The influence of gastrin on gastrointestinal function

To improve intestinal function in children with short bowel syndrome, our laboratory has focused on identifying substances, which may enhance the function of small intestine epithelium. Previous studies have demonstrated that gastrin appeared to exert a trophic effect on the gastrointestinal tract. We chose to evaluate the influence of chronic, systemic, and luminal administration of gastrin-17 on substrate absorption in both fetal and mature rat small intestine. Transplanted fetal small intestine, mature small intestine in situ, and isolated mature small intestine segments were the surgical preparations used. Saline (control) or gastrin-17 (13.5 nmol/kg/d) was administered continuously for 14 days either systemically or luminally using osmotic pumps. The response to the saline or gastrin-17 infusions was determined by measuring absorption of radiolabeled substrates (14-C-galactose and 14-C-glycine). Following transplantation of fetal small intestine to a syngeneic host, galactose absorption rose 250% (P less than .01) and glycine absorption rose 130% (P less than .05) when compared with controls (N = 10). The response of mature jejunum and ileum following systemic gastrin infusion was a mild to moderate rise in galactose and glycine absorption, although statistical significance was not achieved. However, following luminal gastrin infusion into mature small intestine segments, there was a 4.54 fold rise in galactose absorption (P less than .01) and a 4.79 fold rise in glycine absorption (P less than .01) when compared with controls. These data suggest that gastrin can enhance substrate absorption in rat fetal and mature small intestine and that luminal perfusion appears to induce the greatest response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancement of small intestine absorption by intraluminal gastrin

Several studies have suggested that gastrointestinal peptides can produce trophic changes in the small intestine epithelium. In a previous study utilizing a rat fetal intestine transplant model, we reported that chronic, continuous, systemic administration of gastrin-17 increased carbohydrate absorption 2.5-fold and protein absorption 1.3-fold. The present study was designed to evaluate the effect of chronic luminal perfusion of gastrin on substrate absorption in rat mature small intestine. A 10-cm segment of mid small intestine was isolated with both ends brought out as abdominal wall stomas (creating a Thiry-Vella loop) and bowel continuity was established by end-to-end anastomosis. After a 1-week recovery, the tips of two catheters were positioned at approximately 3 and 6 cm from the proximal end of the isolated small intestine segment. A 14-day continuous luminal perfusion was accomplished by connecting the other ends of the catheters to subcutaneously placed osmotic pumps filled to deliver saline (control; N = 10) or gastrin-17 (13.5 nM/kg/day; N = 7). At the completion of the luminal perfusion, intestinal absorption was determined with labeled substrates [14C]galactose and [14C]glycine) using a closed, recirculation technique. Absorption (microM/cm2 small intestine) of galactose in the control animals was 1.44 +/- 0.18 and for the gastrin infused rats, it was 6.56 +/- 0.46. Glycine absorption was 1.63 +/- 0.31 for the control group and 7.83 +/- 0.62 for the gastrin infused group. Thus, in this rat model, intraluminal gastrin infusion was capable of increasing carbohydrate (galactose) absorption 456% (P less than 0.01) and protein (glycine) absorption 480% (P less than 0.01). These data represent the first demonstration that intraluminal gastrin can influence small intestine mucosal function by enhancing substrate absorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Can gastrointestinal hormones enhance intestinal absorption?

Recent studies have suggested that certain gastrointestinal peptides exert a trophic effect on the small intestine. We chose to evaluate the effect of glucagon and cholecystokinin-octapeptide (CCK-OP) on absorption of substrates in both developing and mature small intestine. Developing small intestine was evaluated in a rat fetal intestine transplant model, and mature rat small intestine was studied in in situ but isolated 10 cm segments of jejunum and ileum. Glucagon, 10 micrograms/kg/day, and CCK-OP, 45 micrograms/kg/day, were delivered continuously for 14 days through a subcutaneous osmotic pump. Intestinal absorption was determined with labeled substrates (14C-galactose and 14C-glycine) by a recirculation perfusion technique. Absorption results were expressed as percentage increase over control. The fetal intestine response to glucagon infusion was a 13% rise in galactose absorption and a 27% rise in glycine absorption. After CCK-OP infusion, fetal galactose absorption was 11% and glycine absorption rose 17%. Mature jejunal galactose absorption rose 53% and glycine absorption rose 55% after glucagon infusion. The ileal response to glucagon was a 271% rise in galactose absorption (p less than 0.05) and a 21% increase in glycine absorption. Infusion of CCK-OP decreased jejunal galactose absorption 3% but increased glycine absorption 41%. The ileal response was a 224% increase in galactose absorption (p less than 0.05) and a 19% increase in glycine absorption. Our data suggest that chronic administration of glucagon and CCK-OP can increase substrate absorption in developing and mature rat small intestine. Perhaps manipulation of the gastrointestinal hormone environment may result in increased absorption in man.     

Endogenous opiates in the mediation of early meal-induced jejunal absorption of water and electrolytes

The purpose of this study was to investigate the role of endogenous opiates in mediating meal-stimulated jejunal absorption. Jejunal Thiry-Vella loops, 25 cm long, were studied in awake conditioned dogs, using luminal perfusion with carbon-14 polyethylene glycol. Fluxes of water, sodium, and chloride were calculated every 15 minutes over a 1-hour basal period, followed by a 3-hour experimental period. The animals were divided into four groups: control, naloxone, meal, and meal plus naloxone. In the control and naloxone groups, the fluxes did not change over the 4-hour observation period. Meal alone immediately stimulated the absorption of water and electrolytes in the Thiry-Vella loop (p less than 0.05). The addition of naloxone infusion to the meal stimulus resulted in significantly reduced absorption during the first hour after the meal (p less than 0.05). We concluded that endogenous opiates play a role in meal-stimulated jejunal absorption.     

GLP-2alpha accelerates recovery of mucosal absorptive function after intestinal ischemia/reperfusion

BACKGROUND/PURPOSE: The authors' previous laboratory results have shown that rats treated for 3 days with intravenous GLP-2alpha, a synthetic protease-resistant form of glucagonlike peptide-2, showed increased mucosal mass and absorptive function when compared with saline-treated controls after intestinal ischemia/reperfusion (I/R). This study was designed to explore the temporal relationship between injury that occurs secondary to intestinal I/R and recovery of mucosal absorptive function with and without GLP-2alpha treatment. METHODS: Each of 18 male Sprague-Dawley rats (300 to 333 g) was subjected to superior mesenteric artery occlusion for 30 minutes, during which time a jugular venous catheter was placed and connected to a subcutaneous infusion pump. Rats were divided into 4 groups based on the type and duration of infusion as follows: group 1, systemic saline at 1 microL/h for 24 hours (n = 5); group 2, systemic GLP-2alpha at 100 microg/kg/d for 24 hours (n = 5); group 3, systemic saline at 1 microL/h for 72 hours (n = 4); and group 4, systemic GLP-2alpha at 100 microg/kg/d for 72 hours (n = 4). Immediately after the infusions, (14)C-galactose and (14)C-glycine absorption was measured using an in vivo, closed-recirculation technique and expressed as micromoles per square centimeter intestine +/- SEM. Statistical analysis was performed using analysis of variance. RESULTS: Twenty-four hours after intestinal I/R injury, there was a decrease in substrate absorption but no significant difference between the saline and GLP-2alpha-treated groups (galactose absorption, 1.13 +/- 0.09 in group 1 v 1.35 +/- 0.11 in group 2, P =.15; glycine absorption, 1.18 +/- 0.13 in group 1 v 1.34 +/- 0.15 in group 2, P =.36). However, after the 72-hour infusion, absorption of galactose and glycine was significantly increased in the rats receiving GLP-2alpha as compared with the saline-infused control group (galactose absorption, 1.24 +/- 0.13 in group 3 v 1.88 +/- 0.10 in group 4, P <.01; glycine absorption, 1.64 +/- 0.07 in group 3 v 2.05 +/- 0.08 in group 4, P <.05). Compared with previously determined levels of absorption in normal, uninjured rat intestine (1.50 +/- 0.12 micromol/cm(2) for galactose and 1.85 +/- 0.17 micromol/cm(2) for glycine), after I/R a 72-hour infusion of GLP-2alpha increased galactose absorption 26% (P <.05) and glycine absorption 11% (P =.29) beyond baseline. CONCLUSIONS: When initiated at the time of intestinal I/R, a continuous infusion of GLP-2alpha accelerated recovery of mucosal absorptive function in rats. Remarkably, carbohydrate absorption at 72 hours was increased to a level significantly greater than that in normal, uninjured rat intestine. J Pediatr Surg 36:570-572.     

Expression of Her-2/neu oncogene protein product and epidermal growth factor receptors in surgical specimens of human breast cancers.

Her-2/neu protein product was immunocytochemically analyzed in 139 breast cancers. Epidermal growth factor receptors were similarly analyzed in 74 breast cancers from the same patient pool. These results were also separated on the basis of estrogen receptor proteins and of combined aneuploidy with elevated S-phase from flow cytometry. Invasive breast cancer yielded a positive label for Her-2/neu protein (26%) and for epidermal growth factor receptor (25%), with no significant difference. Correlations with estrogen receptor labeling yielded differences significant inversely for both Her-2/neu protein (p less than 0.02) and epidermal growth factor receptor (p less than 0.01). Positive Her-2/neu protein labels correlated with a positive combination of aneuploidy and elevated S-phase (37%) and a negative combination of aneuploidy and elevated S-phase (21%), with a statistically nonsignificant difference. Positive epidermal growth factor receptor cases with aneuploidy and an elevated S-phase (75%) and without aneuploidy and elevated S-phase (42%) did differ with significance at p less than 0.05. There were eight cases positive for both Her-2/neu protein and epidermal growth factor receptor, four of six cases with negative estrogen receptor, four of six cases with negative estrogen receptor, six of six cases aneuploid, and five of six cases with an elevated S-phase. All eight cases had threatening disease--either stage III or stage IV, with one case of extensive ductal carcinoma in situ (comedo). Correlation of negative Her-2/neu protein with negative epidermal growth factor receptor was significant (p less than 0.05) in 74 cases. However, positive Her-2/neu protein did not correlate with positive epidermal growth factor receptor; there was a trend toward inverse correlation. We conclude that epidermal growth factor receptor labeling results show similarities to Her-2/neu protein results, but epidermal growth factor receptor tended to correlate with unfavorable ploidy and S-phase. Epidermal growth factor receptor labeling might be useful in breast cancers with macrocysts reported to show high epidermal growth factor activity.     

Enhancement of small intestine function by gastrin

Frequently, congenital or acquired small intestine (SI) abnormalities in infants lead to inadequate absorption. Gastrin has been suggested as a trophic hormone for SI epithelial cells. We chose to evaluate the effect of gastrin on the function and maturation of developing SI using a rat fetal intestine transplant model. Jejunoileal segments (7-8 cm) obtained from 19 to 20 days gestation fetal rats were implanted subcutaneously in syngeneic adult rats. Two weeks following transplantation the control group (N = 10) was continuously infused with saline and the study group (N = 9) was continuously infused with gastrin-17 (13.5 nM/kg/day) for 14 days. Following the infusion, intestinal maturation and function were evaluated by mucosal DNA concentration, disaccharidase activity, and absorption of [14C]galactose and [14C]glycine. Absorption (microM/cm2 SI) by the control and study groups for galactose was 1.10 +/- 0.18 vs 2.73 +/- 0.25, and for glycine was 1.68 +/- 0.23 vs 2.22 +/- 0.26, respectively. DNA concentration (microgram/mg SI) of the control and study groups was 410 +/- 43 vs 1031 +/- 158, respectively. Lactase and sucrase activity were similar in both groups. Although maltase (microM substrate hydrolyzed/min/g SI) was 13.5 +/- 2.7 for the gastrin group vs 7.9 +/- .9 for the control group, statistical significance was not achieved. Thus, gastrin produced a statistically significant increase in DNA concentration (cell mass) (P less than 0.01). More importantly, to our knowledge, this is the first demonstration that exogenously administered gastrin can increase absorption of carbohydrate (galactose; P less than 0.01) and protein (glycine; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Motilin's induction of phasic contractility in canine jejunum is mediated by the luminal release of serotonin

To determine whether mucosal serotonin (5-HT) is involved in the intestinal motility response to motilin, we studied the effects of intra-arterial infusions of motilin (5 X 10(-10) mol/L) in isolated, vascularly perfused segments of canine jejunum. Intraluminal pressures were continuously recorded through a perfused manometric catheter, and venous and luminal 5-HT levels were measured by radioimmunoassay. Luminal 5-HT output rose from a basal of 54 +/- 12 to a peak of 151 +/- 30 ng/min X 100 gm (p less than 0.01) with the motilin infusion. The earliest significant rise in luminal (5-HT), which occurred at 1 minute after the start of the motilin infusion, preceded the onset of phasic contractility. The rise in the motility index induced by motilin demonstrated a strong correlation (r = 0.72, p less than 0.01) with rises in luminal 5-HT output. 5-HT tachyphylaxis abolished the motility response to motilin; prior treatment with atropine abolished, while tetrodotoxin inhibited the luminal release of 5-HT. An infusion of exogenous 5-HT giving equivalent luminal 5-HT levels as induced by motilin led to similar phasic contractility and rise in the motility index. These findings suggest that motilin initiates phasic contractility in canine jejunum through the cholinergically mediated release of mucosal serotonin.     

The selective epidermal growth factor receptor tyrosine kinase inhibitor PD153035 suppresses expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro

OBJECTIVE: Malignant pleural mesothelioma is notoriously refractory to aggressive multimodality therapy. Epidermal growth factor receptor expression has been observed on malignant pleural mesothelioma cells. Epidermal growth factor receptor-mediated signaling promotes tumorigenesis and metastasis of cancer cells. The purpose of this study is to evaluate the ability of the epidermal growth factor receptor tyrosine kinase inhibitor PD153035 to abrogate the expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro. METHODS: Epidermal growth factor receptor expression of malignant pleural mesothelioma cells and primary normal cells was quantitated by means of flow cytometry. PD153035-mediated growth inhibition was determined by means of 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan and clonogenic assays. Cell motility and invasion of extracellular matrix was evaluated with in vitro wound-healing and Matrigel invasion assays, respectively. Vascular epidermal growth factor levels in conditioned media were measured by using enzyme-linked immunosorbent assay. RESULTS: Epidermal growth factor receptor expression was detected on all 6 cultured malignant pleural mesothelioma cells, with 4 of 6 having normal receptor expression and 2 of 6 overexpressing the receptor. PD153035 suppressed cell motility and cell invasion through a Matrigel membrane, regardless of the baseline epidermal growth factor receptor expression. Decreased vascular epidermal growth factor production and significant inhibition of growth only occurred in malignant pleural mesothelioma cells that overexpress epidermal growth factor receptor. CONCLUSIONS: Epidermal growth factor receptor tyrosine kinase inhibitor PD153035 significantly inhibited motility and invasion in malignant pleural mesothelioma cells in vitro, regardless of their epidermal growth factor receptor expression levels. Inhibition of epidermal growth factor receptor-dependent signaling might be a useful strategy to diminish malignant pleural mesothelioma recurrence after aggressive cytoreductive surgery.     

Interleukin-11 enhances small intestine absorptive function and mucosal mass after intestinal adaptation

BACKGROUND/PURPOSE: Interleukin-11 (IL-11) recently has been shown to enhance mucosal mass after massive small bowel resection (MSBR). However, enhanced mucosal mass may not correlate with increased substrate absorption. This study was designed to examine the effect of systemic administration of increasing doses of IL-11 on small intestine absorptive function and mucosal mass after MSBR. METHODS: Twenty-five Sprague-Dawley rats underwent an 80% small bowel resection and end-to-end jejunoileal anastomosis. Seven days after resection, all rats had placement of a jugular venous catheter connected to a subcutaneously placed osmotic pump. The rats were divided into 5 groups based on the content of the pump: group 1 (control, n = 5) received 0.1% bovine serum albumin (BSA) and groups 2 through 5 (n = 5 each) received IL-11 at 250, 500, 750, and 1,000 microg/kg/d, respectively. After a 14-day infusion period, [14C] galactose and [14C] glycine absorption was measured using an in vivo closed-recirculation technique. Mucosal DNA content also was determined for each group. Statistical analysis was performed by analysis of variance and expressed as mean +/-SEM. RESULTS: IL-11 administered at 250 microg/kg/d, a dose used in previous studies, did not significantly affect substrate absorption. However, compared with the control group, administration of higher doses of IL-11 produced a significant increase in substrate absorption and mucosal mass. The dose of IL-11 producing the overall optimal response based on the parameters measured (galactose absorption, 72% increase over control; glycine absorption, 112% increase over control; and DNA content, 98% increase over control) was 750 microg/kg/d. CONCLUSIONS: In addition to an increase in mucosal mass, these data show for the first time that IL-11 enhances absorptive function beyond the normal adaptive response after MSBR. Furthermore, the maximum effect of IL-11 on absorptive function was shown at 750 microg/kg/d, which is 3 times the dose used in previously reported studies. This study suggests that IL-11 may be useful clinically in patients with inadequate intestinal function.     

Glucagonlike peptide-2 analogue enhances intestinal mucosal mass and absorptive function after ischemia-reperfusion injury

BACKGROUND/PURPOSE: This study was designed to explore the efficacy of a synthetic analogue of glucagonlike peptide-2 (GLP-2a) in enhancing mucosal mass and absorptive function in a rat model of intestinal ischemia-reperfusion (I-R) injury. METHODS: Each of 20 Sprague-Dawley rats underwent placement of a jugular venous catheter connected to a subcutaneous osmotic pump designed to deliver its contents over 3 days. Rats were divided into 4 groups (n = 5 per group): (1) normal intestine/saline infusion; (2) 30-minute superior mesenteric artery occlusion/saline infusion, (3) normal intestine/ GLP-2alpha infusion, and (4) 30-minute superior mesenteric artery occlusion/GLP-2alpha infusion. Subsequently, mean mucosal 14C-galactose and 14C-glycine absorption and DNA content were determined for each group. RESULTS: In saline-treated rats, 30 minutes of mesenteric ischemia decreased mean mucosal galactose absorption by 29% (P < .05), glycine absorption by 22% (P = .12), and DNA content by 28% (P < .01) when compared with rats with uninjured intestine. In rats subjected to 30 minutes of intestinal ischemia, GLP-2alpha significantly improved galactose absorption by 46% (P < .05), glycine absorption by 84% (P < .01), and DNA content by 63% (P < .01) when compared with saline-treated control rats. In rats with mesenteric I-R injury treated with GLP-2a, galactose absorption was returned to normal. Glycine absorption and DNA content were increased significantly by 44% (P < .01) and 18% (P < .05), respectively, beyond the baseline for normal intestine. CONCLUSIONS: Thirty minutes of intestinal ischemia followed by immediate reperfusion significantly decreased mucosal mass and absorptive function, validating this rat model of I-R injury. After mesenteric I-R, GLP-2a significantly increased mucosal DNA content and absorption of 14C-galactose and 14C-glycine when compared with untreated control rats. After I-R injury, GLP-2a restored mucosal mass and absorptive function to normal or above-normal levels.     

Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques

OBJECTIVE: Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. METHODS: Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. RESULTS: Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5- to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. CONCLUSIONS: These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.     

Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry

To investigate the significance of immunohistochemical molecular subtyping, we evaluated outcomes of subtypes based on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67. Using tissue microarrays, 1006 breast cancer patients between November 1999 and August 2005 were categorized into four subtypes: luminal A (ER+ and/or PR+, HER2-, Ki-67 < 14%), luminal B (ER+ and/or PR+, HER2-, Ki-67 ≥ 14% or ER+ and/or PR+, HER2+), HER2-enriched (ER-, PR-, HER2+), and triple-negative breast cancer (TNBC) (ER-, PR-, HER2-). Demographics, recurrence patterns, and survival were retrospectively analyzed using uni-/multivariate analyses. Luminal A, luminal B, HER2-enriched, and TNBC accounted for 53.1%, 21.7%, 9.0%, and 16.2% of cases, respectively. Luminal A presented well-differentiation and more co-expression of hormone receptors comparing to luminal B. HER2-enriched showed larger size and higher nodal metastasis. TNBC demonstrated younger age at diagnosis, larger size, undifferentiation, higher proliferation, and frequent visceral metastases. The peak of recurrence for luminal A was at 36 months postoperatively, while that for HER2-enriched and TNBC peaked at 12 months. The relapse risk of luminal B was mixed. Luminal A showed the best survival, but no difference was observed between the other three subtypes. When matched by nodal status, however, TNBC showed the worst outcomes in node-positive patients. In multivariate analyses, luminal A remained a positive prognostic significance. Immunohistochemically-defined subtypes showed different features, recurrence patterns, and survival. Therefore, molecular subtypes using four biomarkers could provide clinically useful information of tumor biology and clinical behaviors, and could be used for determining treatment and surveillance strategies.     

Effects of rapid mannitol infusion on cerebral blood volume. A positron emission tomographic study in dogs and man

Positron emission tomography was used to study the effect of a rapid infusion of mannitol on cerebral blood volume (CBV) in five dogs and in three human subjects. The ability of mannitol to reduce intracranial pressure (ICP) has always been attributed to its osmotic dehydrating effect. The effects of mannitol infusion include increased osmolality, total blood volume, central venous pressure (CVP), and cerebral blood flow, and decreased hematocrit, hemoglobin concentration, serum sodium level, and viscosity. Mannitol's ability to dilate the cerebral vasculature, either directly or indirectly, and thus to transiently increase ICP, is a subject of controversy. By in vivo labeling of red cells with carbon-11, the authors were able to demonstrate an early increase in CBV in dogs of 20%, 27%, and 23% (mean increase, p less than 0.05) at 1, 2, and 3 minutes, respectively, after an infusion of 20% mannitol (2 gm/kg over a 3-minute period). The animals' muscle blood volume increased by 27% (mean increase, p less than 0.05) 2 minutes after infusion. In the human subjects, lower doses and a longer duration of infusion (1 gm/kg over 4 minutes) resulted in an increase in CBV of 8%, 14% (p less than 0.05), and 10% at 1, 2, and 3 minutes, respectively, after infusion. In dogs, ICP increased by 4 mm Hg (mean increase, p less than 0.05) 1 minute after the infusion, before decreasing sharply. The ICP was not measured in the human subjects. Hematocrit, hemoglobin, sodium, potassium, osmolality, heart rate, mean arterial pressure (MAP), and CVP were measured serially. Results of these measurements, as well as the significant decrease in MAP that occurred after mannitol infusion, are discussed. This study demonstrated that rapid mannitol infusion increases CBV and ICP. The increase in muscle blood volume, in the presence of a decreased MAP and an adequate CVP, suggests that mannitol may have caused vasodilation in these experiments.     

Interleukin-11 enhances intestinal absorptive function after ischemia-reperfusion injury

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 [mu ]g/kg/d. After the infusion, ¹⁴C-galactose or ¹⁴C-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 [mu ]moles/cm² (P [lt ] .01), and glycine from 2.79 to 1.72 [mu ]moles/cm² (P [lt ] .01). Rats treated with systemic IL-11 showed improved absorption of galactose of 2.39 [mu ]moles/cm² (P [lt ] .05), and glycine at 2.21 [mu ]moles/cm² (P [lt ] .05). Mucosal DNA content was reduced significantly from 7.37 to 5.61 [mu ]g DNA/mg by IR (P [lt ] .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.     

Effects of glycine on hemodynamic responses and visual evoked potentials in the dog

To study the potential contribution of glycine toxicity in the transurethral resection syndrome, we evaluated hemodynamic and visual evoked potential responses to glycine infusion (1 g/kg) in 22 dogs anesthetized with halothane (1.0-1.2% end tidal. Three dogs received 5% glucose in normal saline without glycine; three received arginine (4 mg/kg) in normal saline without glycine; three received arginine (4 mg/kg) in normal saline without glycine; 10 received glycine (1 g/kg), then arginine (4 mg/kg) 120 min after the completion of glycine infusion; and six received arginine 30 min after the completion of glycine infusion. Arginine was infused to evaluate potential antagonistic effects of glycine toxicity. Blood levels of glycine, ammonia, arginine, urea, and formate were determined after infusions of glycine or arginine. All animals received about 5 ml X kg-1 X hr-1 of normal saline during the 2-4 hr of study. Immediately after glycine infusion, cardiac output increased 57%, whereas systemic vascular resistance and mean arterial pressure decreased 32% and 8%, respectively. Later cardiac output and mean arterial pressure were 41% and 18% less than control levels, whereas systemic vascular resistance returned to control levels. Both amplitude and latency of visual evoked potential waveforms were altered in the animals receiving glycine infusion but not in the control animals. These responses were associated with elevations of blood glycine (149 +/- 5 to 9591 +/- 809 microM/L, mean + SEM) and blood NH3 (10.5 +/- 2.8 to 100.0 +/- 13.6 microM/L), but not with formate levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Small-bowel origin of the signal for meal-induced jejunal absorption

A meal stimulates the absorption of water and electrolytes from the proximal jejunal lumen. Neither sham feeding nor gastric distention alters this meal-induced jejunal absorption, implying no role for the cephalic or gastric phases of digestion. This study tested the hypothesis that the small bowel is the origin of the proabsorptive signal for meal-induced jejunal absorption. Twenty-five-centimeter canine proximal jejunal Thiry-Vella fistulas were constructed, and chronic duodenal catheters were placed. Jejunal absorption studies (n = 72) were performed by luminal perfusion of the jejunal segments with an isotonic buffer containing radioactive carbon-labeled polyethylene glycol. Each study consisted of a 1-hour basal period followed by a 3-hour experimental period. Ten groups were studied: control, orally ingested mixed meal, and 600 ml duodenal infusions of either water, saline solution, protein, lipid, carbohydrate, 150 mmol/L mannitol, 300 mmol/L mannitol, or 600 mmol/L mannitol, each delivered at 10 ml/min over 60 minutes. The control, water, and saline solution groups showed no significant changes in integrated 3-hour jejunal absorption above basal. The ingested mixed meal significantly increased water and electrolyte absorption (p less than 0.0001). The isovolumetric, isocaloric duodenal nutrient infusions of protein, lipid, and carbohydrate all significantly increased jejunal water and electrolyte absorption (p less than 0.0001). The poorly absorbed solute mannitol significantly increased absorption (p less than 0.0001) in a dose-dependent fashion. These results indicate that the proabsorptive signal for meal-induced jejunal absorption originates from or distal to the duodenum. This newly defined enteroenteric response occurs independently of nutrient composition and responds to increasing osmolarity of poorly absorbed solutes such as mannitol.     

Gastric luminal epidermal growth factor is affected by diet.

OBJECTIVE: Diet is an area of major interest to those investigating the causes of cancer of the oesophagus in the Transkei. This study looked at the associations between intragastric epidermal growth factor level, diet and intragastric pH. SETTING AND SUBJECTS: A dietary survey was co-ordinated with studies of gastric luminal epidermal growth factor and gastric fluid pH in 120 rural Transkeians. RESULTS: Gastric fluid epidermal growth factor was associated with low dietary intake of animal products (p = 0.002) and vegetables (p = 0.026). There was no association with pH. CONCLUSION: A dietary subgroup has been identified in the Transkei population with high levels of epidermal growth factor in the upper gastrointestinal lumen. This adds to previously demonstrated diet-related changes in the upper gastrointestinal tract in Transkei. These changes may affect the disease pattern of the population.     

Rapid dilation of the abdominal aorta during infusion of angiotensin II detected by noninvasive high-frequency ultrasonography

BACKGROUND: Infusion of angiotensin II (AngII) via subcutaneous osmotic pumps into mice promotes the development of abdominal aortic aneurysms (AAAs). These AngII-induced AAAs develop via a complex process in which there is a transmedial break, lumen dilation, thrombus formation, inflammation involving cells of both the innate and acquired immune systems, and remodeling. The recent development of a high-frequency ultrasound machine has permitted the noninvasive detection of murine abdominal aortas. We assessed the ability of a Visualsonics Vevo 660 high-resolution imaging system to detect AAAs and sequentially quantify the aortic luminal diameter. This system had 100% accuracy in detecting AngII-induced AAAs in vivo, with intrauser and interuser variation coefficients of less than 10% for quantification of the aortic lumen diameter. METHODS: Male apolipoprotein E (apoE)(-/-) mice were infused subcutaneously with either saline or AngII and were monitored with this ultrasonic system to define the temporal changes in aortic lumen diameter. Aortic luminal diameters were measured in the aneurysm-susceptible region of the suprarenal aorta. For internal controls, abdominal aortic diameters were measured at the level of the left renal branch, because this landmark region did not dilate during AngII infusion. RESULTS: Luminal diameters of the suprarenal aorta did not change significantly in saline-infused mice over 28 days of measurement (P = .71). In contrast, AngII infusion led to rapid dilation of suprarenal aortas during the initial 7 days of infusion (0.071 mm/d; P = .0037 for the change in the initial expansion rate). Further luminal diameter expansions occurred for the remaining 21 days of observation at a more modest rate (0.023 mm/d; P = .0001 for continued expansion after day 7). Within the initial 14 days of AngII infusion, some apoE(-/-) mice died as a result of rupture of the aorta in the suprarenal region. We had previously assumed that aortic dilation and rupture occurred simultaneously. However, in the AngII-infused mice that succumbed to aortic rupture, luminal diameters increased several days before death. CONCLUSIONS: High-frequency ultrasonography demonstrated that suprarenal aortic expansion occurs rapidly after the initiation of AngII infusion into apoE(-/-) mice.     

Comparison of regional versus systemic chemotherapy with adriamycin

To achieve the high drug concentrations in a target tissue (tumor) with minimal drug levels in organs not involved by cancer, thereby avoiding serious systemic side effects, three methods of Adriamycin administration: 1) Isolation perfusion, 2) Intra-arterial infusion, and 3) Intravenous infusion were studied in 22 dogs. Latter two methods were studied in several patients with soft tissue sarcoma of the extremities. Isolation perfusion of the hind extremity was done through the femoral vessels; intra-arterial and intravenous infusions were done through the femoral artery and cephalic vein, respectively. Adriamycin levels in tissues of the hind extremity and blood were determined. The highest Adriamycin levels in tissues could safely be achieved by isolation perfusion. Drug concentrations in regional tissues were not significantly different after intra-arterial infusion as compared to those after intravenous infusion. Much of the drug went into systemic circulation after intra-arterial infusion and almost none after isolation perfusion. Hematologic and histologic evidence of lethal systemic toxicity was noted only in dogs receiving Adriamycin by infusions. Edema, patchy muscle necrosis, hemorrhages, and skin ulcerations were observed in the perfused extremities only. In human studies, drug levels in blood were comparable to those in animal study when Adriamycin was administered by the latter two methods.