D.Curtis Lawson

Clinical application of porcine small intestinal submucosa in the management of infected or potentially contaminated abdominal defects

The repair of abdominal wall defects in potentially contaminated or grossly infected fields presents a difficult clinical problem. Polypropylene mesh is relatively contraindicated in these settings because of the potential for chronic infection. The alternatives to polypropylene include polyglactin mesh, which is not associated with chronic infection but is associated with a 100% recurrence of hernia. The ideal prosthetic for this patient group should be resistant to infection and ensure a low rate of hernia recurrence. We studied the use of small intestinal submucosa, which has been reported to be resistant to infection and incorporates into the fascia over 3 to 6 months, in 20 patients with ventral or inguinal hernias (18 ventral, 2 inguinal hernia) in the setting of bacterial contamination. The early postoperative complication rate was 50%. One patient with fasciitis had degradation of the small intestinal submucosa and loss of the bioprosthesis within 7 days. Other early complications included seroma (n = 2), ileus (n = 1), and wound infection (n = 8). No patient experienced chronic infection. Mean follow up was 15.7 months and the rate of recurrence documented by CT or physical examination was 30%. We concluded the following: (1) small intestinal submucosa is an effective alternative bioprosthesis in the management of ventral/inguinal hernia when there is associated bacterial contamination; (2) human vs. pig immune response has not been seen in this patient population; (3) early graft failure due to overwhelming fascial infection was noted in one patient and may be a limitation of this technology in a minority of patients; and (4) early hernia recurrence is relatively low but long-term follow-up has not been completed.

Safety and efficacy of India ink and indocyanine green as colonic tattooing agents

BACKGROUND Controversy exists concerning the safety and efficacy of colonic tattooing for the intraoperative identification of polypectomy sites. The purpose of this study was to determine (1) the concentrations of India ink and indocyanine green that resulted in high-visibility tattoos without significant tissue inflammation and (2) the India ink injection volume that produces best visibility at colonoscopy, laparoscopy, and laparotomy. METHODS Twenty-two New Zealand white rabbits (2 kg) were anesthetized and injected with India ink (undiluted 1:10, 1:50, 1:100, 1:1000, 1:10,000) and indocyanine green as an undiluted, concentrated formulation (25 mL/2 mL solvent) or in a diluted form (25 mg/5 mL solvent) at various concentrations (1:10, 1:50, 1:100). Tuberculin syringes were used to create a 0.1 mL serosal bleb at two injection sites 2 cm apart. Laparotomy was repeated at days 1, 3, and 7 after injection. Additionally, 16 rabbits were injected with India ink at laparotomy and re-explored at 1 and 5 months. Twelve mongrel dogs (20 kg) were injected with 1.0 mL volumes. Re-exploration by colonoscopy, laparoscopy, and laparotomy was done at 7 days and 1 month. Tattoo visibility at re-exploration in both animal models was graded on a scale (0 = agent not seen, 1 = seen with difficulty, 2 = easily seen). Histology in the rabbit was judged by degrees of inflammation (0 = no inflammation, 2 = mild inflammation, 4 = moderate inflammation, 6 = severe inflammation). RESULTS The concentrated indocyanine green solution was easily visible only on day 1 in the rabbit. Injections of both concentrated and diluted indocyanine green caused mucosal ulceration and moderate to severe inflammation. India ink studied at 7 days, 1 month, and 5 months after injection in the rabbit model was visible at all concentrations. The undiluted and 1:10 concentrations were easily seen and showed evidence of mucosal ulceration. Tattoos produced with all other India ink concentrations were visible without gross inflammation. India ink was also studied at 7 days and 1 month in dogs. The tattoo with the 1:100 concentration at 0.5 mL was seen consistently at colonoscopy, laparoscopy, and laparotomy with only a mild submucosal reaction at 7 days. The tattoos produced with the 1:100 and 1:1000 concentrations at 0.5 mL and 1.0 mL injection volumes were easily seen by all methods of intraabdominal visualization at 1 month with similar histology. CONCLUSION Indocyanine green was an ineffective colonic tattooing agent. India ink was an effective colonic tattooing agent. Dilute concentrations that caused little to no inflammation could be visualized at 7 days and 1 month in rabbits and dogs and at 5 months in rabbits. India ink, at appropriated concentrations, appears to be a safe short- and long-term colonic tattooing agent.

Evaluation of porcine-derived small intestine submucosa as a biodegradable graft for gastrointestinal healing.

High-risk anastomoses in the gut may benefit from the application of a synthetic reinforcement to pre vent an enteric leak. Recently a porcine-derived small intestine submucosa (SIS) was tested as a bioscaffold in a number of organ systems. The aim of this study was to evaluate the effectiveness of SIS in stimulating healing in the stomach. Twelve rats underwent surgical removal of a full-thickness gastric defect (1 cm) and subsequent repair with a double-layer patch of porcine-derived SIS. The graft was secured with interrupted sutures placed within 1 mm of the edge of the graft. After 21 days, the animals were killed and their stomachs harvested for histologic examination. Cross sections were processed for paraffin embedding and 4-micron sections were stained with hematoxylin and eosin. All animals survived, gained weight, and demonstrated no signs of peritonitis over the 3-week postoperative period. On postmortem examination, the defect was completely closed in all animals by granulation tissue and early fibrosis. Although most of the luminal surface of the grafted areas remained ulcerated, early regeneration of normal gastric mucosa was seen at the periphery of the defect. SIS may act as an effective scaffolding agent for intestinal mucosa and may offer protection in high-risk anastomoses.

Intracerebroventricular neuropeptide Y increases gastric and pancreatic secretion in the dog

BACKGROUND Neuropeptide Y (NPY), a centrally located neurotransmitter, is known to increase appetite in fasted and satiated animals. In addition to evaluating NPYs effect on eating behavior, this study was intended to determine whether intracerebroventricular (ICV) NPY would have an effect on canine gastric and pancreatic secretion. METHODS Four dogs were prepared with cerebroventricular guides and gastric and pancreatic fistulas. ICV and intravenous NPY was administered during intragastric titration of a glucose and peptone meal. During this study, gastric and pancreatic secretion was measured, as well as insulin levels and pancreatic polypeptide (PP). An additional set of four dogs were prepared with esophageal fistulas and cerebroventricular guides, and the effect of ICV NPY on sham feeding was studied. RESULTS ICV NPY significantly increased sham feeding, meal-stimulated gastric and pancreatic secretion, basal gastric acid, pancreatic bicarbonate, insulin levels, and PP. Vagotomy blocked the effect of ICV NPY on gastric acid secretion in a urethane-anesthetized rat model with acute gastric fistula. CONCLUSIONS ICV NPY increased sham feeding, gastric and pancreatic secretion, insulin levels, and PP in the dogs. NPYs effect on gastric secretion was blocked by vagotomy in a rat model. NPY should be considered a candidate mediator of cephalic phase secretion.

Effect of CGRP Antagonist, alpha-CGRP 8-37, on Acid Secretion in the Dog

The recently synthesized calcitonin gene-related peptide (CGRP) antagonist, human alpha-CGRP 8-37, was used to study its effects on gastric acid secretion. Four dogs with gastric fistula were used to measure the antagonists physiologic effects in the stomach. All dogs received a bactopeptone dextrose meal (intragastric titration to pH 5.5) with either continuous CGRP 8-37 (1000 pmol/kg/hr) or saline (control). Additionally, intravenous bombesin (75–600 ng/kg/hr) and bethanecol (12.5–100 µg/kg/hr) was tested in the presence of the antagonist. Plasma gastrin levels also were measured via radioimmunoassay (RIA) in control and CGRP 8-37-stimulated animals. Gastric acid secretion increased by 100% with infusion of 1000 pmol/kg/hr CGRP 8-37 when compared to the control. Acid output increased 98% with both intravenous antagonist and 600 ng/kg/hr bombesin when compared to bombesin alone. However, no augmentation of acid secretion by CGRP 8-37 was shown with 25 µg/kg/hr bethanecol. RIA of plasma gastrin demonstrated no effect with the antagonist when given alone and did not increase bombesin-stimulated gastrin release. We conclude that CGRP 8-37 blocks native CGRP inhibitory effects on gastric acid secretion. Our findings of potentiation of acid secretion by bombesin as well as no change in gastrin levels in the presence of the antagonist is likely due to a blockage in a noncholinergic neuron to the somatostatin cell. Furthermore, CGRP 8-37 did not increase bethanecolstimulated acid secretion, most likely due to bethanecols (acetylcholine) nearly ubiquitous positive effects on acid secretion.

The effect of taste on gastric and pancreatic responses in dogs

Six mongrel dogs with gastric and esophageal fistulas (n = 4) or with gastric and pancreatic fistulas (n = 2) were studied to determine the role of taste on gastric and pancreatic secretion. Stimulation of the back of the throat with a range of tastants produced gastric acid, bicarbonate, protein, and pancreatic polypeptide levels that were statistically equivalent to those produced with stimulation of the entire tongue. This suggests that the vagus nerve is the primary mediator of the cephalic phase response to tastants. There were marked individual differences among dogs in the responses to the ten tastants that were tested. On average, monosodium glutamate and seltzer, which mongrel dogs do not normally encounter in their diets, produced lower gastric acid secretion and pancreatic polypeptide release than sweet, sour, salty, bitter, and meaty tastes. The gastric acid secreted by the dogs with esophageal fistulas in response to tastes was only one-half as large as levels previously reported for sight/smell of food and only one sixth as large as those obtained with sham feeding.

Intracerebroventricular neuropeptide Y increases gastric acid secretion by decreasing tonic adrenergic inhibition of acid in dogs.

Neuropeptide Y (NPY) has been shown to increase basal gastric acid secretion in dogs. We examined the hypothesis that NPY might increase gastric acid secretion by interaction with central catecholaminergic control of acid secretion in dogs. Studies were performed in awake canines with gastric fistulas and cerebroventricular guides which allowed injection into the lateral cerebral ventricle. Intracerebroventricular (i.c.v.) injection of yohimbine (5 micrograms/kg) increased acid secretion compared to control (yohimbine: 9.1 +/- 3.3 mmol/h; control: 1.8 +/- 1.0 mmol/2 h P < 0.05), whereas prazosin and propranolol (both 5 micrograms/kg i.c.v.) had no effect, suggesting that there is tonic central alpha 2-adrenergic inhibition of acid secretion. NPY13-36 significantly increased acid secretion compared to control (NPY13-36 1000 pmol/kg i.c.v.: 5.6 +/- 1.9 mmol/2 h; control: 1.3 +/- 0.8 mmol/2 h, P < 0.05), whereas [Leu31,Pro34]-NPY had no effect, suggesting that the central effect of NPY is mediated at a Y2, probably pre-synaptic receptor. Finally, i.c.v. desmethylimipramine (DMI) inhibited the acid response to i.c.v. NPY when injected before but not after NPY (i.c.v. DMI then i.c.v. NPY: control, 15.2 +/- 6.6 mmol/2 h; DMI, 3.5 +/- 1.2 mmol/2 h, P < 0.05; i.c.v. NPY followed by i.c.v. DMI: control, 8.9 +/- 4.0 mmol/2 h; DMI, 9.9 +/- 2.9 mmol/2 h, P > 0.05). This suggests that NPY acts by decreasing noradrenaline release. These findings are compatible with the hypothesis that i.c.v. NPY increases acid secretion by decreasing tonic central adrenergic inhibition of acid by decreasing release of noradrenaline at a pre-synaptic level.

Neuropeptide Y functions as a physiologic regulator of cephalic phase acid secretion.

Neuropeptide Y (NPY) has been established as a potent orexigenic peptide, and recent studies suggest that NPY stimulates cephalic phase secretion as well. However, it is not known whether NPYs effects are pharmacologic or physiologic. In order to determine the physiologic significance of NPY, we examined the effects of two putative NPY receptor antagonists, PYX-1 and PYX-2, on sham feeding and gastric acid secretion in dogs. Our results demonstrate that intracerebroventricular (i.c.v.) injection of PYX-1 and PYX-2 at 1000 pmol/kg doses significantly suppresses the gastric acid response to sham feeding in dogs. The volumes sham fed were not significantly altered with i.c.v. administration of the antagonists. Peripheral administration did not affect acid secretion nor sham feeding volumes. Our data suggest that central administration of the novel NPY antagonists, PYX-1 and PYX-2, results in significant suppression of acid secretion in dogs. This supports our hypothesis that NPY functions as a physiologic modulator of cephalic phase acid secretion.

Short-term oral sensory deprivation: Possible cause of binge eating in sham-feeding dogs

Six mongrel dogs (18-20 kg) were prepared with gastric and esophageal fistulas. All dogs were studied under four experimental conditions. In conditions 1 and 3 the dogs were allowed to sham feed either a high-palatable or low-palatable meal on days 1-5 followed by a sham feed of a high-palatable or low-palatable meal on day 6. In conditions 2 and 4 the dogs were not sham fed (oral sensory deprived) on days 1-5 but were allowed to sham feed either a high-palatable or low-palatable meal on day 6. Total caloric requirement during each 6-day study was given by infusion of a liquid diet (Isocal) through the gastric fistula following the experiment. In condition 4, dogs deprived of oral sensation on days 1-5, significantly overconsumed their low-palatable meal on day 6. In condition 2, dogs deprived of oral sensation on days 1-5 also overconsumed their high-palatable meal on day 6, although this did not reach statistical significance. Dogs that received oral stimulation days 1-5 (conditions 1 and 3) did not overconsume their high- and low-palatable meals on day 6, suggesting that binge eating following short-term oral deprivation may be avoided if the diet provides adequate oral sensory stimulation. Body weights were well maintained throughout each study period and no changes were observed.

Conflict of interest issues pertinent to Veterans Affairs Medical Centers

Conflicts of interest exist when an arrangement potentially exerts inappropriate influence on decision making or professional judgment, or is perceived to do so, and can thus damage the public trust and undermine the integrity of those decisions. Concerns regarding financial conflicts of interest in the medical arena have reached their height as of late, given that physicians now function in a milieu of complex and delicate relationships with pharmaceutical, biotechnology, and medical device industries. Even when such relationships do not correlate with actual compromise of judgment or patient care, it threatens the credibility of both the health care professional and the institution because of the social perception of the effect of these relationships. Although most institutions in the Western world set forth a code of ethics and conflict-of-interest policies to be followed under threat of termination, the Veterans Health Administration (VHA) presents itself as a unique environment in which conflicts of interest are subject to governmental laws, violation of which may not only result in employment-related discipline, but may be sanctioned by civil and criminal penalties. Moreover, these provisions are developed by a national authoritative organization rather than being institution-specific guidelines. Given that many academic physicians working within the VHA may also have a component of their practice in a University setting, it becomes important to understand the differences in policy between these contexts so as not to threaten the public trust in the veracity of decisions made and, therefore, maintain the integrity of the relationship between physician and patient. This article will review aspects of conflict-of-interest policies in the realm of research, financial relationships, foreign travel, and vendor contracting that are particular to the VHA and make it a unique environment to function in as a physician and scientist.