Faculty Bibliography

This study was designed to investigate the benefits of administration of hepatocyte growth factor in a rat model of inflammatory bowel disease. Transfection of the HLA-B27 gene into Fisher rats induces a phenotype similar to inflammatory bowel disease. Fisher rats and HLA-B27 rats were divided into six groups: (1) Fisher, intravenous saline; (2) HLA-B27, intravenous saline; (3) HLA-B27, intravenous hepatocyte growth factor; (4) Fisher, luminal saline; (5) HLA-B27, luminal saline; and (6) HLA-B27, luminal hepatocyte growth factor. Rats received a 14-day infusion through an osmotic pump attached to a catheter positioned in either the jugular vein or the terminal ileum. Rats were evaluated for stool character, and gross and microscopic bowel inflammation. Statistics were analyzed using analysis of variance or the Kruskal-Wallis nonparametric test. A value of P<0.05 was significant. Compared to untreated HLA-B27 rats, intravenous administration of hepatocyte growth factor decreased diarrhea by 41% and microscopic inflammation by 54% (P<0.05). Luminal hepatocyte growth factor exposure decreased total bowel lesions by 53% and microscopic inflammation by 40% compared to untreated HLA-B27 rats (P<0.05), but it did not have an effect on diarrhea. Administration of hepatocyte growth factor ameliorates many of the features of bowel disease in this rat model and theoretically could have therapeutic applications in the management of inflammatory bowel disease in humans

The authors present the case report of a 13-year-old boy in whom organoaxial gastric volvulus developed four months after a laparoscopic Nissen fundoplication and placement of gastrostomy. Intraoperative findings were significant for volvulus about an axis defined by 2 fixation points, one at the fundoplication site and the other in the area of the gastrostomy tube, positioned close to the pylorus. Of the 142 pediatric cases of gastric volvulus reported to date, only 7 describe it as a complication subsequent to gastric surgery, and just one case has been reported after laparoscopic Nissen fundoplication. This case shows that fundoplication and gastrostomy, a recommended treatment for gastric volvulus, does not always preclude its development. Increasing numbers of pediatric surgeons are performing laparoscopic Nissen fundoplication procedures. The authors advise surgeons to consider this potentially fatal complication, both intraoperatively when selecting a location for gastrostomy and postoperatively when evaluating complaints

BACKGROUND: Intestinal ischemia-reperfusion (IR) injury results in enterocyte necrosis and apoptosis. This study was designed to evaluate the potential protective effects of interleukin-11 (IL-11) pretreatment on intestinal mucosa following IR injury. MATERIALS AND METHODS: Sham (n = 7) and control animals (n = 7) received 48 h of intravenous saline while treatment animals (n = 7) received IL-11 (750 microg/kg/day). Sham animals then underwent laparotomy alone, while control and treatment animals underwent 35 min of mesenteric artery occlusion and 120 min of reperfusion. Midjejunum samples were obtained and serum was drawn. Fluorometric assays were performed for hexosaminidase A (HEX A) and beta-glucuronidase (GLUC), markers of enterocyte necrosis. Apoptosis was quantified by TUNEL and confirmed by DNA fragmentation. Transcription of Bcl-2, an antiapoptotic regulator, was assessed by multiplex RT-PCR. Statistical analysis was performed using ANOVA and expressed as means +/- SEM. RESULTS: In pretreated animals, HEX A and GLUC activities after IR were reduced from 570 +/- 54 to 426 +/- 47 nmol/ml/h (P < 0.05) and from 183 +/- 29 to 125 +/- 7 nmol/ml/h (P < 0.01), respectively. Pretreated animals had a reduced number of apoptotic cells per 10 crypts (79 +/- 11) compared with untreated rats (255 +/- 17) after IR injury (P < 0.01). Mucosal DNA from pretreated rats qualitatively showed less fragmentation on electrophoresis. Relative Bcl-2 band intensity was higher in pretreated animals (1.04 +/- 0.09) compared with controls (0.78 +/- 0.07) (P < 0.05). CONCLUSIONS: IL-11 pretreatment reduced crypt cell apoptosis after IR injury, possibly by upregulating Bcl-2. Treated animals also demonstrated attenuation in the release of certain lysosomal enzymes. These data indicate that following IR injury, IL-11 improves enterocyte survival by reducing necrosis and apoptosis

BACKGROUND/PURPOSE: Intestinal ischemia-reperfusion (IR) injury produces necrosis and apoptosis resulting in tissue loss. The authors have observed previously that pretreatment with hepatocyte growth factor (HGF) attenuates enterocyte apoptosis after IR. This study investigated the effects of HGF on tissue levels of caspase-8, an apoptosis initiator, and caspase-3, an apoptosis effector, in intestinal mucosa after IR. METHODS: Thirty rats underwent placement of jugular venous catheters connected to osmotic pumps; 15 rats received vehicle, and 15 rats received HGF (150 microg/kg/d). After a 48-hour infusion, 5 rats from each group underwent either 35 minutes of superior mesenteric artery occlusion alone, or ischemia followed by 2 or 6 hours of reperfusion. Mucosal protein was analyzed for caspase-8 and caspase-3 activity. DNA fragmentation was used to measure the presence of apoptosis. Statistical significance was determined using analysis of variance. RESULTS: After 6 hours of reperfusion, caspase-3 activity was increased significantly in control animals (P <.05). In HGF-pretreated animals, caspase-8 and caspase-3 activities were significantly reduced at 6 hours compared with control animals (P <.05). CONCLUSION: By preventing the activation of enterocyte caspase enzymes, and, thus, reducing apoptosis, HGF may enhance preservation of the intestine after IR injury

BACKGROUND/PURPOSE: Ischemia-reperfusion (IR) injury to the intestine can result in mucosal damage and cellular death. This study was designed to evaluate the protective effects of pretreatment with hepatocyte growth factor (HGF) on intestine after moderate IR injury. METHODS: Control animals (n = 7) received 48 hours of intravenous saline, and treatment animals (n = 7) received HGF (150 microg/kg/d). After 35 minutes of mesenteric artery occlusion and 120 minutes of reperfusion, serum and jejunal mucosa samples were obtained. Fluorometric assays were performed for hexosaminidase A (HEX A) and beta-glucuronidase (GLUC), enzyme markers of enterocyte necrosis. Apoptosis was quantified by the TUNEL method. Transcription of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was assessed by multiplex reverse transcription polymerase chain reaction (RT-PCR) Statistical analysis was performed using the Student's t test. RESULTS: After HGF pretreatment, HEX A and GLUC activities were reduced from 543 +/- 28 to 343 +/- 35 nmole/h/mL (P <.01) and 183 +/- 29 to 119 +/- 22 nmole/h/mL (P <.01), respectively. Pretreated animals had a reduced number of apoptotic cells per 10 crypts (33 +/- 11) compared with untreated rats (225 +/- 24) after IR injury (P <.01). Mean IFN-gamma band intensity was lower in HGF-pretreated animals (0.05 +/- 0.02) compared with controls (0.31 +/- 0.09; P <.05). CONCLUSIONS: Pretreatment with HGF reduces the severe crypt apoptosis and cellular necrosis after IR injury to the intestine. These data suggest that HGF may be beneficial in attenuating IR damage and thus may have significant clinical application

BACKGROUND/PURPOSE: One hundred ninety-three cannulation procedures for extracorporeal membrane oxygenation (ECMO) have been performed at the authors' institution from 1994 to now. Before 1996, their practice had been to position these catheters exclusively by clinical assessment and chest radiograph. Since then, the authors have utilized intraoperative ultrasound guidance during cannulation procedures to confirm proper tip position. This retrospective analysis was undertaken to establish whether this practice has reduced the rate of surgical repositioning of ECMO catheters in these patients. METHODS: A retrospective chart review was performed for all infants who underwent ECMO cannulation procedures at the authors' institution. Numbers of infants requiring surgery to readjust ECMO catheter position were totaled. Cases were categorized according to the presence or absence of intraoperative ultrasound scan. Statistical significance was determined using X(2) analysis, Student's t test, or analysis of variance where appropriate. RESULTS: There were 193 ECMO cannulations performed. Of the 101 procedures done without ultrasound scan, 18 necessitated surgical repositioning. In contrast, only 3 of the 92 catheters placed with ultrasound assistance required reoperation. This represents a reduction the rate of repositioning from 17.8% to 3.3% of cannulations (P =.003). CONCLUSIONS: Based on these findings, the authors advocate the use of intraoperative ultrasound imaging to optimize the position of ECMO catheters. This high rate of initial success helps avoid the potential morbidity of ECMO circuit malfunction, repeat neck dissection, and catheter manipulation in these critically ill, anticoagulated patients

BACKGROUND/PURPOSE: Interleukin-11 (IL-11) is a multifunctional cytokine that has been shown to improve small bowel adaptation and enhance cellular recovery after bowel ischemia. This study was designed to examine the effects of systemic IL-11 on small bowel absorptive function in a rat model of intestinal ischemia and reperfusion (IR) injury. METHODS: Sprague-Dawley rats underwent placement of a venous catheter connected to an osmotic pump, which delivered its contents over 3 days. Rats were divided into 3 groups: sham operation/systemic saline; 30-minute superior mesenteric artery occlusion/systemic saline; superior mesenteric artery occlusion/systemic IL-11, 750 microgram/kg/d. After the infusion, (14)C-galactose or (14)C-glycine absorption was measured using an in vivo, recirculation technique. Statistical significance was determined using analysis of variance. RESULTS: In control rats, 30 minutes of IR decreased absorption of galactose from 2.62 to 2.02 micromoles/cm(2) (P <.01), and glycine from 2.79 to 1.72 micromoles/cm(2) (P <.01). Rats treated with systemic IL-11 showed improved absorption of galactose of 2.39 micromoles/cm(2) (P <.05), and glycine at 2.21 micromoles/cm(2) (P <.05). Mucosal DNA content was reduced significantly from 7.37 to 5.61 microgram DNA/mg by IR (P <.01). IL-11 treatment did not significantly alter DNA content during this period. CONCLUSIONS: These data show that 30 minutes of intestinal IR significantly decreases intestinal absorptive function in this animal model. When compared with untreated control animals, administration of systemic IL-11 significantly increased the absorption of carbohydrate and amino acid in rats recovering from mesenteric IR

A review of the pharmacologic substances and growth factors that have been studied experimentally and administered clinically for the management of short bowel syndrome is presented. The medical management of short bowel syndrome is multifaceted. In the acute phase, efforts focus on fluid and electrolyte management and the reduction of gastric acid output. As enteral feeding is initiated, antimotility and antisecretory agents may be effective in reducing gastrointestinal losses. Additional modalities of management, including nutrients and growth factors, may be directed at maximizing absorptive function beyond that which occurs with intestinal adaptation. Continued research aimed at further elucidating the process of intestinal adaptation may allow us to use the various peptides and hormones that act as growth factors for the bowel mucosa. Knowledge gained from these studies combined with gene therapy techniques will result in the permanent enhancement of intestinal function beyond the normal adaptation process, eliminate the dependence on total parenteral nutrition, and avoid the need for intestine transplantation