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Background: Inadequate or inappropriate cell-substrate contact triggers a subset of apoptotic cell death, termed anoikis. Resistance to anoikis is a characteristic of malignant cells that is associated with increased tumorigenesis and metastasis. Focal adhesion kinase (FAK) is an important regulator of cell survival and migration and cell cycle progression. We tested the hypothesis that FAK gene silencing would promote anoikis and reverse acquired anoikis resistance in human pancreatic adenocarcinoma cells., Methods: FAK expression was assessed by Northern and Western blot analysis. Anoikis was induced in PANC1, BxPC3, MiaPaCa2, and Mia(AR) (an anoikis-resistant derivative of MiaPaCa2) with the use of polyHEMA culture. FAK expression was suppressed by RNA interference. Anoikis was detected by YO-PRO-1/propidium iodide staining and flow cytometry. Fluorometric caspase profiling was performed. Metastasis was assayed in a nude mouse orthotopic xenograft model., Results: The cell lines that were tested showed marked variation in their anoikis resistance, greater resistance being associated with higher levels of FAK expression. FAK gene silencing promoted anoikis in all cell lines and reversed acquired anoikis resistance in Mia(AR), which was associated with increased caspase activation. Suppression of FAK expression also inhibited metastasis in the nude mouse model., Conclusion: FAK gene silencing suppresses anoikis resistance in pancreatic adenocarcinoma cells. FAK represents a potential target for novel antimetastatic therapies.

Background: Despite more than three decades of research on iatrogenesis, surgical adverse events have not been subjected to detailed study to identify their characteristics. This information could be invaluable, however, for guiding quality assurance and research efforts aimed at reducing the occurrence of surgical adverse events. Thus we conducted a retrospective chart review of 15,000 randomly selected admissions to Colorado and Utah hospitals during 1992 to identify and analyze these events., Methods: We selected a representative sample of hospitals from Utah and Colorado and then randomly sampled 15,000 nonpsychiatric discharges from 1992. With use of a 2-stage record-review process modeled on previous adverse event studies, we estimated the incidence, morbidity, and preventability of surgical adverse events that caused death, disability at the time of discharge, or prolonged hospital stay. We characterized their distribution by type of injury and by physician specialty and determined incidence rates by procedure., Results: Adverse events were no more likely in surgical care than in nonsurgical care. Nonetheless, 66% of all adverse events were surgical, and the annual incidence among hospitalized patients who underwent an operation or child delivery was 3.0% (confidence interval 2.7% to 3.4%). Among surgical adverse events 54% (confidence interval 48.9% to 58.9%) were preventable. We identified 12 common operations with significantly elevated adverse event incidence rates that ranged from 4.4% for hysterectomy (confidence interval 2.9% to 6.8%) to 18.9% for abdominal aortic aneurysm repair (confidence interval 8.3% to 37.5%). Eight operations also carried a significantly higher risk of a preventable adverse event: lower extremity bypass graft (11.0%), abdominal aortic aneurysm repair (8.1%), colon resection (5.9%), coronary artery bypass graft/cardiac valve surgery (4.7%), transurethral resection of the prostate or of a bladder tumor (3.9%), cholecystectomy (3.0%), hysterectomy (2.8%), and appendectomy (1.5%). Among all surgical adverse events, 5.6% (confidence interval 3.7% to 8.3%) resulted in death, accounting for 12.2% (confidence interval 6.9% to 21.4%) of all hospital deaths in Utah and Colorado. Technique-related complications, wound infections, and postoperative bleeding produced nearly half of all surgical adverse events., Conclusion: These findings provide direction for research to identify the causes of surgical adverse events and for targeted quality improvement efforts.

We evaluated retrospectively the effect of perioperative blood transfusions on survival in esophageal cancer. The records of all patients who underwent esophageal resection (n = 316) at UCLA Medical Center from 1970 to 1993 were reviewed. Statistical analysis included univariate (log-rank chi 2) and multivariate (Cox proportional hazards) analyses with other known risk factors. High-volume blood transfusions (> 8 units) but not low-volume blood transfusions (1 to 8 units) were associated with a significant decrease in long-term survival (median survival: no transfusion, 22 months; low-volume blood transfusion, 14.5 months, versus high-volume blood transfusions, 6.5 months; p < 0.01). Multivariate analysis revealed that the shorter survival with high-volume blood transfusions was a result of an increased number of postoperative complications. High-volume blood transfusions were not associated with increases in tumor recurrence or infectious complications. The association between shorter survival and high-volume blood transfusions in esophageal cancer may, therefore, be because of the circumstances necessitating transfusion rather than any immunosuppressive effects of the transfused blood. These findings suggest that the transfusion of blood does not by itself decrease the chance of cure after esophageal resection.

Background: Plasma peptide YY (PYY) levels rise after a meal and have recently been shown to increase small bowel-absorption. The purpose of this study was to determine whether immunoneutralization of PYY would block postprandial absorption in vivo., Methods: Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm) were created in six mongrel dogs. After a 2-week recovery luminal perfusion with an isotonic buffer, containing [14C]-polyethylene glycol as a volume marker, was used to analyze water and sodium flux after an oral meal. Each meal was accompanied by either intravenous anti-PYY (0.5 mg.kg-1.h-1) or nonspecific immunoglobulin IG (control). PYY antibody binding was determined by radioimmunoassay., Results: Displacement studies showed complete PYY neutralization. In control experiments feeding increased absorption of sodium and water in both segments. PYY immunoneutralization had no effect on jejunal absorption but significantly diminished ileal absorption (p < 0.05)., Conclusions: These results suggest that PYY acts selectively in the ileum to increase postprandial fluid and electrolyte absorption after a meal. Agents directed at PYY-stimulated absorption may prove to be of therapeutic benefit in patients with malabsorptive conditions.

Background: The mechanisms of intestinal adaptation after resection are not completely defined. The purpose of this study was to examine the changes after resection in the enterocyte basolateral Na+,K+ adenosine triphosphatase (ATPase) known to play a critical role in epithelial transport and homeostasis., Methods: Lewis rats underwent 70% small bowel resection or transection. At 6 hours, 24 hours, 1 week, and 2 weeks, jejunum and ileum were harvested for analysis of Na+,K+ ATPase activity, kinetic analysis, and alpha 1-ATPase messenger RNA and protein levels., Results: Na+,K+ ATPase activity increased (p < 0.05) in both the jejunum and ileum by 2 weeks after resection. This rise in activity correlated with an increase in the maximal activity of ATPase, from 20.8 to 101.01 mumol inorganic phosphate.mg-1.hr-1. ATPase messenger RNA levels increased sixfold in the jejunum and tenfold in the ileum by 2 weeks after resection (p < 0.05). Protein levels rose at 6 hours and remained elevated in both tissues., Conclusions: After intestinal resection, enterocyte Na+,K+ ATPase activity rises as a result of an increase in the number of transporters per cell. This occurs through both transcriptional and translational mechanisms. It appears that intestinal adaptation after resection involves not only an increase in absorptive surface area but also functional adaptation by the individual enterocyte.

Background: We present an unusual case of a malignant mixed tumor (carcinosarcoma) of the head of the pancreas that was surgically resected and whose tissue pathologic condition supported the concept of organ-induced differentiation of malignancy., Methods: After a pancreaticoduodenectomy, tissue sections from various anatomic regions of the tumor were studied by routine histologic examination and immunocytochemistry. Genomic DNA from various regions of the tumor was extracted and digested with Hpa II, and a 511 bp region of the hypoxanthine phosphoribosyltransferase gene was amplified with the polymerase chain reaction to assess clonality., Results: The pathologic findings revealed areas of both adenocarcinoma and leiomyosarcoma, but these disparate areas were not randomly distributed but rather were polar in nature. The adenocarcinomatous areas localized to the tumor within the head of the pancreas, an area of normal ontogenetic glandular development, whereas the leiomyosarcomatous areas localized to regions of the tumor infiltrating the duodenal wall, an area of normal ontogenetic smooth muscle development. Both the adenocarcinomatous and the leiomyosarcomatous areas showed evidence of monoclonality and clonal identity., Conclusions: This interesting polar distribution of histologic patterns illustrated by this malignant mixed tumor (carcinosarcoma) supports the hypothesis of organ-induced differentiation of malignancy.

Polyarteritis nodosa, a disease of the media of small and medium-sized arteries, has protean manifestations and many presenting signs and symptoms. Gastrointestinal involvement is common but involvement of the biliary tree is rare. We report a unique case of polyarteritis presenting as a biliary stricture.

Seven patients with solid and papillary epithelial neoplasms of the pancreas are reported. All were young women with a mean age of 22 years (range, 16 to 33 years old). Each patient had a large asymptomatic abdominal mass. The tumors ranged in size from 7 to 20 cm (average size, 13 cm) and were evenly distributed throughout the head, body, and tail of the pancreas. One patient had a metastatic tumor to her liver, which was unresectable. All other patients underwent resection, which included two distal pancreatectomies, two total pancreatectomies, one pancreaticoduodenectomy, and one local excision. Four of the seven patients had evidence of local invasions alone, and one had a liver metastasis and local invasion. All patients had the characteristic histologic pattern of a solid and papillary epithelial pancreatic neoplasm. All patients are alive with a mean follow-up of 10 years (range, 4 to 20 years). This is an unusual malignant neoplasm of the pancreas occurring predominantly in young women. Even though they are locally invasive, long-term survival is the rule. Surgical therapy should be aggressive, since liver metastasis may occur.

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.

Methionine-enkephalin is an endogenous opiate pentapeptide, originally isolated in the brain, that exists within enteric plexuses and enterocytes. The purpose of this study was to delineate the effects of the opiate agonist methionine-enkephalin on intestinal water and electrolyte transport, with the stable analog D-ala2-metenkephalinamide (m-ENK). Ileal segments from New Zealand white rabbits (n = 39) were harvested and vascularly and luminally perfused ex vivo. Net fluxes of H2O, Na+, and Cl- were calculated for three 20-minute periods: basal, drug infusion, and recovery. Six groups were studied: (1) control, (2-4) m-ENK at three doses, (5) naloxone, and (6) naloxone plus m-ENK. Oxygen consumption and arterial perfusion pressure were assessed as measures of metabolic activity and viability. The control and naloxone groups had no changes in the fluxes of water and electrolytes. Significant proabsorptive effects were demonstrated for the fluxes of H2O, Na+, and Cl- at increasing doses of m-ENK (p less than 0.05). Naloxone completely prevented m-ENK-induced absorption. These results with exogenous m-ENK suggest that endogenous methionine-enkephalin, serving as an enteric neurotransmitter and acting through naloxone-sensitive opiate receptors, may function as a physiologic modulator of intestinal water and electrolyte absorption.

Glucose intolerance is often associated with pancreatitis. Pancreatitis-induced diabetes represents a different clinical syndrome than type I and type II diabetes mellitus. Patients with pancreatitis-induced diabetes may be extremely sensitive to exogenous insulin, rarely develop ketoacidosis, and rarely exhibit classic diabetic complications, such as retinopathy, nephropathy, or accelerated vasculopathy. Pancreatic polypeptide (PP) deficiency has been implicated in the defect of glucose homeostasis found after pancreatitis. This study evaluated intravenous and oral glucose tolerance and insulin response to glucose loading, in the setting of pancreatitis, with and without short-term PP replacement. Dogs (n = 7) underwent pancreatic duct ligation (PDL) and were studied with and without PP infusion (2 micrograms/kg/hr) before PDL and at 1 week, 6 weeks, and 4 months after PDL by means of intravenous and oral glucose tolerance tests. Basal and bombesin-stimulated PP levels at 4 months after PDL were subnormal, verifying PP deficiency in these animals with pancreatitis. PP levels during PP infusion reproduced normal postcibal levels, averaging 897 +/- 40 pg/ml. Glucose tolerance, expressed as the glucose decay constant for the intravenous glucose tolerance tests and as the integrated glucose response for the oral glucose tolerance tests, deteriorated over time and was not improved by acute PP replacement. The integrated insulin response to glucose was not affected by PP. The acute infusion of PP at a dose that reproduces normal postprandial PP levels fails to improve glucose tolerance or augment insulin release in this model of pancreatitis-induced diabetes.

A case report of a patient with Marfan's syndrome who developed acute supravalvular aortic stenosis following aortic valve replacement and reconstruction of the ascending aorta is presented. Early recognition of this complication permitted reoperation and successful repair. One similar case has been reported previously.

Exogenous substance P (SP) was perfused into the lumen of the proximal jejunum in 16 fasted cats at a rate of 6.04 +/- 1.96 ng/min. Regional blood flow was measured by radioactive microspheres after successive 15-minute perfusions with saline (basal), neural blockers, SP, and saline. Endoluminal SP caused mucosal hyperemia in the perfused jejunal segment that was not blocked by preperfusion of the segment with lidocaine (2% or 4%) or tetrodotoxin (3 X 10(-7) M). In addition, there was no increase in blood flow to any other organ tested, gastrointestinal or systemic. Local luminal SP levels rose but there was no significant rise in portal SP levels, indicating that the peptide was not absorbed. The data suggest that SP acts locally by a nonneural mechanism to influence local gastrointestinal blood flow.

Microaggregates have been implicated as a contributory cause of respiratory distress syndrome. Blood flow and resistance changes are compared between the right and left lungs following the selective administration of stored autologous heparinized blood into the left pulmonary artery. Eight dogs were bled 1,160 +/- 47 c.c. over 3 days. Following storage for 5 days the volume, number and size of microaggregates were measured by multichannel particle size analyzer and compared to 14-day-old human blood. Distribution of blood flow and resistance were calculated from data derived from injection of radioactively tagged microspheres into the right atrium and determination of cardiac output and pulmonary artery and wedge pressures. These measurements were made during a control period, following resuscitation from a 2 hour hemorrhagic shock period with the stored blood and 3 hours after resuscitation. Despite the administration of stored blood with massive amounts of microaggregates into the left pulmonary artery, the distribution of blood flow immediately and 3 hours following resuscitation was the same as in the control period. The pulmonary vascular resistance increased across both lungs but the increase was the same on the left as the right. These data suggest that microaggregates may not be important in the development of the respiratory distress syndrome.

Hemorrhage to a mean arterial pressure of 41 mm. Hg in ten dogs decreased Heidenhain pouch blood flow to 6 ml. per minute and aminopyrine clearance to 0.93 ml. per minute. Pouch oxygen consumption fell from 1.47 to 0.74 ml./min.-100 Gm. and total body oxygen consumption remained unchanged. Net ion fluxes during shock and reinfusion did not change significantly from control values of minus 89.8 muGq./30 min.-100 cm.-2 for H-+ and 88.6 muEq./30 min.-100 cm-2 for Na-+. However, PD decreased from 54 to 24 mv. in parallel with a fall in net Cl-minus flux from 56.8 to minus 11.7 muEq./30 min.-100 cm-2. Nine of ten pouches subjected to shock and instilled acid test solution (ATS) developed superficial mucosal erosions. No ulcerations were found in either seven control dogs (anesthesia + ATS) or in three dogs subjected to shock without ATS. Acid appears to be of prime importance in the production of stress ulcers during or following ischemia, even though there is no increase in mucosal ionic permeability.

The actions of serotonin and substance P have been examined with use of an isolated, vascularly perfused rabbit ileal preparation. The vascular perfusate was composed of a modified Krebs' buffer solution that contained washed human red blood cells (hematocrit, 15% to 20%) and 3% albumin, with no added hormones or peptides. Ileal blood flow was held constant at 49.3 +/- 3.1 ml/min per 100 gm wet weight of intestine. Net intestinal water and electrolyte fluxes were calculated by means of an isosmotic buffer that contained carbon-14 polyethylene glycol as a nonabsorbable volume marker. Viability of this isolated perfused ileal preparation was confirmed on the basis of light microscopy, oxygen consumption, and transmucosal potential difference measurements. Control experiments, without exogenous hormone infusion, resulted in a stable preparation with a basal secretory state. Intra-arterial serotonin at 2.5 micrograms/min (n = 10) significantly stimulated secretion of H2O, Na+, and Cl- (p less than 0.01). Intra-arterial substance P at 2.5 x 10(-1) micrograms/min (n = 7) significantly increased the secretion of H2O, Na+, and Cl- (p less than 0.02). The dose of serotonin was designed to yield serotonin levels that resembled those found circulating in patients with carcinoid syndrome. These data indicate that serotonin and substance P are potent secretagogues in a mammalian system, independent of their effect on mesenteric blood flow and in the absence of extra-intestinal hormonal and neural influences.

The effects of intra-arterial infusions of epinephrine, norepinephrine, and isoproterenol upon right and left gastric blood flow were studied in anesthetized dogs. Blood flow was measured electromagnetically before and after adrenergic blockade. Infusion of epinephrine (0.05 mug Kg.(-1) min.(-1)) resulted in vasoconstriction (-50 +/- 6 ml. min.(-1)) with autoregulatory escape in the right gastric artery (RGA) and constriction (-41 +/- 8 ml. min.(-1)) followed by significant dilation (+ 56 +/- 10 ml. min.(-1)) in the left gastric artery (LGA). Alpha adrenergic blockade with phenoxybenzamine produced only a dilator response in both RGA and LGA to epinephrine infusion and beta adrenergic blockade resulted in a constrictor response with no autoregulatory escape. Norepinephrine infusions produced a constrictor response of similar magnitude as epinephrine but with little evidence of autoregulatory escape in either RGA and LGA. Alpha adrenergic blockade significantly attenuated this response in both circulations. Isoproterenol is a dilator in both circulations and its response is attenuated only by beta adrenergic blockade. This study demonstrates that the canine stomach has two regionally distinct circulations with the fundus and body exhibiting a greater dilator response than the antrum and pylorus.

The aorta was exposed by a standard "nephrectomy" incision through the eleventh interspace in 53 patients with aneurysmal or occlusive disease. The plane posterior to the kidney and ureter was developed easily, enabling exposure of the aorta above the level of the celiac axis to its bifurcation by dividing only the crus of the diaphragm and the lumbar branch of the left renal vein. Twenty-five patients with abdominal aortic aneurysms were treated in this fashion. In all but four there were significant risk factors, including extension of the aneurysm to or above the level of the renal arteries in eight and coexisting renal artery stenosis with hypertension in two. Twenty-eight patients with occlusive vascular disease were treated surgically. In eight, this was the second operation on the aorta while in 11, major occlusive disease involved the aorta as well as the renal/visceral arteries. The operative mortality rate was 8%. Eighty-nine percent of the patients were alive at this writing. Of 18 hypertensive patients, 9 were not taking medication and only 3 have not improved significantly. We recommend this approach for reoperations on the aorta and for patients who have extensive aneurysmal and/or occlusive disease of the aorta, renal, and visceral arteries.

The undecapeptide substance P (SP) is contained in enterochromaffin cells and circulates in high concentrations in patients with carcinoid syndrome. We have previously reported that elevated SP levels, simulating those reported in patients with carcinoid syndrome, induce profound changes in intestinal water and electrolyte secretion, motility, and blood flow in a canine model. The purpose of this study was to attempt to block the effects of circulating carcinoid levels of SP on intestinal secretion and motility with the calcium channel blocker verapamil. In five dogs a chronic proximal jejunal Thiry-Vella loop was constructed, and after a 2-week recovery the loops were perfused with an isotonic test solution containing 14C-polyethylene glycol as a volume marker. Motor activity was measured by changes in intraluminal pressure and a motility index was calculated with computer-assisted planimetry and expressed as square millimeters per 5 minutes. After a 30-minute baseline period, SP was infused at 50 ng/kg/min for 90 minutes. SP circulating levels rose from a baseline of 6.2 +/- 1.3 pg/ml to a peak of 93.3 +/- 3.1 pg/ml during this infusion. Thirty minutes after the start of this SP infusion, a simultaneous infusion of verapamil (5.0 micrograms/kg/min) was begun at a separate site. During SP infusion there was a significant secretory response of water (-48 +/- 12 microliters/min), Na+ (-7.7 +/- 2.5 microEq/min), Cl- (-8.8 +/- 2.7 microEq/min) and K+ (-0.57 +/- 0.14 microEq/min), and hypermotility (motility index: 1479 +/- 138 mm2/5 min). When verapamil was added a reversal of secretion to net absorption was observed (water: + 116.9 +/- 15.6 microliter/min; Na+: + 13.8 +/- 2.1 microEq/min; Cl-: + 5.5 +/- 2 microEq/min; K+: + 0.38 +/- 0.9 microEq/min) (p less than 0.05). In addition, there was a reduction in motility (motility index: 853 +/- 92 mm2/5 min; p less than 0.05). These results confirm that SP has profound effects on both intestinal motility and secretion and that calcium channel blockade reduces these effects significantly.

Sequential femoral-distal bypass grafts were employed to revascularize 21 ischemic limbs. An end-to-side distal anastomosis plus an additional side-to-side anastomosis to an isolated popliteal segment or an additional distal tibial vessel were employed. If one graft that underwent successful early revision is included, the initial patency rate was 100%. After a median follow-up of 8 months, complete graft failure had occurred in three patients. A previously unreported occurrence in two patients was proximal graft segment occlusion, with patency of th distal segment that was successfully revascularized. One additional patient had occlusion of the distal graft segment. Limb salvage was achieved in 20 of the 21 patients. This approach offers several hemodynamic advantages and may be the procedure of choice in patients with distal runoff that si not ideal for a routine femoropopliteal bypass graft.

We investigated the effects of infusion of somatostatin (200 and 500 ng/kg/min) on central hemodynamics and renal blood flow measured with radioactive microspheres. At the lower dose infusion rate somatostatin did not alter any hemodynamic parameter, but at 500 ng/kg/min somatostatin caused minor transient bradycardia, lowered cardiac output, and increased peripheral resistance. Both infusions inhibited renal arterial flow, with decreases noted in both cortical and medullary components. The 20% fall in renal perfusion was confirmed by the hippurate clearance technique, and there was a corresponding 17% decrease in the glomerular filtration rate. In contrast, no changes were noted in urine output, urinary concentrations of sodium or potassium, or urine osmolarity. These hemodynamic and renal side effects might limit the therapeutic usefulness of somatostatin infusion.

Cerebral blood flow (CBF) was measured by electromagnetic and radioactive microsphere (RMS) techniques in the anubis baboon. Regional cerebral blood flows were calculated by distribution of intracardiac injections of RMS, labeled with one of three radionuclides: 51Cr, 85Sr, or 141Ce. In Group I (six animals, normocapnia), CBF's as estimated by electromagnetic measurement of internal carotid blood flow, were 65 +/- 10 and 74 +/- 4 (S.E.M.) ml. per minute per 100 Gm. for the right (RH) and left (LH) cerebral hemispheres, respectively; whereas CBF's as estimated by the RMS technique were 65 +/- 5 and 70 +/- 4 ml. per minute per 100 Gm., respectively, and these values were not significantly (p greater than 0.05) different. CBF, as determined by RMS techniques in Group 1, was not altered by unilateral internal carotid arterial ligation. In Group 2 (seven animals), arterial PCO2 was varied randomly from a low range (18 +/- 2 mm. Hg, L), to a middle range (PCO2 36 +/- 2, M), and a high range (PCO2 64 +/- 2, H), and CBF was measured by the RMS technique. During L, M, and H, CBF's were 44 +/- 10, 75 +/- 15, and 159 +/- 27 ml. per minute per 100 Gm., respectively, for RH, whereas CBF's were 44 +/- 10, 75 +/- 15, and 160 +/- 26 ml. per minute per 100 Gm., respectively, for LH. During H, RH and LH were significantly (p less than 0.05) greater than during L and M. Changes in regional CBF were uniform throughout the brain. These data demonstrate the correlation between CBF, as estimated by electromagnetic and RMS techniques, as well as confirm the adequacy of collateral cerebral circulation during unilateral carotid arterial ligation in the baboon. The usefulness of the RMS technique for hemispheric and regional CBF measurements is prevented also.

substance P concentrations in plasma increase in response to a meal. The effects of intravenous substance P infusions were investigated in seven conscious dogs with doses of peptide (7 ng/kg/min) designed to reproduce the normal postprandial circulating increase in substance P. Substance P levels measured by radioimmunoassay increased 8.6 +/- 4.8 pg/ml in arterial plasma (P less than 0.05) and 3.0 +/- 1.5 pg/ml in mixed venous plasma (P less than 0.05). By use of decay equations, the calculated half-life of exogenous immunoreactive substance P was less than 30 seconds, and this corresponded to rapid abolition of the biologic effects of the peptide upon cessation of the infusion. The integration of the arterial and mixed venous concentration curves allowed calculation of the peripheral inactivation of exogenous immunoreactive substance P as 65.6%. During substance P infusion, mean arterial pressure fell 20 +/- 6 mm Hg at 5 minutes from 124 +/- 6 mm Hg (P less than 0.02). Total systemic vascular resistance was 3102 +/- 196 dynes/sec/cm5 basally, and it fell by 667 +/- 137 dynes/sec/cm5 (P less than 0.05) at 10 minutes. Plasma glucose, insulin, and cortisol concentrations did not change significantly from 83 +/- 4 mg/dl, 5.1 +/- 1.0 microU/ml, and 4.6 +/- 0.5 micrograms/dl, respectively. Radioactive 15 micron microspheres injected at times 0, 20, and 50 minutes into the infusion allowed for identification of statistically significant (P less than 0.05) increases in blood flow to the adrenal gland and the muscular layers of the fundus and the ileum. Thus the infusion of substance P to reproduce postprandial circulating levels of this peptide was followed by an orderly sequence of hemodynamic alterations in the conscious dog. Regional blood flow changes were seen in the muscular layers of the fundus and ileum, which are regions of high substance P concentration.

Neurohumoral agents modulate intestinal transport by interactions with cell membrane receptors. Intracellular second messenger systems implicated in mediation of membrane receptor regulation of cellular events include the phosphoinositide and adenylate cyclase systems. In this study we have investigated the effects of direct postreceptor activation of key components of these systems on intestinal water and electrolyte transport. Rabbit ileal segments (n = 35) were arterially perfused ex vivo with an oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing 14C-polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- in six experimental groups were calculated for three 20-minute periods: basal, drug infusion, and recovery. The control group had no drug infusion. Two phorbol esters--phorbol 12, 13-diacetate (PDA; 10(-5) mol), and phorbol 12, 13-dibutyrate (PDB; 10(-5) mol)--were used to activate protein kinase C, an important component of the phosphoinositide system. The inactive 4 alpha-phorbol 12, 13-didecanoate (PDD; 10(-5) mol) served as a drug-infused control. Forskolin at two doses (FOR; 10(-5) mol and 10(-6) mol) was used to activate adenylate cyclase. The control and PDD groups had no changes in the flux of water and electrolytes. Both PDA and PDB had proabsorptive effects, with the more lipophilic and potent phorbol ester (PDB) having a more pronounced, significant effect (p less than 0.05). FOR caused significant secretion of H2O, Na+, and Cl- in a dose-dependent fashion (p less than 0.05). These results indicate that direct protein kinase C activation causes a proabsorptive effect and that direct activation of adenylate cyclase causes a secretory effect in the isolated small bowel. The activation status of these second messenger systems has a major influence on the transport state of the intestine.

Five cases that illustrate the spectrum of biliary complications of pancreatitis and pancreatic pseudocyst are discussed. Obstructive jaundice, hemobilia, and bilious ascites were the major problems in these five patients. Sonography, transhepatic cholangiogram, endoscopic retrograde cholangiopancreatography, operative cholangiography, and arteriography are important in establishing the diagnosis and planning the treatment. Three patients had biliary obstruction caused by chronic pancreatitis, a pancreatic pseudocyst, or both. Two patients had a fistula between the common duct and the pseudocyst. Simple decompression of the pseudocyst was curative for only one patient. Three patients required decompression of the biliary tract, which emphasizes the need for intraoperative cholangiography. One patient required a Whipple operation to control hemorrhage but died in the immediate postoperative period. The operative findings determine the specific procedures for biliary tract decompression and pseudocyst drainage.

Adrenergic control over intestinal homeostasis has been associated with changes in intestinal vascular resistance, motility, and transport. With the use of selective alpha-adrenergic agents, this study was designed to discriminate between the vascular and transport effects. Rabbit 20 cm ileal segments (n = 31) were vascularly perfused at a rate of 1.5 ml/min by means of a modified Krebs solution containing 15% to 20% red cells. The intestinal lumen was perfused with an isotonic solution containing carbon 14-polyethylene glycol as a nonabsorbable marker. Net fluxes of water and electrolytes were calculated during 20-minute basal, experimental, and recovery periods. Norepinephrine (mixed alpha 1- and alpha 2-agonist) significantly increased intestinal absorption and vascular resistance. Phenylephrine (alpha 1-agonist) significantly increased vascular resistance without altering transport. Clonidine (alpha 2-agonist) stimulated intestinal absorption without changing vascular perfusion pressure. Yohimbine (alpha 2-antagonist) prevented norepinephrine-induced absorption but had no effect on norepinephrine-induced increases in perfusion pressure. In this isolated perfused whole gut model, alpha 1-adrenergic stimulation was responsible for increases in vascular resistance, and alpha 2-adrenergic stimulation was responsible for increases in the absorption of water and electrolytes. The ability to discriminate between alpha 1- and alpha 2-effects has potential therapeutic implications in patients with malabsorption and diarrhea.