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Biomedical subjects

P J Pasricha

Publications and source records attributed to P J Pasricha.

At least 19 recordsLinked to original sources
PubMed2006

Transgastric endoscopic splenectomy: is it possible?

BACKGROUND: We have previously reported the feasibility of diagnostic and therapeutic peritoneoscopy including liver biopsy, gastrojejunostomy, and tubal ligation by an oral transgastric approach. We present results of per-oral transgastric splenectomy in a porcine model. The goal of this study was to determine the technical feasibility of per-oral transgastric splenectomy using a flexible endoscope. METHODS: We performed acute experiments on 50-kg pigs. All animals were fed liquids for 3 days prior to procedure. The procedures were performed under general anesthesia with endotracheal intubation. The flexible endoscope was passed per orally into the stomach and puncture of the gastric wall was performed with a needle knife. The puncture was extended to create a 1.5-cm incision using a pull-type sphincterotome, and a double-channel endoscope was advanced into the peritoneal cavity. The peritoneal cavity was insufflated with air through the endoscope. The spleen was visualized. The splenic vessels were ligated with endoscopic loops and clips, and then mesentery was dissected using electrocautery. RESULTS: Endoscopic splenectomy was performed on six pigs. There were no complications during gastric incision and entrance into the peritoneal cavity. Visualization of the spleen and other intraperitoneal organs was very good. Ligation of the splenic vessels and mobilization of the spleen were achieved using commercially available devices and endoscopic accessories. CONCLUSIONS: Transgastric endoscopic splenectomy in a porcine model appears technically feasible. Additional long-term survival experiments are planned.

Animals↗
PubMed2006

Effect of a novel pancreatic stent design on short-term pancreatic injury in a canine model.

BACKGROUND AND STUDY AIMS: Attempts to address the problem of injury to the pancreas by indwelling pancreatic stents are limited by our lack of knowledge of the pathogenesis of stent-induced injury and its relationship to stent morphology and the duration of stenting. The aim of our study was to evaluate pancreatic injury induced by 1 week of stenting with a 5F indwelling pancreatic stent of novel design, the "wing stent." METHODS: Pancreatic stents (5F) were placed surgically in eight dogs; wing stents (WS-5F) were used in four dogs and conventional stents (CS-5F) in another four. Two dogs underwent duodenotomy without stent placement (controls). The pancreas was harvested for microscopy at 1 week. A pathologist who was unaware of the source of the specimens graded the pancreatic injury. RESULTS: Although pancreatic injury was observed in both the CS-5F and WS-5F groups after 1 week of indwelling pancreatic stenting, it was considerably less severe in the WS-5F group compared with the CS-5F group (1.01 +/- 0.10 vs. 1.63 +/- 0.14, P < 0.01). All components of pancreatic injury were affected, with the most dramatic differences noted in inflammation, fibrosis, and edema. The differences were most marked in the stented segment ( P < 0.001) and in the upstream segment of the pancreas ( P < 0.05). CONCLUSIONS: Indwelling conventional pancreatic stents can cause significant pancreatic injury even when left in place for only 1 week. A wing design can significantly ameliorate stent-induced changes.

Animals↗
PubMed2006

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Consensus Statements as Topic↗
PubMed2006

Suppression of nNOS expression in rat enteric neurones by the receptor for advanced glycation end-products.

Diabetes mellitus results in a loss of neuronal nitric oxide synthase (nNOS) expression in the myenteric plexus but the underlying mechanisms remain unknown. We hypothesized that this may be mediated by advanced glycation end-products (AGEs), a class of modified protein adducts formed by non-enzymatic glycation that interact with the receptor for AGE (RAGE) and which are important in the pathogenesis of other diabetic complications. Whole mount preparations of longitudinal muscles with adherent myenteric plexus (LM-MPs) from the duodenum of adult male rats were exposed to glycated bovines serum albumin (AGE-BSA) or BSA for 24 h. Western blotting, immunohistochemistry and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for mRNA showed a significant reduction in nNOS expression in LM-MPs after exposure to AGE-BSA. NO release, as measured by the Griess reaction, was also significantly reduced by AGE-BSA. A neutralizing antibody against RAGE attenuated the reduction of nNOS protein caused by AGE-BSA. Immunohistochemistry revealed co-localization of RAGE expression with Hu, a marker for neuronal cells but not for S-100, a glial marker. Advanced glycation end-products reduce nNOS expression in the rat myenteric neurones acting via the receptor RAGE. Our results suggest novel pathways for disruption of the nitrergic phenotype in diabetes.

Animals↗
PubMed2005

Transoral obesity surgery: endoluminal gastroplasty with an endoscopic suture device.

BACKGROUND AND STUDY AIMS: Surgical creation of a small gastric pouch with a restricted outlet is a well-established option for the treatment of morbid obesity. This report describes initial experience with endoscopic transoral stomach partition using a newly designed suturing apparatus. MATERIALS AND METHODS: A fresh porcine stomach was placed in the Erlangen model. A prototype suture device, incorporating a curved needle and an intracorporeal tightening mechanism, was used in this procedure. A long fishing line was first introduced into the stomach, with the two ends left outside. The suturing device, premounted outside a standard gastroscope, was inserted into the stomach and delivered several stitches attaching the fishing line to both the anterior and posterior walls along the line for the stomach to be partitioned. Five throws of half-hitches were tied onto the fishing line extracorporeally and separately pushed into place, creating a gastric pouch just below the esophagogastric junction. A flexible sheath of 8 cm long was then put on one side of the fishing line and pushed into the stomach. Additional extracorporeal knots were tied on the fishing line, forming a restrictive ring at the outlet of the pouch. The ring was then anchored to the stomach wall with similar endosutures. RESULTS: The proximal gastric pouch, with an estimated volume of approximately 100 ml, was successfully created with a restrictive band at its outlet. All of the stitches were securely sutured, with consistent penetration of the muscular layer of the stomach wall. CONCLUSIONS: In a bench model, it is technically possible to accomplish transoral gastroplasty endoscopically with an intraluminal suturing device. Further live animal studies will be needed in order to confirm the efficacy and safety of this procedure before clinical application.

Animals↗
PubMed2005

Assessing the adequacy of endoscopically tied knots: a functional approach.

BACKGROUND AND STUDY AIMS: Endoscopic intracorporeal knots have potentially enormous applications in endoscopic surgery. We describe a method for testing the security of various types of endoscopically tied knots using a vessel perfusion manometer system. METHODS: A 4-cm segment of porcine splenic artery was placed on the mucosal surface of a pig stomach. The two ends of the vessel were brought out through the gastric wall and connected to a two-way manometer. One end was also joined to a pressure infusion bag. The stomach was mounted in an Erlangen training model. A long 3/0 nylon thread, previously introduced into the submucosal layer of the stomach and encircling the vessel, was brought out from the mouth. Three-throw square knots, Mayo knots, "surgeon's" knots and five-throw square knots were tied and pushed into place using a cap attached to a gastroscope. The pressure at the two ends of the artery was compared. If the pressure could be increased to over 200 mm Hg at one end without a change in the other, the knot was considered secure. RESULTS: Each type of knot was tested 12 times under endoscopic vision. The range for mean knotting time was 3.4 - 4.5 minutes. Five-throw knots took significantly longer to tie than three-throw knots (P < 0.005). There was one loose knot in each of the three-throw and Mayo groups, and three each in the "surgeon's" and five-throw groups (P > 0.05). CONCLUSIONS: This system is a reliable model for testing intracorporeal knots tied endoscopically. A three-half-hitches square knot with 3/0 nylon, tied using a flexible endoscope and knot-tightening cap, can withstand pressure up to 200 mm Hg.

Animals↗
PubMed2005

Graded esophageal mucosal ablation with cryotherapy, and the protective effects of submucosal saline.

BACKGROUND AND STUDY AIMS: Knowledge about the extent of damage with endoscopic cryotherapy is of critical importance before its potential as an ablative therapy is explored. The aims of this study were to evaluate the extent of transmural esophageal necrosis at 48 hours after cryospraying for varying durations, using a novel device based on the Joule-Thomson effect and with carbon dioxide as the refrigerant gas, and to examine the role of submucosal injection of saline in preventing deeper injury. METHODS: Cryospray was applied to several different segments of the esophagus for various lengths of time (15, 30, 45, 60, and 120 seconds) in a pig model. In another set of experiments performed subsequently, 2 ml of saline was injected into the submucosa and cryospray was applied for 60 seconds. RESULTS: Esophageal cryotherapy resulted in a dose-dependent injury to the esophagus: esophageal necrosis was minimal or limited to the mucosa after 15 seconds of cryospraying, extended to involve the submucosa after 30 seconds of cryospraying, and involved the muscularis propria also after 45 seconds, with frank transmural necrosis found after 120 seconds of cryotherapy. Prior submucosal saline injection protected against muscular necrosis from prolonged cryotherapy. CONCLUSIONS: We have shown a dose-dependent effect of cryotherapy on esophageal mucosal ablation. When more extensive lesions are encountered, it may be advisable to consider using submucosal saline injections as an additional safeguard against deeper injury.

Animals↗
PubMed2005

Developing an animal model of massive ulcer bleeding for assessing endoscopic hemostatic devices.

BACKGROUND: Existing animal models of ulcerative bleeding are not suitable for endoscopic investigation. We describe a new porcine model of massive arterial bleeding in the stomach and its use for assessing a novel endoscopic suturing device. METHODS: Two animal models were investigated. In model 1, the short gastric artery (mean diameter 2 mm) was divided near its gastric end. A mucosal defect was created near the greater curve and the divided artery was brought into the lumen of the stomach through a submucosal tunnel. An inflatable plastic cuff was placed around the base of the artery. Cuff deflation led to massive bleeding. In model 2, the short gastric artery was carefully exposed along a segment of 2 cm on the side facing the stomach. It was then anchored to a small gastrostomy made at the posterior wall near the vessel. At endoscopy an ulcer-like lesion could be seen with a pulsatile vessel at the base and brisk bleeding could be started by cutting a hole in the artery using endoscissors. The pigs were heparinized by an intravenous bolus of 110-300 units per kilogram, in both models. A prototype suturing device, the Eagle Claw, was inserted using a gastroscope and the curved needle was driven around the bleeding artery. Extracorporeal knotting or intracorporeal ligation was done endoscopically. RESULTS: Pulsatile arterial bleeding was successfully created in four pigs using model 1, and in another four pigs using model 2. Model 2 was more reproducible and less time-consuming to create. Endoscopic suturing controlled arterial bleeding in five out of eight pigs with a single stitch and in another three pigs with an additional stitch. CONCLUSION: This animal model provides reproducible massive hemorrhage suitable for endoscopic studies. Control of gastric bleeding from large arteries by endoscopic suturing is possible.

Animals↗
PubMed2005

Caspase inhibition increases survival of neural stem cells in the gastrointestinal tract.

Neural stem cell (NSC) transplantation is a promising tool for the restoration of the enteric nervous system in a variety of motility disorders. Post-transplant survival represents a critical limiting factor for successful repopulation. The aim of this study was to determine the role of both immunological as well as non-immune-mediated mechanisms on post-transplant survival of NSC in the gut. Mouse CNS-derived NSC (CNS-NSC) were transplanted into the pylorus of recipient mice with and without the addition of a caspase-1 inhibitor (Ac-YVAD-cmk) in the injection media. In a separate experiment, CNS-NSC were transplanted in the pylorus of mice that were immunosuppressed by administration of cyclosporin A (CsA). Apoptosis and proliferation of the implanted cells was assessed 1 and 7 days post-transplantation. Survival was assessed 1 week post-transplantation. The degree of immunoresponse was also measured. The addition of a caspase-1 inhibitor significantly reduced apoptosis, increased proliferation and enhanced survival of CNS-NSC. CsA-treatment did not result in improved survival. Our results indicate that caspase-1 inhibition, but not immunosuppression, improves survival of CNS-NSC in the gut. Pre-treatment with a caspase-1 inhibitor may be a practical method to enhance the ability of transplanted CNS-NSC to survive in their new environment.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Enteric neural crest-derived cells and neural stem cells: biology and therapeutic potential.

The enteric nervous system arises from two regions of the neural crest; the vagal neural crest which gives rise to the vast majority of enteric neurones throughout the gastrointestinal tract, and the sacral neural crest which contributes a smaller number of cells that are mainly distributed within the hindgut. The migration of vagal neural crest cells into, and along the gut is promoted by GDNF, which is expressed by the gut mesenchyme and is the ligand for the Ret/GFRalpha1 signalling complex present on migrating vagal-derived crest cells. Sacral neural crest cells enter the gut after it has been colonized by vagal neural crest cells, but the molecular control of sacral neural crest cell development has yet to be elucidated. Under the influence of both intrinsic and extrinsic cues, neural crest cells differentiate into glia and different types of enteric neurones at different developmental stages. Recently, the potential for neural stem cells to form an enteric nervous system has been examined, with the ultimate aim of using neural stem cells as a therapeutic strategy for some gut disorders where enteric neurones are reduced or absent.

Animals↗
PubMed2001

The proteinase-activated receptor 2 is involved in nociception.

The proteinase-activated receptor 2 is expressed on a subset of primary afferent neurons and may participate in the neurogenic component of inflammation. We hypothesized that this receptor may also play a role in neuronal sensitization and contribute to the pathogenesis of pain in inflammatory conditions such as pancreatitis. Using a specific proteinase-activated receptor 2 activating peptide, we found evidence of such sensitization in vitro in the form of enhanced capsaicin- and KCl-evoked release of calcitonin gene-related peptide, a marker for nociceptive signaling. We then demonstrated that injection of the proteinase-activated receptor 2 activating peptide into the pancreatic duct can activate and sensitize pancreas-specific afferent neurons in vivo, as measured by Fos expression in the dorsal horn of the spinal cord. These observations suggest that proteinase-activated receptor 2 contributes to nociceptive signaling and may provide a novel link between inflammation and pain.

Animals↗
PubMed2001

Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons.

Nerve growth factor (NGF) regulates the nociceptive properties including sensitivity to capsaicin of a subset of dorsal root ganglion neurons, which express the high-affinity NGF receptor, trkA. Capsaicin sensitivity co-localizes with the expression of a cloned capsaicin receptor, vanilloid receptor type 1 (VR-1), which displays properties similar to the native capsaicin response. To determine whether VR-1 mRNA levels are regulated by NGF, VR-1 mRNA levels and the ability to respond to capsaicin by release of the neuropeptide calcitonin gene related peptide (CGRP) were measured as a function of NGF concentration in cultures of adult dorsal root ganglion neurons. NGF treatment increased both VR-1 mRNA expression and capsaicin evoked release of CGRP. These effects were inhibited by treatment with the trkA inhibitor k252a.

Animals↗
PubMed2001

Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population.

BACKGROUND & AIMS: To assess the prevalence of flat and depressed (F&D) colorectal adenomas in the United States, we performed a prospective study of 211 American patients. METHODS: Dye-assisted colonoscopy was performed in the presence of both an American and a Japanese investigator. RESULTS: F&D lesions were found in 22.7% of patients, and these were more likely to be adenomatous than polypoid lesions (82% vs. 67%; P = 0.03) and contained more invasive cancer (4.5% vs. 0%; P = 0.04), which also appeared to be at a disproportionately advanced stage. The average size of all F&D advanced lesions (high-grade dysplasia and cancer) was significantly smaller than comparable polypoid lesions (10.75 +/- 2.7 mm vs. 20 +/- 2.9 mm; P < 0.05). F&D adenomas showed significantly stronger fragile histidine triad (FHIT) expression and lower p53 reactivity than similarly sized polypoid adenomas, whereas proliferative and apoptotic indices were similar in both groups. CONCLUSIONS: We conclude that there is a significant prevalence of colonic F&D colorectal adenomas in this country and that these lesions have significantly different biologic features than polypoid lesions. The clinical and epidemiologic implications of these findings for American patients need to be addressed in further studies.

Acid Anhydride Hydrolases↗