Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation.

This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-(13)C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone-sulfate (0.5 microM each) exerted a 39 and a 23% maximum inhibitory effect on cell proliferation in culture, which was increased to 60% when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46% decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9% after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruiting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.

Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation.

Neoplasms of the endocrine pancreas are extremely rare, and molecular mechanisms influencing their development are poorly understood. Nevertheless, gastrinomas have become a paradigm for the study of hormonally active tumors. In the present study, 12 gastrinoma and nonfunctioning pancreatic neuroendocrine tumor specimens were evaluated for genetic alterations of the p16/MTS1 tumor suppressor gene. DNA extracted from microdissected portions of paraffin-embedded tumor sections were examined for mutations and homozygous deletions using "Cold" single-strand conformation polymorphism and semiquantitative PCR-based analyses, respectively. Samples were also analyzed for the presence of 5' CpG island hypermethylation using methylation-specific PCR. The p16/MTS1 gene was found to be homozygously deleted in 41.7% of tumors and methylated in 58.3%, but no mutations were identified by single-strand conformation polymorphism analyses. Overall, 91.7% of the specimens demonstrated inactivating alterations in p16/MTS1. These data suggest that transcriptional silencing of p16/MTS1 is a frequent event in these rare and poorly understood tumors.

Somatostatin receptor imaging of neuroendocrine tumors with indium-111 pentetreotide (Octreoscan).

Somatostatin, a naturally occurring 14-amino acid peptide, can be thought of as an anti-growth hormone and functional down-regulator of sensitive tissue. Most neuroendocrine tumors seem to possess somatostatin receptors in sufficient abundance to allow successful scintigraphic imaging with radiolabeled somatostatin congeners. Several of these, including Indium-III-DTPA Pentetreotide (Octreoscan [Mallinckrodt Medical, St. Louis, MO]), which was approved for clinical use by the Food and Drug Administration in June 1994, have been of considerable value in scintigraphically identifying various neuroendocrine tumors. The Octreoscan compares favorably with other imaging modalities. The success of somatostatin receptor imaging in evaluating patients with suspected neuroendocrine tumors, including identifying otherwise radiographically occult lesions, has resulted in ranking somatostatin receptor imaging as the prime imaging procedure in patients with suspected neuroendocrine tumors at The Ohio State University.

The "right stuff": five Nobel Prize-winning surgeons.

Alfred Nobel's will specified that his estate be placed in a fund, the interest of which was to be distributed on an annual basis "to those who during the preceding year had conferred the greatest benefit on mankind." The first Nobel Prize in Physiology or Medicine was awarded in 1901, and its receipt is widely regarded as one of the highest accolades in science. This article reflects upon five surgeons who have been recognized as worthy of this honor. They are Emil Theodore Kocher, Alexis Carrel, Frederick Grant Banting, Werner Theodor Otto Forssman, and Charles Brenton Huggins. By winning this coveted prize these men have elevated the discipline of surgery to the summit of the scientific world. We review their legacy as an inspirational reminder of what we, the future of surgery, are capable.

Reversal of enhanced pancreatic cancer growth in diabetes by insulin.

BACKGROUND: Epidemiologic and animal studies have linked pancreatic cancer growth with both diabetes and fat intake. This study examined the influence of insulin treatment on pancreatic cancer growth in diabetes. Diabetes-induced elevations in levels of glucose and free fatty acids were correlated with enhanced tumor growth both in vivo and in vitro. METHODS: Hamsters were divided into three groups: control (n = 15), streptozocin-diabetic (n = 20), or insulin-treated diabetic (n = 20). Diabetes was induced with streptozocin and treated with a continuous subcutaneous infusion of insulin delivered via osmotic pumps. Five x 10(5) H2T hamster pancreatic cancer cells were implanted into the cheek pouch. Levels of plasma glucose and fatty acids were measured, and their effect on H2T cell division was assessed in vitro with a spectrophotometric cell proliferation assay. RESULTS: Levels of plasma glucose and fatty acids were elevated in streptozocin-diabetic animals and normalized with insulin treatment. After 21 days of growth, tumor weight was 36 mg in the control group, 156 mg in the diabetic group (p < 0.01 versus other groups), and 33 mg in the insulin-treated diabetic group. In vitro dose-dependent promotion of cell growth was shown for glucose (250%), linoleic acid (287%), linolenic acid (169%), and oleic acid (98%). CONCLUSIONS: Insulin ameliorated enhanced tumor growth in this model of diabetes. Glucose and free fatty acids mobilized during diabetes may serve as fuel for established pancreatic cancers.

Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse.

BACKGROUND: Streptozotocin-diabetes prevents induction of pancreatic tumors in several animal models and inhibits the growth of established human pancreatic cancer implants in nude mice. However, it also promotes growth of the hamster pancreatic cancer cell line, H2T, in the Syrian hamster. To test the hypothesis that these contradictory effects are due to tumor host differences, the growth of the H2T cell line was examined in the streptozotocin-diabetic nude mouse. METHODS: H2T cells were implanted subcutaneously into streptozotocin-diabetic nude mice (n = 10) and untreated control mice (n = 10). After 21 days, tumors were excised and weighed. Plasma insulin and somatostatin were determined by radioimmunoassay. RESULTS: After 3 weeks, tumors in the control group weighed 118 mg and tumors in the diabetic group weighed 28 mg (p < 0.001). Plasma insulin was significantly decreased in the streptozotocin-treated animals compared with control animals (insulin, 23 microU/ml vs 31 microU/ml; p < 0.001). In contrast, somatostatin was significantly elevated in the streptozotocin-diabetic group compared with the control group (somatostatin, 179 pg/ml versus 54 pg/ml, p < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin (Kd, 15.5 nmol/L), and somatostatin (Kd, 2.5 nmol/L) on the H2T cells. In an in vitro cell proliferation assay, cell division was promoted by insulin (p < 0.01, maximum +11%) and inhibited by somatostatin (p < 0.01, maximum -18%). CONCLUSIONS: The variable effect of streptozotocin-diabetes on pancreatic cancer growth is due to differences in the tumor host. The growth of pancreatic cancer, particularly in streptozotocin-diabetic nude mice, may be influenced by gut peptides in a receptor-dependent fashion.

The impact of a resident-directed survey on the education curriculum of a university surgical training program.

Surgical training programs use various objective and subjective means to evaluate housestaff performance. However it is less clear how to assess the quality of the educational experience the program itself provides. This study examines the use of a resident-directed survey as a means of identifying and rectifying weakness in a surgical training curriculum. Multiple choice questionnaires covering each of 14 senior rotations were prepared by chief residents and distributed to all senior surgical residents in April 1989 (year I). The survey covered factors considered vital to resident education, including operative experience, input into preoperative and postoperative decisions, autonomy, and time demands, and an overall rating (OR) of the educational quality of the rotations. Responses were numerically graded: 1, appropriate; 0, fair; -1, inadequate (or "excessive" for the variable "time demands"). The results, which were presented and discussed at a departmental retreat that spring, prompted specific curriculum changes for the 1989-1990 academic year. An identical survey was conducted the next spring (year II). Major reorganizational changes were made in three of the four negatively rated rotations from year I. The OR for each of the rotations improved dramatically in year II (average increase of 0.64/rotation; p less than 0.05). None of the eight favorably rated rotations in year I suffered a reduction in OR as a result of the changes. Case load, intraoperative involvement, and input in both preoperative and postoperative decisions correlated most frequently with favorable ORs in both years. This study shows that a resident survey is an effective tool for critically assessing the education curriculum of a surgical training program.

Effective organ blood flow and bioenergy status in murine peritonitis.

Whether organ dysfunction frequently encountered in overwhelming bacterial sepsis is a result of a direct cellular "toxic" effect or diminished cellular perfusion remains controversial. To assess the effects of peritonitis on cellular energy status and visceral blood flow, peritonitis was induced in rats by means of cecal ligation and perforation. Five, 10, or 20 hours after cecal ligation and perforation, cardiac outputs were determined by thermodilution, effective hepatic blood flow was determined by low-dose galactose clearance, and effective renal plasma flow was determined by paraminohippuric acid clearance. In similar groups of rats with peritonitis or sham controls, tissue samples of liver, kidney, and skeletal muscle were obtained by freeze-clamp technique for analysis of adenine nucleotides, energy charge, pyruvate, lactate, and pyruvate/lactate ratios (P/L). Despite an increase in cardiac output (p less than 0.05), results indicated in this model that effective hepatic blood flow and effective renal plasma flow were significantly reduced (p less than 0.05). The energy charge and P/L ratios of hepatic (p less than 0.01) and renal (p less than 0.05) tissues were also decreased. In contrast, skeletal muscle energy charge and P/L ratio were unchanged by 20 hours duration. These data support the hypothesis of diminished visceral perfusion as contributory to the cellular dysfunction observed in sepsis. Skeletal muscle appears either nonischemic or more tolerant of ischemia in sepsis.

Dehydroepiandrosterone-sulfate inhibits pancreatic carcinoma cell proliferation in vitro and in vivo.

BACKGROUND: Dehydroepiandrosterone-sulfate (DHEA-S) is a potent inhibitor of glucose-6 phosphate dehydrogenase, the rate limiting enzyme of the hexose monophosphate shunt, a biochemical pathway that provides substrate for DNA synthesis in neoplastic tissue. DHEA-S has been shown to inhibit the growth of neoplasms arriving from human skin, lung, colon, and mammary tissue. This study evaluates the effect of DHEA-S on human pancreatic cancer cell lines in vitro and in vivo. METHODS: In vitro, the human pancreatic adenocarcinoma cell lines MiaPaCa-2, Capan-1, Capan-2, CAV and Panc-1 were treated with concentrations of 1.9 mumol/L to 1000 mumol/L DHEA-S in 1% dimethylsulfoxide (DMSO) for 5 consecutive days. Cell proliferation was determined by a nonradioactive cell proliferation assay and compared with DMSO treated controls. In vivo testing was performed by inoculating two cell lines, MiaPaCa-2 and Panc-I, into the flank of 40 male nude athymic mice in four study groups. After 1 week of growth, 667 mg/kg DHEA-S in 1% DMSO or 0.2 ml 1% DMSO alone in the control group was administered by daily intraperitoneal injection. Body weight and tumor size was recorded weekly, and tumor weight was measured after 3 weeks of treatment. RESULTS: In vitro cell proliferation was decreased in the five cell lines by 36% to 62% of controls (p < 0.001) at 500 mumol/L DHEA-S. In vivo, after 2 weeks, tumor size was only 76% (p < 0.008) and 67% (p < 0.005) of the controls. After 3 weeks of treatment, tumor size was 73% (p < 0.001) and 53% (p < 0.001) of controls, and tumor weight was decreased by 73% in MiaPaCa-2 (p < 0.001) and 66% in Panc-1 (p < 0.001). Radioimmunoassay measurements of DHEA-S and testosterone from DHEA-S treated mouse plasma showed a significant increase in circulating levels of these hormones. CONCLUSIONS: DHEA-S achieves high serum levels after intraperitoneal injection without elevation of serum testosterone levels and produces no significant toxicity. Treatment with DHEA-S results in a significant reduction of proliferation of human pancreatic cancer cells in culture and when grown as subcutaneous tumors in athymic nude mice.

Indium-111-pentetreotide scanning versus conventional imaging techniques for the localization of gastrinoma.

BACKGROUND: The present study evaluates 111In-pentetreotide scanning as a method for detection of gastrinomas. Operative findings serve as the benchmark for comparison of the efficacy of 111In-pentetreotide versus conventional imaging studies. METHODS: Twelve patients (seven female and five male; age, 37 to 80 years) with histologic confirmation of gastrinoma underwent thin section dynamic computed tomography (CT) scanning and 111In-pentetreotide scanning. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 111In-pentetreotide and CT scanning are compared on the basis of tumor size and location. RESULTS: Thirty discrete foci of intrahepatic and extrahepatic tumors were detected at operation. CT scanning detected three of nine pancreaticoduodenal lesions, whereas eight of these nine extrahepatic primary tumors were imaged by 111In-pentetreotide scanning. No false-positive 111In-pentetreotide scans were noted. The sensitivity of CT scanning for detection of metastatic disease was 56% versus 94% for the 111In-pentetreotide scan. Successful CT imaging was highly dependent on tumor size. No tumor smaller than 1 cm was imaged by CT, whereas four of seven lesions greater than 1 cm were imaged by 111In-pentetreotide scintigraphy. The smallest gastrinoma imaged by 111In-pentetreotide scanning was a 4 mm duodenal tumor. CONCLUSIONS: 111In-pentetreotide scanning was superior to CT scanning for localizing gastrinomas. Further studies are required to determine whether 111In-pentetreotide scans will complement or replace traditional imaging methods.

Expression of the somatostatin receptor subtype-2 gene predicts response of human pancreatic cancer to octreotide.

BACKGROUND: Somatostatin inhibits proliferation of many solid tumors. The current study examines whether inhibition of the growth of pancreatic cancer by the somatostatin analog, octreotide, requires tumor expression of somatostatin receptors. METHODS: We studied five human pancreatic cancer cell lines, Capan-1, Capan-2, CAV, MIA PaCa-2, and Panc-1. Solid tumors were established in nude mice (n = 20/cell line) by flank injection of tumor cells. Subcutaneous octreotide (500 micrograms/kg/day) was administered by osmotic pumps to 10 of the animals in each group, and the other 10 received control infusions of saline solution. On day 36, the tumors were excised and weighed. Plasma levels of the putative trophic peptides cholecystokinin, epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin were assessed by radioimmunoassay. Each of the five cell lines was assayed for the presence of cell surface somatostatin receptors by using whole cell competitive binding assays with 125I-somatostatin. Expression of the somatostatin receptor subtype-2 (SSR2) gene was determined with reverse transcriptase-polymerase chain reactions. Southern blot hybridization was used to assess the presence of the SSR2 gene. RESULTS: Octreotide inhibited tumor growth in the MIA PaCa-2 group (512 +/- 75 mg control versus 285 +/- 71 mg treated; p < 0.05) but had no significant effect on tumor weight in the other four cell lines. Plasma levels of cholecystokinin, epidermal growth factor, insulin-like growth factor-1, and insulin were not altered by chronic octreotide infusion. Cell surface somatostatin receptors and SSR2 gene expression were detected only in the MIA PaCa-2 tumors. The gene for the SSR2 receptor was found in all five tumor lines. CONCLUSIONS: Octreotide-mediated inhibition of pancreatic cancer growth is dependent on expression of somatostatin receptors. The expression of somatostatin receptors should be considered in the design and interpretation of clinical trials with somatostatin analogs for treatment of pancreatic cancer.

Enhanced myocardial protection with verapamil prior to postischemic reflow.

Reperfusion of the heart after induced myocardial ischemia may be associated with severe myocardial damage, characterized by massive calcium influx and accumulation in the heart cells. The present study was undertaken to investigate whether verapamil, a slow channel calcium blocker, administered prior to reperfusion, might reduce this reflow injury without causing depression of heart function. Thirty-two isolated, perfused rabbit hearts were subjected either to 45 minutes of normothermic or 150 minutes of hypothermic global ischemia. Half of the heart in each group received verapaMil immediately prior to reperfusion, while the remaining hearts received no verapamil. Following ischemia and 60 minutes of reperfusion, left ventricular (LV) contractivity was superior in both groups of verapamil-treated hearts, compared to control hearts (LV developed pressure [DP] in normothermic hearts 63 +/- 6% of preischemic DP for verapamil-treated hearts versus 46 +/- 6% of preischemic DP for control hearts; in the hypothermic group, 65 +/- 8% of preischemic DP for verapamil-treated hearts versus 33 +/- 10% DP for control hearts). Postischemic LV compliance also was significantly improved in the verapamil-treated hearts through the period of reperfusion, compared to control hearts. No differences were noted in coronary flow, myocardial water content, or the onset of electromechanical activity between the verapamil and control hearts, but there was significantly improved ultrastructural preservation in both verapamil groups. These data demonstrate that verapamil, when administered just prior to reperfusion, results in improved recovery of myocardial function and excellent cellular preservation, presumably for reducing calcium influx into myocardial cells.

Intraoperative localization of neuroendocrine tumors with 125I-TYR(3)-octreotide and a hand-held gamma-detecting probe.

BACKGROUND: This study evaluates a novel method of intraoperative localization of endocrine gastroenteropancreatic tumors with a hand-held gamma-detecting probe to detect in situ tumor binding of the radioiodinated somatostatin analog 125I-TYR(3)-octreotide. METHODS: Seven patients with biochemical and radiologic evidence of a specific endocrine tumor, one patient with biochemical evidence of gastrinoma but no tumor localized by conventional imaging techniques, and four patients with equivocal preoperative biochemical or radiologic study results but suspected of harboring a neuroendocrine tumor underwent abdominal exploration with intraoperative injection of 125I-TYR(3)-octreotide. 298 +/- 63 microCi. A hand-held gamma-detecting probe was used during operation to determine whether gross tumor accumulated the radiolabeled analog and occult tumor could be detected. Positive uptake was defined as tumor/background ratios exceeding 2:1. RESULTS: The tumor in all seven patients with gross disease accumulated 125I-TYR(3)-octreotide. Occult tumor beyond that appreciated with preoperative imaging or by routine operative exploration was detected in a patient with carcinoid tumor. In the patient with the occult gastrinoma the probe detected the lesion within the duodenal bulb before duodenotomy and also predicted what proved histologically to be positive peripancreatic adenopathy. There was a single false-positive reading from the stomach in a patient with suspected carcinoid tumor in whom no tumor could be found grossly or histologically. A pancreatic mass that probed negative proved to be an adenocarcinoma of ductal origin. CONCLUSIONS: Tumor-specific peptide-receptor binding can be detected in situ with 125J-TYR(3)-octreotide and a hand-held gamma-detecting probe. This technique may facilitate neuroendocrine tumor localization and operative cytoreduction.

Recombinant human tumor necrosis factor produces hemodynamic changes characteristic of sepsis and endotoxemia.

Tumor necrosis factor (TNF) is a macrophage-derived peptide mediator released during endotoxemia and sepsis. We examined the systemic and visceral hemodynamic response to low doses of human recombinant TNF in rats. Each animal received a 30-minute intravenous infusion of either saline solution (n = 8) or TNF (n = 8) in a dose of 0.25 mg/kg or 1.0 mg/kg. Thermodilution cardiac output, blood pressure, pulse, vascular resistance, effective hepatic blood flow (galactose clearance), and effective renal plasma flow (p-aminohippurate clearance) were determined at time = 2 hours. The 0.25-mg/kg dose had no apparent effect on systemic hemodynamics. The 1.0-mg/kg dose produced a hyperdynamic systemic circulatory response with an elevated cardiac output, tachycardia, and a diminished systemic vascular resistance. Effective hepatic blood flow was exquisitely sensitive to even the lowest dose of TNF, with a 29% reduction despite the normal cardiac output. Renal flow was unaffected by either dose. Tumor necrosis factor-induced systemic and visceral hemodynamic changes are remarkably similar to those seen in gram-negative sepsis, suggesting that TNF may occupy a proximal position in the pathogenesis of overwhelming infection.

Galactose elimination kinetics in sepsis. Correlations of hepatic blood blow with function.

To study hepatic blood flow with clearance techniques during sepsis, it is essential to work within the limitations of the test being applied. Based on galactose elimination kinetics, this study validates galactose clearance at low concentrations as an estimate of effective hepatic blood flow in a rat peritonitis model of cecal ligation and puncture. Hepatic function as determined by galactose elimination capacity fell 25% at ten hours after induction of peritonitis, which correlated closely with the 20% reduction in effective hepatic blood flow at the same time point despite a normal cardiac output. The pattern of reduced flow and reduced function is consistent with intrahepatic flow redistribution. Inadequate flow at the microvascular level with secondary cellular injury may explain the liver dysfunction observed during sepsis.

Femur fracture with associated soft-tissue injury produces hepatic ischemia. Possible cause of hepatic dysfunction.

Clinical studies demonstrate that early débridement and operative fixation of femur fractures in multiply injured patients lowers both the incidence and severity of hepatic failure. Perhaps the single most important determinant of hepatic function is nutrient hepatic perfusion. This study compares systemic and hepatic blood flow in rats that have sustained femur fractures with or without associated soft-tissue injury. Femur fracture without soft-tissue trauma resulted in a hyperdynamic state with normal blood flow distribution at 24 hours after injury and normal hemodynamics at 48 hours. When femur fracture was associated with soft-tissue trauma, the elevated cardiac output at 24 hours was not matched by a proportionately elevated hepatic blood flow. In this latter group, the cardiac output was normal at 48 hours, but the hepatic perfusion defect remained. Retained fracture fragments, hematoma, and injured and necrotic soft tissue may serve as a stimulus leading to a pathologic reduction in hepatic perfusion.

Systemic complement activation produces hemodynamic changes characteristic of sepsis.

Zymosan was administered intravenously in graded doses to Sprague-Dawley rats to investigate the hemodynamic effects of systemic complement activation. At two hours, thermodilution cardiac output, mean arterial pressure, heart rate, systemic vascular resistance, hematocrit, effective hepatic and renal blood flows, and percent change in total hemolytic complement activity were measured on all animals. Progressively increasing doses of zymosan produced characteristic hemodynamic changes of progressively deteriorating stages of hyperdynamic sepsis. In addition, complement activation resulted in a redistribution of systemic blood flow with hepatic hypoperfusion similar to that seen in sepsis. Renal blood flow was unaffected early after complement activation. Additional rats were studied from the control and a representative zymosan-treated group at 24 and 48 hours to determine if the hemodynamic changes observed at two hours persisted or resolved. All systemic hemodynamic measures returned to normal at both 24 and 48 hours. Liver blood flow, however, remained depressed and actually deteriorated over time. Renal perfusion, which was stable at both two and 24 hours, fell below control values in the zymosan-treated group at 48 hours. We conclude that complement may be a mediator of both systemic and visceral flow abnormalities that precede, and perhaps precipitate, organ failure in trauma and sepsis.

Effective hepatic blood flow during cardiopulmonary bypass.

Hepatic dysfunction following cardiopulmonary bypass (CPB) is a relatively frequent finding, and jaundice occurring after CPB is associated with an increased mortality rate. Post-CPB jaundice may be a consequence of inadequate liver perfusion during CPB. To evaluate the potential impact of CPB on effective hepatic blood flow, 10 patients undergoing CPB for cardiac procedures were studied. Effective hepatic blood flow was measured in each patient during the operative procedure but before institution of CPB and during CPB as well. Effective hepatic blood flow was measured by the galactose clearance technique. Blood lactate and pyruvate levels were also measured before and during CPB. During CPB, effective hepatic blood flow was consistently reduced by an average of 19%. Although for most patients this reduction seems well tolerated, in a minority of patients it may contribute to postoperative hepatic dysfunction.

Laparoscopic bile duct injuries. Risk factors, recognition, and repair.

Records of 11 patients undergoing biliary reconstruction after laparoscopic cholecystectomy are reviewed. Ductal injuries resulted from failure to define the anatomy of Calot's triangle. Risk factors include scarring, acute cholecystitis, and obesity. Presenting findings included anorexia, ileus, failure to thrive, pain, ascites, and jaundice. All patients required hepaticojejunostomies, which were multiple and above the hepatic bifurcation in four patients. Given the extensive nature of these injuries and the frequent need for intrahepatic anastomosis and early stenosis of repairs by referring physicians, we recommend reconstruction be undertaken by an experienced hepatobiliary surgeon. To avoid injuries, a greater appreciation of risk factors and anatomic distortion and variance and strict adherence to principles of dissection and identification of anatomic structures are suggested. The use of cholangiography and a low threshold for conversion to the open procedure are advised.

Alterations in renal perfusion and renal energy charge in murine peritonitis.

Whether acute renal failure following overwhelming bacterial septicemia is a initially a consequence primarily of a cytotoxic insult or a perfusion insufficiency remains unclear. To assess the effects of intra-abdominal sepsis on the distribution of renal blood flow and renal cell bioenergy status, the glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and energy-charge ratios were measured in rats following cecal ligation/puncture (CLP) or sham laparotomies. The CLP animals demonstrated a decrease in ERPF of 42% and 58% from sham groups at ten and 20 hours, respectively. The GFR showed similar but more severe impairments of 53% and 71% at ten and 20 hours, respectively, following insult despite moderate increases in cardiac output. The disproportionate decrease in GFR over ERPF supports the hypothesis of a corticomedullary redistribution of renal blood flow in sepsis. Renal energy charge, unchanged at ten hours, decreased significantly at 20 hours. Diminished renal perfusion and the redistribution of renal blood flow precedes and may contribute to the renal cell bioenergy derangements in septic acute renal failure.