 DOI: 10.1111/j.1365-2982.2011.01773.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Due to the dispersed nature of neurites and fibers, the microtome-based 2-dimensional histology provides only a limited perspective of the enteric nervous system. To visualize the enteric plexus, we applied optical clearing to avoid scattering in the human ileum to facilitate photon penetration for 3-dimensional (3-D) microscopy of the neural tissue. METHODS Human ileal specimens were derived by trimming the donor bowel due to its excess length during the clinical trial of small intestinal transplantation. The pan-neuronal marker PGP9.5 was used as the immunostaining target to reveal the enteric plexuses. The labeled tissues were immersed in the optical-clearing solution prior to deep-tissue confocal microscopy. The serial sections were digitally analyzed and processed by reconstruction algorithms for 3-D visualization. KEY RESULTS Optical clearing of the ileal specimen led to less fluorescence signal decay along the focal path in the tissue and a higher signal-to-noise ratio of the confocal micrographs in comparison with the untreated saline control. Taking advantage of the high signal-to-noise ratio images, we applied software-based signal analysis to identify the presence of the nerve fibers and quantify the signal peaks. The image stacks derived from the serial anatomic micrographs created panoramic views of the gut wall innervations with their associated microstructures. CONCLUSIONS & INFERENCES We provide an optical approach to improve the imaging depth in 3-D neurohistology of the human ileum. This methodology has significant promise in facilitating our understanding of the enteric nervous system in health and disease.
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Affiliation(s)
- Y-A Liu
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
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20
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Grover M, Farrugia G, Lurken MS, Bernard CE, Faussone-Pellegrini MS, Smyrk TC, Parkman HP, Abell TL, Snape WJ, Hasler WL, Ünalp-Arida A, Nguyen L, Koch KL, Calles J, Lee L, Tonascia J, Hamilton FA, Pasricha PJ, NIDDK Gastroparesis Clinical Research Consortium. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology 2011; 140:1575-85.e8. [PMID: 21300066 PMCID: PMC3081914 DOI: 10.1053/j.gastro.2011.01.046] [Citation(s) in RCA: 329] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Revised: 12/09/2010] [Accepted: 01/20/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis. METHODS Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy. RESULTS Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders. CONCLUSIONS This study suggests that on full-thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found.
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Collaborators
Pankaj Jay Pasricha, Linda Nguyen, Nighat Ullah, William Snape, Robin Bishop, Nata DeVole, Mary Greene, Sue Louiseau, Amy Marincek, Shelly Parker, Eve Pillor, Courtney Ponsetto, Katerina Shetler, Gianrico Farrugia, Madhusudan Grover, Cheryl Bernard, Matt Lurken, K Robert Shen, Michael Sarr, Michael Kendrick, Henry P Parkman, Siva Doma, Javier Gomez, Steven Kantor, Vanessa Lytes, Amiya Palit, Zeeshan Ramzan, Priyanka Sachdeva, Kellie Simmons, Sean Harbison, Richard W McCallum, Reza Hejazi, Irene Sarosiek, Denise Vasquez, Natalia Vega, William Hasler, Michelle Atkinson, Radoslav Coleski, Thomas Abell, JoAnne Fordham, Olivia Henry, Archana Kedar, Valerie McNair, Susanne Pruett, Margaret Smith, Danielle Spree, Kenneth Koch, Lynn Baxter, Jorge Calles, Samantha Culler, Judy Hooker, Frank Hamilton, Steven James, Rebecca Torrance, Rebekah Van Raaphorst, James Tonascia, Patricia Belt, Ryan Colvin, Michele Donithan, Mika Green, Milana Isaacson, Wana Kim, Linda Lee, Alison Lydecker, Pamela Mann, Laura Miriel, Alice Sternberg, Aynur Ünalp-Arida, Mark Van Natta, Ivana Vaughn, Laura Wilson, Katherine Yates,
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Mazzone A, Bernard CE, Strege PR, Beyder A, Galietta LJV, Pasricha PJ, Rae JL, Parkman HP, Linden DR, Szurszewski JH, Ördög T, Gibbons SJ, Farrugia G. Altered expression of Ano1 variants in human diabetic gastroparesis. J Biol Chem 2011; 286:13393-403. [PMID: 21349842 PMCID: PMC3075685 DOI: 10.1074/jbc.m110.196089] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 02/23/2011] [Indexed: 01/02/2023] Open
Abstract
Diabetes affects many organs including the stomach. Altered number and function of interstitial cells of Cajal (ICC), the gastrointestinal pacemaker cells, underlie a number of gastrointestinal motility disorders, including diabetic gastroparesis. In the muscle layers, ICC selectively express Ano1, thought to underlie classical Ca(2+)-activated Cl(-) currents. Mice homozygous for Ano1 knock-out exhibit abnormal ICC function and motility. Several transcripts for Ano1 are generated by alternative splicing of four exons. Here, we report expression levels of transcripts encoded by alternative splicing of Ano1 gene in gastric muscles of patients with diabetic gastroparesis and nondiabetic control tissues. Expression of mRNA from two alternatively transcribed exons are significantly different between patients and controls. Furthermore, patients with diabetic gastroparesis express mRNA for a previously unknown variant of Ano1. The 5' end of this novel variant lacks exons 1 and 2 and part of exon 3. Expression of this variant in HEK cells produces a decreased density of Ca(2+)-activated Cl(-) currents that exhibit slower kinetics compared with the full-length Ano1. These results identify important changes in expression and splicing of Ano1 in patients with diabetic gastroparesis that alter the electrophysiological properties of the channel. Changes in Ano1 expression in ICC may directly contribute to diabetic gastroparesis.
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Affiliation(s)
- Amelia Mazzone
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Cheryl E. Bernard
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Peter R. Strege
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Arthur Beyder
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Luis J. V. Galietta
- the Laboratory of Molecular Genetics, Istituto Giannina Gaslini, 16147 Genova, Italy
| | - Pankaj J. Pasricha
- the Division of Gastroenterology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, and
| | - James L. Rae
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Henry P. Parkman
- the Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140
| | - David R. Linden
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Joseph H. Szurszewski
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Tamas Ördög
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Simon J. Gibbons
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
| | - Gianrico Farrugia
- From the Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
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22
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Gomez-Pinilla PJ, Gibbons SJ, Sarr MG, Kendrick ML, Shen KR, Cima RR, Dozois EJ, Larson DW, Ordog T, Pozo MJ, Farrugia G. Changes in interstitial cells of cajal with age in the human stomach and colon. Neurogastroenterol Motil 2011; 23:36-44. [PMID: 20723073 PMCID: PMC2999641 DOI: 10.1111/j.1365-2982.2010.01590.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Aging produces inevitable changes in the function of most organs including the gastrointestinal tract. Together with enteric nerves and smooth muscle cells, interstitial cells of Cajal (ICC) play a key role in the control of gastrointestinal motility, yet little is known about the effect of aging on ICC. The aim of this study was to determine the effect of aging on ICC number and volume in the human stomach and colon. METHODS Gastric and colonic tissues from patients aged 25-70 and 36-92 years old, respectively, and with no co-existent motility disorders were immunolabeled with an anti-Kit antibody and ICC were counted in the circular muscle and myenteric regions. Network volumes were measured using 3D reconstructions of confocal stacks. The effects of aging were determined by testing for linear trends using regression analysis. KEY RESULTS In both stomach and colon, the number of ICC bodies and volume significantly decreased with age at a rate of 13% per decade. ICC size was only affected in the myenteric plexus in the colon. The changes associated with age were not differentially affected by sex or colonic region. CONCLUSIONS & INFERENCES The number and volume of ICC networks in the normal human stomach and colon decline with age. This decrease in ICC likely reduces the functional capacity of the gastrointestinal motor apparatus, may contribute to changes in gastrointestinal motility with aging and may influence intestinal responses to insults such as disease, operative interventions and medications in older patients. Tissue specimens must be carefully age-matched when studying ICC in disease.
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Affiliation(s)
- Pedro J. Gomez-Pinilla
- Enteric NeuroScience Program and Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Simon J. Gibbons
- Enteric NeuroScience Program and Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | | | | | - Tamas Ordog
- Enteric NeuroScience Program and Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Maria J. Pozo
- Dept of Physiology, Nursing School, University of Extremadura and RETICEF, Caceres, Spain
| | - Gianrico Farrugia
- Enteric NeuroScience Program and Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
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Kim ER, Kim KM, Lee JY, Joo M, Kim S, Noh JH, Ward SM, Koh SD, Rhee PL. The clue of Interstitial Cell of Cajalopathy (ICCpathy) in human diabetic gastropathy: the ultrastructural and electrical clues of ICCpathy in human diabetic gastropathy. ACTA ACUST UNITED AC 2010; 64:521-6. [PMID: 21185163 DOI: 10.1016/j.etp.2010.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Accepted: 11/09/2010] [Indexed: 12/31/2022]
Abstract
Recent studies of diabetic animal models suggest an important role of ICC in the pathogenesis of gastropathy. The aim of this study was to characterize the ultrastructural features of ICC and record the electrical properties in the stomach of patients with type 2 DM. Gastric specimens were obtained from 13 diabetic patients and 6 control subjects with gastric cancer that underwent gastrectomy. All specimens were taken from disease-free areas. The samples were processed for both electron microscopic and electrophysiologic examination. The characteristic ultrastructural changes of the ICC were observed in both the nucleus and cytoplasm in patients with type 2 DM. Wrinkling of the nuclear envelope and changes in the cytoplasm such as dilatation of the endoplasmic reticulum, an increase of autophagic vacuoles, were more frequently observed in the diabetic patients. Apoptosis characterized by nuclear karyorrhexis or pyknosis was observed only in the diabetic patients. Slow waves were recorded in the circular muscle of stomach. In diabetic patients, the mean resting membrane potential was higher and amplitude was lower than controls. These changes of electrical activities of slow waves were accompanied with ultrastructural changes of ICC, particularly the characteristic nuclear changes. In human diabetic patients, the characteristic ultrastructural changes of ICC such as preapoptosis, accompanied with electrical dysrhythmia of slow waves, were observed. These results show several evidence converging to support that degeneration of the ICC may be associated with the pathogenesis of diabetic gastropathy.
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Affiliation(s)
- Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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24
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Lei Y, Chen JDZ. A potential and novel therapy for obesity: "appendix" electrical stimulation in dogs. Obes Surg 2010; 21:397-403. [PMID: 20890772 DOI: 10.1007/s11695-010-0281-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Intestinal electrical stimulation (IES) has been introduced as a potential therapy for obesity. However, it is unknown whether the effects of IES on gastrointestinal motility and food intake are location-specific. The aim of this study was to assess the effects of "appendix" (cecum in dog) electrical stimulation (AES) on gastric tone, gastric emptying, and food intake in dogs. METHODS Twelve healthy dogs were used in three experiments. In experiments 1 and 2, gastric tone and food intake were studied in six dogs implanted with a gastric cannula and one pair of stimulation electrodes in the "appendix." Experiment 3 was performed to study gastric emptying in six dogs with a duodenal cannula and one pair of stimulation electrodes in the "appendix." RESULTS (1) AES resulted in proximal gastric distention, with gastric volume increased from 114.9 ± 10.7 mL at baseline to 301.7 ± 37.1 mL during AES (p = 0.001), and the effect was completely blocked by a nitric oxide synthase inhibitor. (2) Gastric emptying was delayed at 90 min from 69.8 ± 9.5% in the control session to 15.2 ± 3.6% in the AES session (p = 0.002). 3) AES reduced food intake (average daily intake over a 1-week period) by 55.4% (550.4 ± 17.6 g at control vs. 245.7 ± 17.1 g with AES, p < 0.001). CONCLUSIONS AES reduces gastric tone via the nitrergic pathway, delays gastric emptying, and inhibits food intake in healthy dogs. These data suggest the therapeutic potential of AES for obesity. Additionally, AES is technically more feasible than electrical stimulation of the stomach or duodenum because a stimulator with electrodes may be placed into the appendix via colonoscopy.
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Affiliation(s)
- Yong Lei
- Veterans Research Foundation, VA Medical Center, Oklahoma City, OK, USA
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25
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Matsuda NM, Miller SM, Szurszewski JH. Heme-oxygenase-2 immunolabelling in pig jejunum. Acta Histochem 2010; 112:402-6. [PMID: 19232687 DOI: 10.1016/j.acthis.2009.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 12/03/2008] [Accepted: 01/12/2009] [Indexed: 10/21/2022]
Abstract
Heme-oxygenase-2 generates carbon monoxide in the enteric nervous system and in interstitial cells of Cajal in the canine, mouse and human jejunum. Carbon monoxide is considered a non-adrenergic and non-cholinergic inhibitory neurotransmitter and it establishes and maintains the resting membrane potential in the stomach and small intestine. The aim of this study was to determine the distribution of heme-oxygenase-2 in the enteric nervous system of the pig jejunum. Heme-oxygenase-2 immunoreactivity was found in neurons of myenteric ganglia and in nerve fibers in the circular and longitudinal muscle layers. These results suggest that carbon monoxide is produced in the enteric nervous system of the pig jejunum and might mediate inhibitory neural activity in myenteric ganglia and inhibitory neural input to smooth muscle cells in the circular and longitudinal muscle layers.
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26
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Gao XK, Yu Y, Yang Y, Chen J, Wang QM. High concentration of glucose enhances the expression of P2X 7 purine receptor in interstitial cells of Cajal in vitro. Shijie Huaren Xiaohua Zazhi 2010; 18:1211-1216. [DOI: 10.11569/wcjd.v18.i12.1211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of high concentration of glucose on the expression of P2X7 purine receptor in the interstitial cells of Cajal (ICC) in vitro and to explore the mechanisms underlying gastrointestinal dysmotility in diabetic mellitus.
METHODS: ICC were isolated from the intestine of newborn mice by enzymatic dissociation and centrifugation and cultured in an incubator containing 50 mL/L CO2. Cultured ICC were identified by immunofluorescence staining using antibodies directed against c-Kit receptor and P2X7 receptor. ICC were then divided into two groups: control group and experimental group, which were treated with normal and high concentrations of glucose, respectively. After treatment, cell morphology was observed under an inverted light microscope. The expression of P2X7 receptor and c-Kit receptor mRNAs in ICC was detected by reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: Immunofluorescence staining demonstrated that both P2X7 receptor and c-Kit receptor were positive on ICC cells. After treatment with high concentration of glucose, ICC became bigger, and cell processes became shorter. RT-PCR analysis proved the expression of P2X7 receptor in ICC. The expression level of c-Kit receptor mRNA was weaker and that of P2X7 receptor mRNA was stronger in the experimental group than in the control group.
CONCLUSION: P2X7 receptor is expressed in ICC. Hyperglycemia may alter cell morphology, decrease the expression of c-Kit receptor, enhance the expression of P2X7 receptor in ICC, and thereby play a role in the pathogenesis of gastrointestinal dysmotility in diabetic mellitus.
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27
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Upton MP. Looking through a keyhole: serrated neoplasia in the vermiform appendix. Am J Clin Pathol 2010; 133:529-32. [PMID: 20231604 DOI: 10.1309/ajcpupmrp1rtdsu2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Parkman HP, Camilleri M, Farrugia G, McCallum RW, Bharucha AE, Mayer EA, Tack JF, Spiller R, Horowitz M, Vinik AI, Galligan JJ, Pasricha PJ, Kuo B, Szarka LA, Marciani L, Jones K, Parrish CR, Sandroni P, Abell T, Ordog T, Hasler W, Koch KL, Sanders K, Norton NJ, Hamilton F. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010; 22:113-133. [PMID: 20003077 PMCID: PMC2892213 DOI: 10.1111/j.1365-2982.2009.01434.x] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Despite the relatively high prevalence of gastroparesis and functional dyspepsia, the aetiology and pathophysiology of these disorders remain incompletely understood. Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders. PURPOSE This manuscript reviews the advances in the understanding of the epidemiology, pathophysiology, diagnosis, and treatment of gastroparesis and functional dyspepsia as discussed at a recent conference sponsored by the American Gastroenterological Association (AGA) and the American Neurogastroenterology and Motility Society (ANMS). Particular focus is placed on discussing unmet needs and areas for future research.
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Affiliation(s)
- H P Parkman
- Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
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Wang XY, Huizinga JD, Diamond J, Liu LWC. Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin-induced diabetes. Neurogastroenterol Motil 2009; 21:1095-e92. [PMID: 19566589 DOI: 10.1111/j.1365-2982.2009.01336.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Interstitial cells of Cajal (ICC) are associated with afferent innervation and peristalsis of the stomach suggestive of a key role in the pathophysiology of gastroparesis. We studied changes in the density and ultrastructure of ICC and enteric nerves in the streptozotocin-induced diabetes mellitus (STZ-DM) in Wistar rats using immunohistochemistry and electron microscopy. Gastric emptying was studied in vivo by single-photon emission computed tomography. In the STZ-DM antrum, a marked reduction was observed in the density of the intramuscular ICC (ICC-IM) and ICC located at the submucosal border of the circular muscle layer of the antrum (ICC-SM). The surviving ICC showed lamellar bodies and partial vacuolation of the cytoplasm content, loss of connections between ICC-IM and nerves; it appeared that injured ICC-IM developed into fibroblast-like ICC. ICC associated with Auerbach's plexus (ICC-AP) in the antrum and ICC in the fundus were not affected significantly except for a loss of connections with nerve structures. Marked reduction in nerve tissue (Protein Gene Product-9.5 positivity) was also restricted to the muscle layers including nitrergic nerves (neuronal nitric oxide synthase positivity). In vivo assessed gastric emptying was markedly reduced in STZ-DM rats. Our data demonstrate in the STZ-DM rat stomach a decreased density of ICC limited to the antrum and to ICC-IM and ICC-SM, and structural degeneration in ICC-IM and associated nerves with a special emphasis on loss of synaptic connections, accompanied by a decrease in gastric emptying. Hence, in this model of gastroparetic diabetes, regional injury to subsets of ICC and nerves are associated with gastric motor dysfunction.
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Affiliation(s)
- X-Y Wang
- Department of Medicine, McMaster University, Farncombe Family Digestive Health Research Institute, ON, Canada
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Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol 2009; 118:271-301. [PMID: 19360428 DOI: 10.1007/s00401-009-0527-y] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Revised: 03/19/2009] [Accepted: 03/22/2009] [Indexed: 01/30/2023]
Abstract
The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented.
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Sumiyama K, Tajiri H, Kato F, Imura T, Ono K, Ikeda K, Imazu H, Gostout CJ. Pilot study for in vivo cellular imaging of the muscularis propria and ex vivo molecular imaging of myenteric neurons (with video). Gastrointest Endosc 2009; 69:1129-34. [PMID: 19215917 DOI: 10.1016/j.gie.2008.08.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2008] [Accepted: 08/02/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND It is challenging to optimally sample the muscularis propria endoscopically for the diagnosis of muscle layer diseases, especially for motility disorders resulting from neuroenteric dysfunction. OBJECTIVES Ultramagnification in vivo imaging of the muscularis mucosa and ex vivo identification of myenteric neuronal elements by confocal microscopy. DESIGN Ex vivo and in vivo porcine animal studies. SETTING Short-term study in an animal laboratory. INTERVENTIONS The muscularis propria in the stomach and esophagus was accessed by resecting the mucosal layer with endoscopic submucosal dissection or cap EMR techniques or by creating a submucosal space by the submucosal endoscopy with mucosal flap technique. The muscularis propria was stained with Nissl stains and 2 types of neuronal molecular stains. The muscular layer was imaged with the endocytoscope in vivo. The muscularis stained with molecular-based stains was also evaluated with a confocal microscope. RESULTS Cellular microstructures resembling spindle-shaped smooth muscle cells were visualized by endocytoscopy in vivo. Confocal endoscopic microscopy demonstrated that in vivo topical application of neuronal molecular stains successfully stained the muscularis and specifically highlighted neuron-like cells. LIMITATION Animal model pilot study. CONCLUSIONS In vivo endoscopic histologic evaluation of the muscularis propria is technically feasible and easy. Minimally invasive advanced endoscopic imaging may be useful for the diagnosis and study of neuroenteric disorders at the level of the muscularis propria, avoiding surgical full-thickness tissue sampling.
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Affiliation(s)
- Kazuki Sumiyama
- Department of Endoscopy, Jikei University School of Medicine, Tokyo, Japan.
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Knowles CH, Martin JE. New techniques in the tissue diagnosis of gastrointestinal neuromuscular diseases. World J Gastroenterol 2009; 15:192-7. [PMID: 19132769 PMCID: PMC2653311 DOI: 10.3748/wjg.15.192] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal neuromuscular diseases are a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular (including interstitial cell of Cajal) dysfunction. Common to most of these diseases are symptoms of impaired motor activity which manifest as slowed or obstructed transit with or without evidence of transient or persistent radiological visceral dilatation. A variety of histopathological techniques and allied investigations are being increasingly applied to tissue biopsies from such patients. This review outlines some of the more recent advances in this field, particularly in the most contentious area of small bowel disease manifesting as intestinal pseudo-obstruction.
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Matsuda NM, Miller SM, Evora PRB. The chronic gastrointestinal manifestations of Chagas disease. Clinics (Sao Paulo) 2009; 64:1219-24. [PMID: 20037711 PMCID: PMC2797592 DOI: 10.1590/s1807-59322009001200013] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 09/18/2009] [Indexed: 12/17/2022] Open
Abstract
Chagas disease is an infectious disease caused by the protozoan Trypanosoma cruzi. The disease mainly affects the nervous system, digestive system and heart. The objective of this review is to revise the literature and summarize the main chronic gastrointestinal manifestations of Chagas disease. The chronic gastrointestinal manifestations of Chagas disease are mainly a result of enteric nervous system impairment caused by T. cruzi infection. The anatomical locations most commonly described to be affected by Chagas disease are salivary glands, esophagus, lower esophageal sphincter, stomach, small intestine, colon, gallbladder and biliary tree. Chagas disease has also been studied in association with Helicobacter pylori infection, interstitial cells of Cajal and the incidence of gastrointestinal cancer.
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Affiliation(s)
- Nilce Mitiko Matsuda
- Departamento de Anatomia e Cirurgia, Universidade de São Paulo - Ribeirão Preto/SP, Brazil.
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Umathe SN, Kochar NI, Jain NS, Dixit PV. Gastrointestinal dysfunction in diabetic rats relates with a decline in tissue L-arginine content and consequent low levels of nitric oxide. Nitric Oxide 2008; 20:129-33. [PMID: 19041728 DOI: 10.1016/j.niox.2008.10.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2008] [Revised: 10/23/2008] [Accepted: 10/31/2008] [Indexed: 11/30/2022]
Abstract
Diabetic subjects exhibit low levels of nitric oxide (NO), its precursor L-arginine, and nitric oxide synthase (NOS) in tissues like endothelium and kidney. In view of this, we speculated that gastrointestinal (GI) dysfunction in diabetes could be related to similar changes in NO turnover in GI tissues. Hence, the studies were carried out in rats after eight weeks of streptozotocin-induced hyperglycemia, wherein the GI functions were assessed in terms of gastric emptying and intestinal transit using barium sulfate semisolid test meal, and the levels of L-arginine and NO in pylorus and ileum were estimated, respectively, by HPLC and amperometry. The results revealed that diabetic group exhibited significant delay in gastric emptying and intestinal transit, and the pylorus and ileum tissues had significantly low levels of NO and L-arginine. Daily treatment of non-diabetic rats with NOS inhibitor [Nomega-nitro-L-arginine methyl ester (10mg/kg/day, p.o.)] for eight weeks produced similar delay in gastric emptying and intestinal transit with associated low levels of NO in GI tissues. Daily supplementation of L-arginine (100mg/kg, p.o.) for eight weeks to diabetic and NOS inhibitor treated non-diabetic group was found to restore the gastric emptying and intestinal transit and improved the levels of NO in GI tissues. The findings indicate that diabetes-induced L-arginine deficiency and consequent low levels of NO in GI tissues could be possible cause for the GI dysfunction, and L-arginine supplementation can prevent the same. However, extensive clinical investigations are necessary to recommend the use of L-arginine for the treatment of GI dysfunctions in diabetes.
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Affiliation(s)
- S N Umathe
- Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India.
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Knowles CH, De Giorgio R. Observations on a vestigial organ: a potential surrogate for enteric neuromesenchymal disease. Neurogastroenterol Motil 2008; 20:263-8. [PMID: 18371008 DOI: 10.1111/j.1365-2982.2008.01090.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Abnormalities of enteric nerves, interstitial cells of Cajal (ICC) and smooth muscle are often associated with severe gastrointestinal motility disorders. In this context, full-thickness biopsy of the gut may provide important diagnostic and prognostic clues as well as some possible therapeutic implications. Nonetheless, the unavoidable risk to further worsen prognosis evoked by laparotomy, and the unclear yield of histopathological analysis has hampered full-thickness gut sampling in patients with severe dysmotility. However, recent advances in minimally invasive surgery have refuelled enthusiasm in gastrointestinal neuromuscular pathology. In this issue of Neurogastroenterology and Motility, Miller et al. provide novel and exciting evidence that the appendix might be used as a surrogate tissue to analyse changes to enteric nerves, ICC and smooth muscle cells in patients with diabetic gastroenteropathy. The objective of this short review was to place this very important work in the context of current understanding of enteric neuromuscular dysfunction.
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Affiliation(s)
- C H Knowles
- Centre for Academic Surgery, Barts & The London, Queen Mary's School of Medicine and Dentistry, London, UK
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