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Peptide YY (PYY) is a potent regulator of intestinal secretion. These studies investigated the role of Y1 and Y2 receptor subtypes in mediating the antisecretory effects of PYY on mucosa-submucosa preparations of rat distal colon. Addition of vasoactive intestinal peptide (VIP) to these tissues resulted in a 140 +/- 18% increase in basal short-circuit current (Isc) and the induction of Cl- secretion. VIP-stimulated increases in Isc were abolished by the addition of each of PYY, (Pro34)-PYY, a Y1 receptor-selective agonist, and PYY-(3-36), an endogenous Y2 receptor-selective ligand. However, when tissue neural transmission was blocked with tetrodotoxin, neither PYY nor its receptor subtype-selective analogs were able to inhibit VIP-stimulated increases in Isc. These results suggest that in the rat distal colon, the antisecretory actions of PYY are mediated through a combination of Y1 and Y2 receptor subtypes or through a novel receptor subtype that is unable to discriminate between (Pro34)-PYY and PYY-(3-36).

Introduction: Peptide YY (PYY) is a 36 amino acid hormone released into the circulation and lumen of the intestine after a meal. Previous studies have shown that exogenous administration of intravenous PYY stimulates water and electrolyte absorption in both the small and large intestines. The purpose of this study was to examine the effects of intraluminal administration of PYY on colonic absorption of electrolytes and water., Methods: Six conditioned 25-kg dogs had 20 cm of colonic Thiry-Vella fistulae surgically constructed under general anesthesia. After a two-week recovery period, the animals received intraluminal PYY at 600 pmol/kg/hour after a 90-minute steady-state basal period. The Thiry-Vella fistulae were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 minutes., Results: On intraluminal infusion of PYY, increased absorption of water, sodium, and chloride was observed in the colon. A twofold increase in absorption rates occurred compared with basal rates lasting more than one hour after cessation of intraluminal PYY (N = 6; P < 0.05 vs. basal by analysis of variance)., Conclusion: PYY-secreting cells of the colon may contribute to the regulation of absorption after a meal. Exogenous administration of intraluminal PYY may also be a therapeutic treatment modality for malabsorption.

Background & Aims: Previous studies have documented the effectiveness of interleukin (IL)-10 if given before the onset of experimental acute pancreatitis. This study examined whether IL-10, a cytokine that inhibits macrophage release of inflammatory mediators, would alter the severity of acute pancreatitis if given before or after the induction of disease., Methods: Eighty-four Sprague-Dawley rats were divided into four groups. Group 1 received intravenous saline, and groups 2, 3, and 4 received intravenous cerulein (8.5 microg x kg(-1) x h(-1)). Group 3 was also given 150,000 U of intraperitoneal IL-10 1 hour before cerulein infusion and every 3 hours thereafter. Group 4 received 150,000 U intraperitoneal IL-10 2 hours after cerulein infusion and every 3 hours thereafter. Serum amylase and tumor necrosis factor (TNF)-alpha levels were measured before and 3, 9, or 15 hours after induction of pancreatitis. Animals were killed at these time points. Pancreata were analyzed for edema and TNF-alpha mRNA and TNF-alpha protein concentrations and were graded histologically., Results: Serum amylase, TNF-alpha mRNA, and TNF-alpha protein levels, pancreatic edema, and histological score were significantly reduced when IL-10 was administered either before or after induction of pancreatitis. Serum TNF-alpha levels were undetectable., Conclusions: IL-10 attenuated the severity of experimental acute pancreatitis if given either before or after the induction of the disease. These results are consistent with the hypothesis that the macrophage is important in determining the severity of acute pancreatitis in this model.

Over the past few years, evidence has accumulated that implicates proinflammatory cytokines as the mediators responsible for the escalation of acute pancreatitis into a multisystem disease. It has been shown that the degree of serum cytokine elevation, particularly the macrophage-derived cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha, correlates with the severity and outcome of acute pancreatitis. Interleukin-10 is an anti-inflammatory cytokine that inhibits cytokine production from the macrophage. The aim of this study was to determine whether interleukin-10 would decrease both the severity of acute pancreatitis and the level of circulating proinflammatory cytokines. Ninety female mice were divided into three equal groups. Group 1 (controls) received intraperitoneal saline solution. Groups 2 and 3 received intraperitoneal cerulein (50 mg/kg/hr) for 7 hours. In addition, group 3 was given 1500 units of intraperitoneal interleukin-10, beginning 1 hour after the induction of acute pancreatitis and every 3 hours thereafter. Animals were killed at 3-hour intervals. Blood samples were obtained for serum amylase and cytokine determinations (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha). Pancreata were dissected free and fixed in formalin for blinded histologic scoring. Interleukin-10 reduced the serum levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and amylase in comparison to untreated animals with pancreatitis (P < 0.05). Pancreatic edema, necrosis, and inflammatory cell infiltrate were also reduced in those animals given interleukin-10 (P <0.05). Histologic score, serum cytokines, and amylase levels are elevated during acute pancreatitis. Interleukin-10 given therapeutically, that is, after the onset of acute pancreatitis, lessened the severity of disease, probably through inhibition of the macrophage. This was associated with a decrease in circulating cytokine levels.

After massive small bowel resection, the intestine adapts to compensate. In addition to proliferation, enterocytes also undergo selective functional adaptation. In this study we examined the effect of intraperitoneal administration of epidermal growth factor (EGF) on the expression of the brush border dissacharidase sucrase, the sodium glucose cotransporter (SGLT1), and the sodium-potassium ATPase pump (NaK ATPase) by enterocytes in the remnant intestine after massive small bowel resection. Adult Lewis rats underwent either ileal transection or 70% proximal intestinal resection. These animals were subdivided into groups that received either saline or EGF intraperitoneally for 1 week. Ilea from each group were harvested 4 weeks postoperatively. Enterocytes were separated from these segments by calcium chelation. The total protein from the isolated cells was subjected to Western blot analysis. Administration of EGF to animals that underwent transection did not significantly alter the expression of sucrase, SGLT1, or NaK ATPase. After intestinal resection, the expressions of sucrase and SGLT1 were significantly increased. The combination of EGF administration and intestinal resection resulted in a further increase in SGLT1 expression. The intraperitoneal administration of EGF selectively enhanced the expression of SGLT1 by enterocytes after massive small bowel resection. Administration of EGF to sham-operated animals did not have similar effects. These results suggest that EGF augments the adaptive response and may therefore have a therapeutic role in the management of patients with short bowel syndrome.

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) 15. Birth parameters and clinical presentation of 79 confirmed UPD cases and 43 deletion patients were compared in order to test whether any manifestations differ between the two groups. There were no major clinical differences between the two classes analyzed as a whole, other than the presence of hypopigmentation predominantly in the deletion group. However, there was a significant bias in sex-ratio (P < .001) limited to the UPD group with a predominance (68%) of males. An equal number of males and females was observed in the deletion group. When analyzed by sex, several significant differences between the UPD and deletion groups were observed. Female UPD patients were found to be less severely affected than female deletion patients in terms of length of gavage feeding and a later onset of hyperphagia. Although these traits are likely to be influenced by external factors, they may reflect a milder presentation of female UPD patients which could explain the observed sex bias by causing under-ascertainment of female UPD. Alternatively, there may be an effect of sex on either early trisomy 15 survival or the probability of somatic loss of a chromosome from a trisomic conceptus.

Full thickness rectal prolapse is a distressing and debilitating condition that often affects elderly patients. Fecal incontinence is usually present. Frequently, comorbid conditions or previous pelvic procedures complicate surgical care. A perineal approach may be used in these patients to avoid the complications of pelvic surgery and general anesthesia. The Delorme operation involves mucosal stripping and muscle plication of the rectal prolapse and is performed externally under regional or general anesthesia. We report our experience with this procedure in six elderly candidates who have undergone the Delorme procedure at the UCLA Center for Health Sciences in the past year. Two men and four women with a mean age of 78 +/- 12 years were followed over a mean of 11 +/- 4 months. Complicating factors included a mean of 1.7 failed prolapse operations per patient (0-6), pelvic radiation in two patients, and severe cardiac and pulmonary disease in two patients. Outpatient bowel preparations and same day admissions were used. Operative time averaged 80 minutes. No blood transfusions were required and postoperative stay averaged 2.7 days. A total of 67 per cent report improvement in continence. There was no major morbidity or mortality and only one recurrence. We conclude that the Delorme procedure is a safe and useful procedure for the treatment of complete rectal prolapse. Elderly patients, patients with failed prolapse operations, and those with prior pelvic surgery or radiation should be considered for this procedure.

Triploidy is a common chromosome abnormality in spontaneous abortions. Previous studies of spontaneous abortions have suggested that approximately 85% of triploid abortuses show the placental changes of partial hydatidiform mole (PHM) and that this appearance was associated, possibly attributable, to paternal origin of the extra haploid set of chromosomes. More recent work, however, has shown that most triploidy is the result of digyny--the extra set of chromosomes originating from the mother. Given the association of PHM with diandry, these results would appear to be at odds with the results of previous studies of placental morphology in triploids. The authors reviewed the placental pathology of all cases of triploidy examined at their institution over a 2-year period and established that PHM occurs in a minority of triploid conceptuses. These results support the findings of studies showing that digyny is the most common origin of triploidy.

In patients with the 3p-syndrome, hemizygous deletion of 3p25-pter is associated with profound growth failure, characteristic facial features, and mental retardation. We performed a molecular genetic analysis of 3p25 breakpoints in four patients with the 3p- syndrome, and a fifth patient with a more complex abnormality, 46,XY,der(3)t(3;?)(p25.3;?). EBV transformed lymphoblasts from each of the patients were initially characterised using fluorescent in situ hybridisation (FISH) and polymorphic microsatellite analyses. The 3p-chromosome from each patient was isolated from the normal chromosome 3 in somatic cell hybrid lines and subsequently analysed with polymorphic and monomorphic PCR amplifiable markers from 3p25. The analysis clearly shows that all five breakpoints are distinct. Furthermore, we have identified yeast artificial chromosomes that cross the 3p25 breakpoints of all four 3p-patients. Two of the patients were deleted for the von Hippel-Lindau (VHL) tumour suppressor gene, although neither has yet developed evidence of VHL disease. The patient with the most centromeric breakpoint, between D3S1585 and D3S1263, had the most severe clinical phenotype including an endocardial cushion defect that was not observed in any of the four patients who had more telomeric breakpoints. This study should provide useful insights into critical regions within 3p25 that are involved in normal human growth and development.

The purpose of this study was to evaluate the utility of ductography, or galactography, in identifying ductal abnormalities in patients presenting with abnormal nipple discharge and to correlate these findings with pathologic results. Abnormal nipple discharge was defined as either bloody or testing positive for occult blood. Milky discharge (galactorrhea) was not evaluated. From July 1992 to June 1994, a total of 43 women presented to the UCLA Breast Center with complaints of abnormal nipple discharge. Mean age of the patients was 54.9 years. All patients underwent technically adequate ductography. A total of 25 patients then underwent 26 excisional biopsies for abnormal ductographic findings. Surgery was usually simplified by the appropriate ductal injection of methylene blue immediately preoperatively. No complications from the procedure were identified. Pathologic entities were correlated with ductographic findings. Ductography identified ductal abnormalities in 33/45 (73%) of ductograms. Filling defects were noted in 19/45 (42%) of ductograms, ductal dilatation in 3/45 (7%), both filling defects and dilatation were noted in 11/45 (24%) of ductograms, and 12/45 (27%) were normal ductograms. Pathologically, ductographic anomalies correlated well with histologic findings. We conclude that ductography is an effective and safe means of identifying ductal abnormalities in patients with abnormal breast discharge. A high incidence of benign intraductal papilloma and a moderate risk of cancer and precancerous lesions were identified. We believe that patients with abnormal nipple discharge should undergo routine ductography and dye localization before surgery.

Objective: To determine the effect of neoadjuvant therapy (NT) (preoperative chemotherapy, radiation therapy, or both) in surgically resectable esophageal cancer., Design: A retrospective review over a 20-year period., Setting: A tertiary academic medical center., Participants: All patients undergoing surgical resection for esophageal cancer (N = 316) over this time period., Main Outcome Measures: Perioperative morbidity and mortality, local and distant recurrences, and overall survival., Results: Patients undergoing NT (n = 106) had prognostic factors similar to those treated with surgery alone (n = 210). No increase was noted in surgical morbidity with NT (anastomotic leaks, reoperation rates, complications, or extended hospital stays). Overall survival was not improved by NT (median survival, 14 months) except in the subset of patients (11/83) who responded completely (100% histological necrosis) to preoperative chemotherapy (median survival, 79.2 months; P < .02). Complete response to radiation therapy alone was not associated with improved survival. Partial necrosis of the primary tumor was seen in 13 (15%) of 83 patients but conferred no survival advantage. Complete response to preoperative chemotherapy was associated with squamous cell pathological features and excellent performance status as measured by preanesthesia evaluation., Conclusions: The addition of NT did not increase perioperative morbidity or mortality. Only the subset of patients who had a complete response to preoperative chemotherapy showed a survival advantage. Excellent performance status and squamous cell pathological features were associated with an increased chance of complete pathological response following preoperative chemotherapy.

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: Cytokines derived from macrophages may play an integral role in the evolution of acute pancreatitis. Interleukin-10 (IL-10), a potent antiinflammatory cytokine, prevents the activation of macrophages and their release of inflammatory cytokines. The aim of this study was to determine whether treatment with IL-10 decreased the severity of experimental acute pancreatitis., Methods: Thirty female Swiss Webster mice were divided into three groups. Acute pancreatitis was induced by using a choline-deficient, 0.5% ethionine supplemented (CDE) diet. Group A (controls) received CDE diet alone. Group B was pretreated with 10,000 units of intraperitoneal IL-10 at the onset of feeding and every 8 hours thereafter. Group C received IL-10 33 hours after beginning the CDE diet and every 8 hours thereafter. One half of the animals in each group was killed at 54 hours; the remaining living animals were killed at 80 hours. Serum amylase levels (units per liter) were determined at 54 and 80 hours. Pancreata were harvested and fixed in formalin. Histologic characteristics were graded on a scale from 0 to 4 (normal to most abnormal) in a blinded fashion by two investigators., Results: Serum amylase level and histologic score (edema, inflammation, hemorrhage, and necrosis) were significantly reduced when IL-10 was administered either prophylactically or therapeutically (p < 0.01). At 54 hours all animals were alive. Mortality was reduced at 80 hours in both groups treated with IL-10 compared with those fed the CDE diet alone (p < 0.001)., Conclusions: These results suggested that macrophages play an integral role in determining the severity of acute pancreatitis in this animal model. The finding that IL-10 decreased inflammation and prevented death, even when given after acute pancreatitis was established, suggests that it may have potential for clinical use.

A previous demonstration of a substantial genetic contribution to the expression of spontaneous otoacoustic emissions (SOAEs) is here extended to an aspect of click-evoked otoacoustic emissions (CEOAEs). CEOAEs were measured in the same twins and non-twins used for the SOAE heritability study. The stimuli were 100-microsecond clicks presented a nominal rate of 2/s; the emitted waveforms from 50 clicks were summed, and a 20-ms sample of that averaged waveform (beginning 6 ms after click presentation) was subjected to spectral analysis. The total power in the spectrum from 1 to 5 kHz in this temporal segment of the CEOAE waveform was used as the primary dependent variable. This overall power was significantly greater in female and right ears than in male and left ears, but the difference between dark- and light-eyed subjects was not significant. The overall power in the two left, and two right, ears of monozygotic co-twins was more highly correlated than in dizygotic co-twins, and structural modeling indicated that about 65-85% of the individual variation in the expression of CEOAE power could be attributed to genes-essentially the same heritability estimate as obtained previously from the SOAE data. Within-subject correlations between CEOAE power and number of SOAEs ranged from about 0.3 to 0.7, suggesting that these two forms of otoacoustic emission may depend upon somewhat different aspects of the same underlying mechanism and, thus, that heritability estimates based on one measure are not completely redundant to those from the other. While the average spectral power of the CEOAEs in opposite-sex dizygotic (OSDZ) females was smaller than that in same-sex dizygotic (SSDZ) females- and thus approached the value for males-the difference did not achieve statistical significance. Thus, the evidence for a prenatal masculinizing effect was less definitive in these CEOAE data than in the SOAE data obtained from the same subjects. An interpretation that accounts for both the CEOAE and SOAE results is that the strength of the so-called cochlear amplifiers is under genetic control that is to some extent mediated and/or modified through prenatal exposure to androgens. The indicated direction of effect is that weak cochlear amplifiers result when prenatal androgen levels are high. Under this view, then, androgen level contribute both to the sex differences observed in otoacoustic emissions and the prenatal masculinizing effects observed in opposite-sex twins, and they may be a factor in individual differences in OAE expression as well. Additionally it is shown that, although the powers of the CEOAE waveforms were reasonably highly correlated for the two ears of subjects in all groups, and across MZ co-twins, cross-correlations on the fine structures of those same pairs of CEOAE waveforms were essentially zero-presumably owing largely to the synchronizing of (different) SOAE frequencies in the ears being compared.

Background: Although laparoscopy reveals undetected metastases in many patients with pancreatic cancer, most surgeons have chosen to proceed directly with laparotomy in an attempt at resection or for palliation of biliary and gastric outlet obstruction. In an effort to overcome this limitation, this study attempted to determine the feasibility of laparoscopic cholecystojejunostomy and gastrojejunostomy., Methods: Under general anesthesia, seven pigs underwent laparoscopic cholecystojejunostomy and gastrojejunostomy using either a hand-sutured or the stapled/sutured technique., Results: Mean operating time was less with the stapled/sutured vs hand-sutured technique (150 +/- 21 vs 230 +/- 13 min, P < 0.05). All animals recovered completely and there was no change in their weight or liver function tests as a result of the procedure. At sacrifice, all anastomoses were patent, although some were significantly narrowed in these unobstructed animals., Conclusions: These results suggest that simultaneous laparoscopic palliation of biliary and gastric outlet obstruction is feasible. We believe these results warrant further study in the clinical setting.

Somatostatin (SMS) is administered to patients with short bowel syndrome and enterocutaneous fistulae. Previous studies have shown detrimental effects of SMS on intestinal adaptation after bowel resection. We examined whether administration of epidermal growth factor (EGF) could reverse the deleterious effects of SMS seen after enterectomy. Sixty-four Sprague-Dawley rats underwent an 80% small bowel resection or transection as control. Rats received either SMS at 50 ng x kg(-1) x h(-1), EGF/Urogastrone at 1.5 microg x kg(1-) x h(-1), or both via subcutaneous miniosmotic pumps. Samples were obtained at 1 day and 1 week after surgery for histologic examination, analysis of apical Na+/glucose cotransporter protein and mRNA expression, and analysis of basolateral Na+/K+ ATPase protein and mRNA expression. Protein expression was analyzed by Western blotting whereas mRNA expression was compared by ribonuclease protection assay. Histologically, villus to crypt length after intestinal resection showed increased adaptation in EGF/SMS vs SMS treated animals in both jejunum and ileum. Analysis of mRNA and protein of epithelial transporters show early increases when EGF is administered with SMS vs SMS only. We conclude that combination therapy using EGF and SMS may be beneficial to intestinal adaptation after small bowel resection. Both histologic and molecular data suggest an enhanced absorptive potential and adaptation of the remaining intestine when EGF is administered.

Intra-abdominal cysts may rise from a variety of organs. However, foreign-body reaction and cyst formation should be considered in the differential diagnosis. In this report, we describe the finding of a preoperatively undetected gossypiboma. A gossypiboma is a mass within the body that is composed of a cotton matrix; in this case, an unmarked laparotomy sponge. The evaluation, findings, and prevention of gossypiboma are discussed.

Peptide YY (PYY) is a 36 amino acid peptide that is released from the endocrine cells of the distal ileum, colon, and rectum following a meal. PYY is strongly proabsorptive in the small intestine. We studied the effects of intravenous PYY on colonic water and electrolyte transport in awake dogs. Dogs had 20 cm neurovascularly intact colon Thiry-Vella fistulas (TVS) surgically constructed. Colonic transport was studied in three experimental groups. Group 1 animals received a standard mixed meal. Group 2 animals were unfed and received intravenous PYY and 100 pmol/kg/hr for two hours. This dose of PYY has previously been shown to simulate the plasma levels of PYY normally seen after a meal. Group 3 received intravenous PYY at the same dose in addition to a mixed meal. Our study shows an increase in colonic water, Na+, and Cl- absorption after a meal (P < 0.05). Infusion of PYY at a 100 pmol/kg/hr was significantly proabsorptive beginning at 60 minutes (P < 0.01). Infusion of PYY in addition to a meal further increased absorption (P < 0.05). PYY is a potent proabsorptive agent in the colon of the conscious dog. PYY, or its analogs, may be useful clinical agents in intestinal malabsorptive disorders or after bowel resection.

Peptide YY (PYY), a 36-amino-acid polypeptide, is found in abundance in the colon, a region where its physiologic roles are unknown. Previous studies have revealed a substantial increase in plasma PYY after cholecystokinin (CCK) administration. PYY is released from the hindgut in response to a meal and inhibits CCK release. In this study we evaluated the effects of CCK and PYY on intestinal absorption of water and electrolytes. Colonic, ileal, or jejunal Thiry-Vella fistulas (TVFs) were created in 12 dogs, and intestinal continuity was reestablished. The TVFs were perfused with an isotonic buffer solution containing [14C] PEG as a volume marker. Electrolyte and water transport were measured every 15 minutes, and plasma PYY and CCK levels were measured by radioimmunoassay. Group 1 dogs received an intravenous bolus of MK329, a specific CCK receptor antagonist, at 20 nmol/kg after a standard mixed meal; group 2 colonic TVF dogs received a meal and an intravenous bolus of PYY polyclonal antibody at 1 mg/kg. Postprandially, all three regions of the bowel became significantly proabsorptive for water, sodium, and chloride. In the colon postprandial absorption was abolished by MK329 starting 60 minutes after a meal, whereas specific CCK receptor blockade blunted ileal absorption. CCK receptor blockade did not affect postprandial absorption in the jejunum. Postprandial PYY levels did not rise in MK329-treated animals. PYY antibody reduced colonic absorption during the postprandial phase. Reduction of meal-induced colonic absorption and PYY release by MK329 in awake dogs suggests an important foregut-hindgut hormonal feedback loop. Foregut-derived CCK stimulates hindgut PYY release, which in turn stimulates colonic absorption while inhibiting further CCK release.

Following massive small bowel resection, the remaining intestine undergoes compensatory adaptation to maintain absorptive capacity. The purpose of this study was to determine the relative importance of mucosal hyperplasia and functional adaptation by individual enterocytes in this process. Distal ileum was harvested from rats 2 weeks following 70% small bowel resection or transection with reanastomosis. Transport parameters were determined in Ussing chambers. Short-circuit current (Isc) responses to additions of 3-0-methylglucose were measured to assess Na+/glucose cotransporter kinetics. Microvillus absorptive surface areas were calculated with computer-assisted morphometric modeling. These surface area values were used to normalize transport parameters. Ileal absorptive surface area was 70% greater in resection tissues than in transection tissues (P < 0.05). Na+ and Cl- fluxes were generally lower in the resection group. Na+/glucose cotransporter delta Isc max (an index of cotransporter quantity) for resection and transection tissues were 0.3 +/- 0.1 and 1.8 +/- 0.3, respectively (P < 0.05). Km (an index of cotransporter affinity for substrate) did not differ significantly. Following intestinal resection, ileal surface area increases; however, transport parameters, when normalized to absorptive surface area values, diminish. During early postresection adaptation, expansion of ileal absorptive surface area due to hyperplasia seems to play a greater role than upregulation of enterocyte Na+, Cl- , and glucose absorption.

Isolated internal iliac aneurysms are rare, and although most are of atherosclerotic origin the cause may also be congenital, traumatic, associated with pregnancy or infectious. A 56-year-old man presented with a swollen, painful left lower limb. Within a few days, weakness of the limb developed with fever and an acute abdomen with free air on x-ray. At emergency laparotomy a small perforation was found in the ascending colon. Examination of the left iliac fossa revealed a ruptured left internal iliac artery aneurysm. Extra-anatomic cross-femoral bypass grafting was done to revascularize the left lower extremity. The patient recovered without complication. At discharge the weakness had improved but knee flexion and extension were weak. Culture of the aneurysm contents grew Staphylococcus aureus and Pseudomonas aeruginosa. The authors discuss the presentation and management of infected internal iliac artery aneurysms.

Meal-stimulated colonic absorption has recently been described, but the cellular transport mechanisms mediating this response are unknown. The purpose of this study was to determine the contribution of Na+ transport pathways to colonic proabsorption. Distal colonic Thiry-Vella loops were constructed in six dogs. Absorption was measured by infusing the loops with a physiological electrolyte solution containing [14C] polyethylene glycol as the impermeant marker. In the first set of experiments, the dose dependence of amiloride-induced inhibition of basal colonic absorption was determined. In the second set of experiments the effect of amiloride, which inhibits both Na+ channels and Na+/H+ exchange in colonocytes, on meal-stimulated colonic absorption was determined. Luminal amiloride inhibited basal colonic absorption in a dose-dependent manner, with significant reductions in Na+ absorption occurring with concentrations of 10(-2)M and higher. Infusion with 10(-3)M amiloride, a concentration that did not alter basal absorption, resulted in significant reductions in postprandial water, Na+, and Cl- absorption. These results suggest that meal-stimulated colonic absorption is mediated, at last in part, by transcellular Na+ absorptive pathways.

To study the influence of extrapancreatic neural and cholinergic activity on the pancreatic response to cholecystokinin (CCK), six dogs underwent creation of Herrera pancreatic fistulas, placement of Thomas gastric cannulas, and distal pancreatectomies (innervated; INN). Six additional dogs were prepared similarly, with the addition of total extrinsic pancreatic denervation (denervated; DEN). The pancreatic protein and bicarbonate response to graded 12.5 to 200 ng/kg/h CCK doses was determined for INN and DEN animals both alone and with 10 micrograms/kg/h atropine infusion. The influence of extra-pancreatic neural and cholinergic activity on secretin's potentiation of the CCK-induced pancreatic response was then determined by repeating the studies with a 125 ng/kg/h secretin infusion. The latter results were compared to those predicted by summating the responses seen during separate 12.5-200 ng/kg/h CCK dose-response and 125 ng/kg/h secretin studies. Unstimulated protein output was diminished by atropine in INN animals (78 +/- 21 vs. 39 +/- 9 mg/15 min; p < 0.05) but not in DEN animals. Unstimulated bicarbonate outputs, integrated bicarbonate and protein outputs, and bicarbonate and protein dose-response curves were unaffected by denervation or atropine. Potentiation of CCK-induced bicarbonate output by secretin was also unaffected by atropine and denervation. We conclude that cholinergic elements are involved in unstimulated, but not CCK-induced, enzyme secretion. Further, potentiation of CCK-induced bicarbonate output by secretin does not depend on extrinsic neural or cholinergic elements.

In the setting of inflammatory bowel disease (IBD), laparoscopic approaches have been avoided because of the often fragile intestinal tissue, thickened mesentery, malnutrition, immunosuppression, and the presence of dense adhesions. In this article, we report 10 successfully managed laparoscopic cases in IBD patients (five with ulcerative colitis, five with Crohn's Disease). Patients with ulcerative colitis underwent total abdominal colectomies, mucosal proctectomies, J-pouch construction, and diverting ileostomies. Procedures in patients with Crohn's disease included ileocecectomy (3), sigmoid colectomy with takedown of a transverse colonic fistula (1), and stricturoplasty (1). One of the 10 cases was converted to an open technique for technical reasons. Six of the 10 patients were on high dose corticosteroids for disease control. Hospital stay ranged from 6-13 days, with a median of 7 days. The morbidity rate was 20 per cent, and included one case of mild postoperative pancreatitis in a Crohn's disease patient and one delayed peri-ileostomy fistula in an ulcerative colitis patient. There was no mortality. Based on these results, we conclude that laparoscopic intestinal surgery is both feasible and safe in selected patients with inflammatory bowel disease. Use of laparoscopic techniques in these patients may reduce hospital stay, lessen adhesion formation, and improve cosmetic results in this generally young group of patients.

The available data suggest that lymph node involvement is an important prognostic factor in patients with carcinoma of the head of the pancreas. Lymph node metastases occur in as many as 50% of the cases of even the smallest pancreatic cancers now being diagnosed and resected (i.e., those < 2 cm in diameter). There is some evidence, especially from clinical experience in Japan, that wider lymphatic dissections (i.e., wider than those commonly done with the standard Whipple resection) may prolong survival. Unfortunately, many of the available data around the world are retrospective and are not randomized between the standard and the radical operation. Moreover, the pathologic material has not been staged uniformly according to accepted criteria. Thus the various series are not comparable. Comparisons between series require standardization with respect to stage of disease, pathologic classification, and treatment protocols. Before any modification of the standard pancreaticoduodenectomy is adopted, an appropriately designed study should be performed to test its efficacy. This study would also require a more comprehensive analysis of the pathologic material than is commonly performed today in the United States and Europe.

Background: Peptide YY (PYY), a 36 amino acid enteric hormone, is known to decrease pancreatic exocrine and endocrine function. Previous studies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic cancer cells in vitro. We investigated the effects of both PYY and BIM-43004-1 on pancreatic cancer growth in vivo., Methods: The 100,000 to 150,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically transplanted into 48 male athymic mice. After 1 week animals were treated with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pumps for 2, 3, or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measured in vitro., Results: All mice had significant human cancer growth within the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor mass was decreased by 60.5% in BIM-43004-1 treated mice and 27.1% in PYY treated mice. Receptor binding studies revealed binding of [125I]-BIM-43004-1 and displacement of ligand on competitive addition of nonradioactive BIM-43004-1. K dissociation constant of 4.5 nmol and 27,000 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5% decrease in intracellular cAMP levels was noted, whereas a 15.3% decrease was seen in PYY treated cells., Conclusions: BIM-43004-1, a novel Y2 synthetic agonist, specifically binds to human pancreatic cancer cells, decreases intracellular cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormonal treatment with this Y2 receptor analog may be beneficial in the treatment of patients with pancreatic adenocarcinoma.

Peptide YY (PYY), a proabsorptive hormone, is released into the circulation and lumen of the small intestine after a meal. We have recently found that intraluminal PYY is proabsorptive in the ileum. The purpose of this study was to examine the effects of intraluminal administration of a new substituted PYY (22-36) analog on intestinal absorption of electrolytes and water. Twelve conditioned 20-kg dogs had 25-cm jejunal, 25-cm ileal, or 20-cm colonic Thiry-Vella fistulas (TVF) surgically constructed under general anesthesia (jejunal and ileal TVF, N = 6, and colonic TVF, N = 6). After a 2-week recovery period, the animals received the intraluminal PYY analog, BIM-43004, in the ileum (200 pmole/kg) or colon (300 pmole/kg) for 60 min after a 90-min steady-state basal period was confirmed. The TVF were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 min. Net water absorptions were significant in the ileum and colon but not in the jejunum upon intraluminal administration of the PYY analog, BIM-43004. Colonic water absorptions were increased more than twofold above basal absorption rates and ileal absorptions were increased more than 1.5-fold upon addition of intraluminal BIM-43004. Sodium and chloride ion absorption in the colon and ileum paralleled water fluxes. We are describing for the first time a synthetic peptide analog of PYY that produces significant water and electrolyte absorption in the ileum and colon when administered luminally. This synthetic analog may have therapeutic potential in patients with malabsorptive disorders.

Purpose: To evaluate the changes since 1970 in the management and outcome of esophageal resection for cancer., Methods: The records of all 316 patients who underwent esophageal resection for cancer at University of California Los Angeles Medical Center during the years 1970 to 1993 were reviewed., Results: When records from 1984 to 1993 were compared to those from 1970 to 1983, significant decreases were seen in operative mortality (10% to 3%, P < 0.01), morbidity (72% to 60%, P < 0.05), anastomotic leaks (12% to 5%, P < 0.03), and reoperations (20% to 8%, P < 0.003). Time spent in hospital and in intensive care decreased 40%. These improvements in short-term outcome were most evident in patients with disease in later stages. The 5-year survival rate increased (12% to 21%, P < 0.01). A greater percentage of tumors presented in early stages (21% versus 37%)., Conclusions: Short-term outcome of surgical resection for esophageal carcinoma improved between 1970 and 1993, in part because of changes in perioperative and surgical management. Long-term survival improved, probably due to earlier detection of tumors.

A new series of semisynthetic, water-soluble pneumocandin analogs has been found to be extremely potent against Pneumocystis carinii in an immunocompromised-rat model. These compounds are 5 to 10 times more potent than the parent natural product, pneumocandin B0 (L-688,786) (R. E. Schwartz et al., J. Antibiot. 45:1853-1866, 1992), and > 100 times more potent than cilofungin. One compound in particular, L-733,560, had a 90% effective dose against P. carinii cysts of 0.01 mg/kg of body weight when delivered parenterally (subcutaneously, twice daily for 4 days). This compound was also effective when given orally for the treatment and prevention of P. carinii pneumonia. For treating acute P. carinii pneumonia, oral doses of 2.2 mg/kg twice daily for 4 days were required to eliminate 90% of the cysts. A once-daily oral prophylactic dose of 2.2 mg/kg prevented cyst development, and a dose of 6.2 mg/kg prevented any development of P. carinii organisms (cysts and trophozoites), as determined through the use of a P. carinii-specific DNA probe (P. A. Liberator et al., J. Clin. Microbiol. 30:2968-2974, 1992). These results demonstrate that the antipneumocystis activities of the pneumocandins can be significantly improved through synthetic modification. Several of these compounds are also extremely effective against candidiasis (K. Bartizal et al., Antimicrob. Agents Chemother. 39:1070-1076, 1995) and aspergillosis (G. K. Abruzzo et al., Antimicrob. Agents Chemother. 39:860-894, 1995) in murine models, making them attractive as broad-spectrum antifungal agents.

Exogenous peptide YY (PYY) decreases pancreatic exocrine secretion, pancreatic endocrine function, and pancreatic blood flow. We hypothesized that pancreatic cancer cell growth may be inhibited by PYY and a new synthetic analog, BIM-43004-1. Two human pancreatic ductal adenocarcinomas, PANC-1 and Mia PaCa-2, were examined in tissue cultures. Viable pancreatic cancer cells were counted with trypan blue on a hemocytometer slide. Cells (10K, 20K, 40K, and 80K) were cultured and allowed to grow for 36 hr (n = 14/cell concentration). Pancreatic cancer cells received either PYY or BIM-43004-1 at various concentrations. Control tissue cultures received an equivalent volume of saline inoculation. After incubation with the above peptides for 24 hr, MTT tetrazolium bromide was added to assay mitochondrial activity of pancreatic cancer cells in response to PYY and its analog. MTT assay reveals a significant decrease in pancreatic cancer cell growth when PYY and BIM-43004-1 are added to the cell culture. Results in Mia PaCa-2 reveal a 24% cell growth reduction after exposure to PYY and a 23% reduction in cell growth when treated with BIM-43004-1. In PANC-1 cells, a 25% reduction in growth of cells is noted after PYY treatment and a 24% reduction in growth after BIM-43004-1 treatment. (means +/- SEM, P < 0.05 by Student's t test). Our results reveal a significant reduction in human ductal pancreatic cancer growth when treated with either PYY or its analog, BIM-43004-1. These agents may be useful hormonal adjuncts in the chemotherapy of pancreatic adenocarcinoma.

Although somatostatin is a potent inhibitor of pancreatic exocrine secretion in vivo, its mechanism of action remains unclear. The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion was studied in conscious dogs. Chronic pancreatic fistulae were created in six mongrel dogs, and a second group of six dogs also underwent complete pancreatic denervation. The pancreatic responses to graded doses of cholecystokinin (12.5-200 ng/kg/h) and bethanechol (57-916 micrograms/kg/h), both alone and during background infusion of somatostatin-14 (800 pm/kg/h), were determined in all dogs. The cholecystokinin dose-response with a somatostatin-14 background was then repeated with the addition of atropine (10 micrograms/kg/h). In both groups of animals, cholecystokinin elicited a dose-dependent increase in pancreatic protein secretion that was inhibited significantly by somatostatin-14. Regardless of the status of extrapancreatic nerves, atropine further inhibited cholecystokinin-induced protein secretion beyond that evoked by somatostatin-14. In both innervated and denervated animals, cholinergic stimulation with bethanechol elicited a dose-dependent increase in pancreatic protein secretion that was unaffected by somatostatin-14. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Somatostatin-14 appears to inhibit cholecystokinin-induced pancreatic secretion by an intrapancreatic cholinergic mechanism.

Background: Previous studies suggest that peptide YY (PYY) and enteroglucagon have an important role in intestinal adaptation after massive small bowel resection. This study was done to define the mechanisms, timing, and anatomic distribution of the PYY and enteroglucagon response., Study Design: Lewis rats underwent resection of 70 percent of the small bowel (leaving equal segments of jejunum and ileum), transection, or laparotomy alone. Jejunum, ileum, and colon were compared in resected, transected, and control bowel six hours, 24 hours, one week, and two weeks postoperatively., Results: Analysis of DNA, RNA, and protein per cm of bowel demonstrated hyperplastic changes. Radioimmunoassay revealed plasma PYY and enteroglucagon to be significantly elevated 24 hours after resection and they remained so through week two. In contrast, tissue PYY and enteroglucagon content decreased significantly in all tissues (p < 0.05) after resection. Reverse transcriptase polymerase chain reaction and Southern blot analysis demonstrated an immediate and sustained increase in PYY messenger RNA (mRNA) in both the ileum (fourfold) and in the colon (2.5-fold) at six hours (p < 0.05). A gradual increase in PYY mRNA was also demonstrated in the jejunum with significance at two weeks (p < 0.05). Proglucagon mRNA was significantly higher in the jejunum, compared with the ileum and colon, at 24 hours, one week, and two weeks postresection., Conclusions: Alterations in PYY and enteroglucagon synthesis occur early in the ileum and colon after massive small bowel resection. The residual jejunum, however, is primarily responsible for the adaptive hyperenteroglucagonemia. These findings suggest that although PYY and enteroglucagon are colocalized to the same cell type, there is a gene-specific response for these two peptides after resection.

Feeding stimulates fluid and electrolyte absorption in the small intestine. Previous studies have suggested that Na+/glucose cotransport is important in initiating this response in the jejunum. The purpose of this study was to determine whether Na+/H+ exchange plays a role in meal-induced absorption. Exteriorized, neurovascularly intact jejunal and ileal loops (25 cm) were constructed in dogs. Following a two-week period of postoperative recovery, the loops of awake dogs were perfused with standard buffer alone or with increasing concentrations of amiloride, a Na+/H+ exchange inhibitor. Water, sodium, and chloride fluxes were calculated following a meal using [14C]PEG as a volume marker. The meal significantly increased absorption in both the jejunum (P < 0.001) and ileum (P < 0.01) in those animals perfused with buffer alone. More significantly, amiloride suppressed the increased absorption seen following a meal in the ileum (P < 0.001) but not the jejunum. The response in the ileum was dose dependent. These findings suggest that a major mediator of postprandial sodium and water absorption in the ileum is the Na+/H+ exchanger.

The influence of extrapancreatic nerves and intrapancreatic adrenergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/h) and cholecystokinin (CCK; 50 ng/kg/h) was administered over 2 h. An infusion of PYY (400 pmol/kg/h) was then given randomly, during either the first or second experimental hour. The experiments were then replicated after establishing adrenergic blockade with continuous background infusions of either phentolamine (0.2 mg/kg/h), propranolol (0.5 mg/kg bolus) or a combination of phentolamine and propranolol. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. Adrenergic blockade failed to eliminate the inhibitory effects of PYY. We conclude that extrapancreatic neural pathways, including adrenergic mechanisms, do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an indirect nonadrenergic mechanism.

Peptide YY (PYY) is a 36-amino-acid peptide known to inhibit pancreatic and gastrointestinal secretion. Immediately following small bowel resection, intestinal PYY mRNA and plasma PYY levels rise. The purpose of this study was to determine whether PYY expression changes in the pancreas during the adaptive period after extensive small bowel resection. Female Sprague-Dawley rats (250 g) underwent 70% small intestinal resection or transection alone as control. Animals were sacrificed at 6 hr, 24 hr, 1 week, or 2 weeks following operation (N = 5/time group). Pancreatic tissue was harvested and RNA was isolated by the guanididium-thiocyanate method. PYY mRNA was analyzed by reverse transcriptase PCR, standardized to glyceraldehyde-3-phosphate dehydrogenase, and semiquantitated by Southern blotting and 32P cpm. Ribonuclease protection assay was used to confirm PCR results. PYY mRNA expression was increased 9 1/2-fold beginning 6 hr after resection compared to transection (P < 0.05). PYY mRNA levels remain elevated, 2 1/4-fold greater than control after 2 weeks (P < 0.05) as analyzed by reverse transcriptase PCR and ribonuclease protection assay. Quantitation by ribonuclease protection assay reveals a gradual elevation of PYY mRNA levels in transected animals compared to a nonoperated rat starting at 1 and 2 weeks. Pancreatic PYY mRNA levels increase rapidly after extensive intestinal resection and remain elevated 2 weeks postoperatively. These results confirm for the first time that the increase in PYY seen after extensive intestinal resection also occurs in extraintestinal sites. In the pancreas, elevated PYY levels may inhibit exocrine secretion, reducing luminal volume, and thereby facilitating intestinal adaptation.

Ingestion of a meal stimulates small intestinal ion and water transport. Current evidence suggests that this response, termed proabsorption, is primarily mediated by the apical Na+/glucose cotransporter. Like glucose, the majority of amino acid absorption occurs by Na(+)-dependent, secondary active transport. The purpose of this study was to determine the role of amino acid transport in meal-induced jejunal ion and water absorption in vivo. Exteriorized, neurovascularly intact jejunal loops measuring 25 cm were created in six female mongrel dogs, and the dogs were allowed to recover for 2 weeks. After an overnight fast, the loops were perfused with a standard buffer containing 10 mM aspartate, leucine, glycine, or lysine. Net water and electrolyte absorption before and after a mixed meal was calculated using [14C]polyethylene glycol as a volume marker. Aspartic acid, leucine, glycine, and lysine are each transported by a separate transporter system. Except for lysine, each amino acid significantly (P < 0.05) potentiated sodium and water absorption after a meal. In addition, this effect was at least as great as that seen with 10 mM glucose. These results demonstrate that amino acid transporter, like the Na+/glucose cotransporter, mediates meal-induced jejunal sodium and water absorption and may be as important in the proabsorptive response.

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.

A reduction of peripheral CD4+ cell levels has been correlated with the onset of Pneumocystis carinii pneumonia in AIDS patients. Most in vivo drug discovery and development for P. carinii have been conducted in corticosteroid-treated rats. There is need for the development of new small animal models with more selective methods of immunosuppression. This study outlines a new mouse model in which specific depletion of the CD4+ T-lymphocyte population was achieved by subcutaneous injection of G.K1.5 hybridoma cells into C3HeB/FeJ mice. A significant reduction in splenic CD4+ cells was maintained over a 10-week period following a single injection of cells. Circulating anti-CD4+ antibody was detected throughout the 10-week period in hybridoma-injected mice, while circulating antibody was undetectable 4 weeks after repeated injection of purified monoclonal antibody. There was no significant increase in the CD8+ cell populations of the hybridoma-injected mice. P. carinii cysts increased in the lungs of CD4+ T-cell-depleted mice, with the number of cysts detected comparable to levels in dexamethasone-treated mice. High levels of cysts were detected when CD4+ cell populations in the spleen remained below 5% and decreased when CD4+ populations increased above the 5% level. In mice whose CD4+ population was not reduced below 5%, there was no significant increase in P. carinii cysts detected. This study presents a new mouse model with specific immunosuppression requiring a minimum of animal manipulation for use in discovery and development of potential new therapeutics for P. carinii pneumonia.

Pancreatic infection remains a significant clinical problem, with substantial morbidity and mortality. Published case reports of Candida species identified in these infections prompted a review of 17 consecutive patients recently treated for peripancreatic infection by scheduled relaparotomy. Six patients were transferred from other hospitals, all having undergone prior operative intervention (median stay elsewhere: 58 days). The 11 other patients underwent initial operation an average of 14 days after admission. Candida species were identified in the initial operative cultures of 5 patients (29%), three of whom had undergone previous drainage at other hospitals. Two patients (11.7%) had Candida identified at subsequent operation. Six patients were treated with Amphotericin B for a median of 12 days (range 6-32) and a median dosage of 420 mg (range 225-830 mg). All patients were cleared of their Candida infection, but three subsequently died, for an overall mortality of 17.6%. Candida infected patients suffered a 42 per cent mortality. Our series supports the suspicion that Candida is much more frequent (41% of patients) than previously recognized in peripancreatic sepsis, and is commonly acquired after the initial operation. Amphotericin B therapy is effective in clearing Candida infection, but affected patients have a high associated mortality.

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.

Following massive small bowel resection, the remaining intestine adapts to compensate for lost absorptive capacity. Although the Na+/glucose cotransporter plays a critical role in nutrient, fluid, and electrolyte transport in the small intestine, its role in adaptation following resection has not been defined. To examine this, we sought to determine whether there were changes in the expression of the Na+/glucose cotransporter, SGTL1, at the messenger RNA level. Lewis rats underwent either transection or 70% small bowel resection and reanastomosis. The animals were sacrificed at intervals following operation. Jejunum proximal to the anastomosis and ileum and colon distal to the anastomosis were harvested and analyzed for Na+/glucose mRNA by reverse transcriptase-polymerase chain reaction and Southern blot. Blots were semiquantitated by 32P labeling and standardized to beta-actin. Histologic sections and analysis of DNA, RNA, and protein content revealed hyperplastic changes. Following resection, mRNA for the Na+/glucose cotransporter in the jejunum increased significantly (P < 0.05) by 1 week and remained elevated. In the ileum, an almost fivefold increase occurred at 6 hr and persisted throughout the study (P < 0.05). The early response was greater in the ileum, distal to the reanastomosis, than that in the jejunum (P < 0.05). In contrast, there was no change in the small amount of transporter mRNA detected in the colon. These results suggest that, in addition to mucosal hyperplasia, the intestinal response to resection involves upregulation of transporter mRNA by the individual enterocyte. This transcriptional increase in the Na+/glucose cotransporter appears to be an early response by the intestine and may be important in maintaining overall intestinal transport capacity following resection.

Background: Pancreatic transplantation results in denervation and loss of splanchnic venous drainage and inflicts numerous metabolic abnormalities. However, it is unclear whether denervation or loss of splanchnic venous drainage is responsible for the observed metabolic abnormalities., Methods: To discern denervation's role in these abnormalities, four mongrel dogs underwent extrinsic pancreatic denervation with preservation of splanchnic venous drainage. These animals, as well as four innervated control subjects, underwent standardized enteral and intravenous glucose tolerance testing. In addition, hyperglycemic clamps that maintained stable serum glucose elevations at either 2.8 or 8.3 mmol/L above basal were also performed., Results: Prestimulated glucose (90.4 +/- 2.7 vs 92.6 +/- 4.9 mg/dl) and insulin levels (6.8 +/- 1.7 vs 8.5 +/- 1.4 muU/ml) did not differ between innervated and denervated groups. Integrated incremental enteral glucose (5320 +/- 1900 vs 7790 +/- 2000 mg/dl) and insulin (2565 +/- 350 vs 2836 +/- 598 muU/ml) levels did not differ between groups. Integrated incremental intravenous glucose (3680 +/- 400 vs 3950 +/- 1000 mg/dl) and insulin (741 +/- 70 vs 1053 +/- 326 muU/ml) levels also did not differ. During glucose clamp studies, time-weighted 60 to 120-minute insulin levels (2.8 mmol/L, 30 +/- 5.0 vs 24 +/- 4.8 muU/ml; 8.3 mmol/L, 57 +/- 5.9 vs 50 +/- 9.8 muU/ml) did not differ between groups. In addition, glucose disposal, cyclic insulin release, and insulin sensitivity indexes were unchanged by denervation., Conclusions: Extrinsic pancreatic neural elements are not necessary for cyclic insulin release in response to enteral or parenteral glucose challenge or physiologic and pharmacologic hyperglycemia. These findings suggest that the previously described posttransplantation glucose and insulin abnormalities are not attributable to denervation.

A moderate dose of quinine sulfate, administered to three young adult males, reduced or eliminated various forms of otoacoustic emission (OAE). The individual differences in response to the drug were substantial, but a number of generalizations did emerge. The time courses of onset and recovery were considerably more rapid than for the parallel effects produced by aspirin. Most spontaneous otoacoustic emissions (SOAEs) were eliminated within 7 h of the first 325-mg dose (about 3 h after the second dose). Most SOAEs showed partial or complete recovery about 24 h after the last dose, although considerable instability often remained. The functions relating the magnitude of a distortion-product OAE (DPOAE) to the sound-pressure level (SPL) of the primary tones producing it were displaced toward higher primary levels and became lower sloped following quinine administration. The magnitudes of SOAEs, DPOAEs, and nonlinear peaks in the click-evoked spectra declined and recovered with grossly similar time courses, but there were some partial dissociations. The ability of a DPOAE to suppress an SOAE lying about 50 Hz below it either increased slightly or remained about constant through the drug episode, even though the magnitudes of both DPOAE and SOAE were changing. On several occasions, increases in SOAE magnitude of as much as 10-20 dB were observed during the first 15-30 min of an SOAE measurement period (an initializing effect). Psychophysical measures revealed hearing losses of as much as 20 dB at some frequencies in some subjects. Several short-lived "enhancements" of OAEs are discussed relative to similar quinine-induced effects reported in an animal model.

Since feeding increases intestinal fluid and electrolyte losses in short bowel syndrome, an agent increasing postprandial small bowel absorption might have a therapeutic role. Peptide YY (PYY) has recently been shown to increase net small bowel absorption under basal conditions. The aim of this study was to determine whether PYY can also augment postprandial absorption. Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm Thiry-Vella loops) were created in dogs (n = 6) and gastrointestinal continuity was restored. Luminal perfusion with [14C]polyethylene glycol was used to calculate the change in water (H2O) and sodium (Na+) and chlorine (Cl-) ion fluxes after an oral meal. Changes in fluxes were also determined after a 2-hour infusion of a physiological dose of PYY (100 pmol/kg per hour). In a third series of experiments, fluxes were measured after a meal, during PYY infusion. Feeding increased small bowel absorption of fluid and electrolytes independent of the luminal content. This effect persisted for 2 hours after the meal. PYY infusion significantly augmented this proabsorptive response in both jejunum and ileum. These results suggest that PYY-agonists may have a therapeutic role in conditions such as short bowel syndrome where postprandial absorption is reduced.

Water-soluble pneumocandin L-693,989, a potent antipneumocystis agent in the rat model for Pneumocystis carinii pneumonia (PCP), inhibits P. carinii cyst development and effectively prevents the development of PCP when used as a prophylactic agent (D. M. Schmatz, M. A. Powles, D. C. McFadden, L. Pittarelli, J. Balkovec, M. Hammond, R. Zambias, P. Liberator, and J. Anderson, Antimicrob. Agents Chemother. 36:1964-1970, 1992). However, because of limited oral bioavailability, this compound would likely be restricted to parenteral use in humans. As an alternative, the aerosol delivery of L-693,989 was explored to determine the dosing regimen required to prevent the onset of PCP. Rats with latent P. carinii infections were immunosuppressed continuously with dexamethasone to promote the onset of PCP. During the 6-week immunosuppression period, L-693,989 was delivered to rats as a nebulized solution (volume median diameter of 3.8 microns) via a nose exposure inhalation chamber. The efficiency of aerosol delivery to the lungs and the rate of clearance were determined by using radiolabelled compound. It was found that a daily dose of 0.7 micrograms of L-693,989 per lung or a weekly dose of 77.9 micrograms/lung effectively prevented the development of P. carinii cysts and trophozoites as well as the associated pneumonia commonly seen in rats with acute P. carinii infections. These results demonstrate that L-693,989 is potentially useful as an aerosol prophylactic agent for PCP.

Although vagal cholinergic stimulation is the predominant regulatory mechanism governing the release of pancreatic polypeptide (PP), recent studies suggest that cholecystokinin (CCK) is also an important mediator. The present study examined the role of cholinergic neural pathways in the PP response to exogenous CCK-8 using a selectively denervated canine pancreas model. Chronic denervated pancreatic preparations were created in five dogs, while five dogs underwent sham laparotomy as controls. On study days, the fasted animals were infused intravenous CCK-8 (40 or 400 pmole/kg/hr) for 60 min both with and without atropine (20 micrograms/kg/hr). Plasma was collected at 20-min intervals and PP levels were determined by radioimmunoassay. CCK-8 elicited a dose-dependent increase in circulating PP in dogs with a neurally intact pancreas. Atropine and pancreatic denervation eliminated the PP response to CCK-8 at 40 pmole/kg/hr (P < 0.01) and inhibited the PP response to CCK-8 at 400 pmole/kg/hr (P < 0.05). The high dose of CCK-8 still elicited a small PP response in the denervated dogs (P < 0.05), which was subsequently abolished by the addition of atropine. These findings suggest that extrapancreatic cholinergic nerves are essential components of CCK-stimulated PP release, and that intrapancreatic cholinergic activity may play a limited role.

The influence of extrapancreatic nerves on the inhibition of meal- and secretogogue-induced pancreatic secretion by galanin was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs and a second group of five dogs also underwent complete pancreatic denervation. After recovery, galanin dose response (150-1,200 pmol/kg/h) revealed that 600 pmol/kg/h was the lowest dose of galanin to significantly inhibit pancreatic exocrine secretion. Pancreatic responses to a mixed meal, cholecystokinin (CCK) dose response (12.5-200 ng/kg/h), and secretin dose response (16-500 ng/kg/h) were determined. The experiments were then replicated with a continuous background infusion of galanin (600 pmol/kg/h). Galanin inhibited meal-, CCK-, and secretin-induced bicarbonate outputs in both the innervated and denervated pancreas. Galanin also inhibited meal- and CCK-induced protein responses in both groups. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of galanin.

The decision to operate on a patient with severe acute pancreatitis is often difficult and requires mature clinical judgment. Those indications that are widely accepted include: 1. For differential diagnosis, when the surgeon is concerned that the symptoms are the result of a disease other than pancreatitis for which operation is mandatory; 2. In persistent and severe biliary pancreatitis, when an obstructing gallstone that cannot be managed endoscopically is lodged at the ampulla of Vater; 3. In the presence of infected pancreatic necrosis; and 4. To drain a pancreatic abscess, if percutaneous drainage does not produce the desired result. Other indications that are less well defined and somewhat controversial are: 1. The presence of sterile pancreatic necrosis involving 50% or more of the pancreas; 2. When the pancreatitis persists in spite of maximal medical therapy; and 3. When the patient's condition deteriorates, often with the failure of one or more organ systems. For these latter three indications, guidelines have been presented that permit a logical approach to management, although uncertainty remains. Surgeons should strive to describe in precise terms the clinical state of their patients at the time that operation is performed, as well as the findings at and technical details of the surgery. This should allow further refinement in the management of this still vexing problem.