Characterization of the insulinotropic potency of polyunsaturated fatty acids.

In this study we have assessed the individual abilities of the essential fatty acids, linoleic and linolenic acids, to release insulin and compared their insulinotropic potencies with those of the more established nutrient insulin secretagogues, glucose and arginine. In each experiment, a total of six islets microdissected from three mice were preperifused at the rate of 1 ml/min with Krebs-Ringer bicarbonate buffer, pH 7.4, containing 2% bovine albumin and 5.5 mM glucose (basal) with a continuous supply of 95% O2-5% CO2 at 37 C for 1 h. After collecting basal samples, the effects of 27.7 mM glucose, 20 mM arginine, 10 mM linoleic acid (18:2, omega 6), and 5 mM linolenic acid (18:3, omega 3) were tested using a sandwich protocol that entails 20-min alternating periods of stimulation with a secretagogue and a washout with basal perifusion. These nutrient concentrations were selected from initial experiments performed to characterize their dose-response effects on insulin secretion. Effluent samples were collected throughout each experiment for measurement of insulin by RIA. In one series of experiments, islets were challenged three times with 27.7 mM glucose, 10 mM linoleic acid, and 5 mM linolenic acid. In another set of experiments, islets were perifused with 20 mM arginine, 27.7 mM glucose, and 10 mM linoleic acid. All of these nutrients stimulated insulin release in a dose-dependent manner. In comparing the insulinotropic potencies of these secretagogues, we assessed insulin secretion as the integrated areas under the curve during 20 min of perifusion with a given nutrient. Thus, the mean integrated area under the curve per 20 min above basal in the presence of 27.7 mM glucose was 6,516 +/- 1,435 pg, which was not significantly different from the value of 4,772 +/- 866 pg obtained during arginine perifusion. However, the area under the curve during 20 min above basal obtained in the presence of linoleate and linolenic acid (8,712 +/- 1,949 and 10,506 +/- 1,490 pg, respectively) were significantly different (P less than 0.05) from those calculated during arginine and glucose perifusions. There was no statistically significant difference between the effects of these two fatty acids at the concentrations tested. In conclusion, our data suggest that linoleic acid and linolenic acid may be, at least in this murine islet preparation, as effective in stimulating insulin release as glucose and arginine, hitherto used to assess the abilities of nutrients to stimulate insulin secretion. However, it remains to be seen whether the efficacy of these polyunsaturated fatty acids in insulin release by murine islets will be obtained in experiments performed on human islets.

Gastrocolic fistula complicating benign unoperated gastric ulcer. Report of four cases and review of the literature.

Of 957 patients undergoing operation for benign gastric ulcer and its complications from 1965 through June 1975, 90 had perforated ulcers. Among these were four patients in whom a gastrocolic fistula had formed. Although two of the four patients had symptoms due to peptic ulcer dating back 12 and 68 months, symptoms of a gastrocolic fistula were the initial presentation of ulcer disease in the other two. All four patients had watery diarrhea and weight loss, and barium enema examination was diagnostic in each case. The perforating ulcers were located in the distal stomach on the greater curvature in all four patients. Although enterostasis was not present in these cases, regurgitation of colonic contents probably results in bacterial overgrowth in the small intestine, causing structural and functional damage to the mucosal cells by bacterial products, manifested clinically by diarrhea in 75% of the patients. Surgery should be advised in all cases after adequate preparation of the patient; bowel preparation with cathartics, enemas, and oral antibiotics is mandatory. The preferred operation is one-stage enbloc hemigastrectomy and resection of the involved segment of colon along with the fistulous tract. The present series brings to 43 the total number of cases of gastrocolic fistulas complicating benign, previously unoperated gastric or duodenal ulcers. There is an appreciable mortality associated with this condition - 7 of these 43 patients (16%) died as a direct consequence of their fistula.

Dumbbell neurogenic tumors of the mediastinum. Diagnosis and management.

Among 706 collected cases of mediastinal neurogenic tumors were 69 patients (9.8%) with extension through an intervertebral foramen, so that the composite neoplastic mass was dumbbell-shaped. Although only 10% of these dumbbell tumors were malignant, the majority of the patients presented with neurologic symptoms of spinal cord compression. In about 40% of reported cases, the intraspinal component, although present, was not clinically apparent. Such cases of asymptomatic intraspinal extension should be suspected when special roentgenologic views of the spine demonstrate erosion of the vertebral pedicle or enlargement of the intervertebral foramen adjacent to the posterior mediastinal mass. Workup of these patients should include myelographic studies to determine whether a dumbbell tumor is indeed present; if it is, surgery should be carried out by a team of thoracic surgeons and neurosurgeons in a one-stage combined resection of both the intraspinal and the mediastinal component of the tumor. With early diagnosis and surgical intervention, long-term survival is the rule. When the patient is in the pediatric age bracket, an orthopedic surgeon should be included on the team to help minimize subsequent skeletal growth deformity.

"Conservative" versus "liberal" approach to parathyroid neck exploration.

Is the recent trend toward more radical parathyroid surgery justified? Surgical outcomes in three groups of 50 patients undergoing operation for primary hyperparathyroidism at the Mayo Clinic between January, 1974, and May, 1976, were compared. One group of patients was operated on by Surgeon A who used a "conservative" approach (removal of grossly enlarged glands only, with or without biopsy of one normal-sized gland). A second group was operated on by a Surgeon B, who used a more "liberal" approach (almost routine removal of at least two glands, removal of three and one-half glands when more than one gland was enlarged, and liberal use of biopsy identification). Symptomatic hypocalcemia requiring treatment occurred in 24% of patients after liberal neck exploration, as compared with 4% in the conservatively treated group. The liberal approach did not yield any higher cure rate. A third group of 50 patients was operated on by Surgeon B using the conservative approach. The incidence of postoperative hypocalcemia was reduced to 2%; one patient remained hypercalcemic. Symptomatic hypocalcemia, even if temporary, represents significant morbidity. A conservative approach to neck exploration in patients with primary hyperparathyroidism is recommended because it is associated with a very low incidence of temporary postoperative hypoparathyroidism (2 to 4%) and a high cure rate (99% in this series).

Neural control of gastrointestinal motility: evidence for noncholinergic regulatory influences.

Although it is well known that neural control of gastric motility occurs via sympathetic, parasympathetic, noncholinergic, and nonadrenergic fibers contained in the vagus nerve, the central sites of origin of these influences are largely unknown. Recent experiments in our laboratory indicate that noncholinergic neural pathways originating in the posterior hypothalamus can markedly influence gastric motility. At least 2 weeks prior to the experiment, mongrel dogs were surgically prepared with bipolar recording electrodes fixed to the serosal surface of the stomach. This prevented violation of the abdominal cavity on the day of testing. Experiments were performed with the animals under alpha-chloralose anesthesia (100 mg kg-1) in temperature-controlled settings. Under stereotactic guidance, bipolar stimulation of the posterior periventricular hypothalamus produced profound reproducible excitatory or inhibitory effects on gastric myoelectric and motor activity. Changes in the frequency and amplitude of pacesetter potentials (PPs) and in the incidence of action potentials associated with them were observed. Stimulation of various loci in 14 dogs resulted in a 71 +/- 7.5% increase in the incidence of action potentials associated with gastric PPs in "excitatory" areas (n = 7) and a 69.1 +/- 4% decrease in this ratio in "inhibitory" areas (n = 19). In general, more lateral stimulation produced greater inhibitory effects. Responses were frequency dependent, with a threshold greater than 25 Hz in most cases. Excitatory gastric responses to hypothalamic stimulation occurred despite full systemic atropinization (0.1 mg kg-1). The physiologic significance of these noncholinergic excitatory pathways influencing distal gastric motility and the neurotransmitters they employ are as yet unknown.

Surgical treatment of adenocarcinoma. Location: junction of the right, left, and common hepatic biliary ducts.

Thirty-eight patients with primary adenocarcinoma arising at the junction of the right, left, and common hepatic biliary ducts were seen at the Mayo Clinic, Rochester, Minn, between 1950 and 1976. Prompt and lasting relief of jaundice and cholangitis occurred in four patients undergoing resection of the tumor combined with left hepatic lobectomy, and their mean survival was 33 months. Relief of symptoms was only temporary in 26 patients treated with drainage of the biliary tree, and their mean survival was only ten months. Eight patients undergoing exploration only had no relief of symptoms, and none survived beyond four months. We conclude that resection of these tumors in selected patients gives good palliation and offers the chance of long-term cure. If resection is not possible, biliary decompression results in satisfactory palliation, whereas exploration only does not.

Radical pancreatoduodenectomy for cancer of the papilla of Vater.

Over a 22-year span, 87 patients with carcinoma of the papilla of Vater underwent radical pancreatoduodenectomy. No patient was lost to follow-up, and extended observation was possible in most cases: the definitive operation was at least five years earlier than this study in 87% and at least ten years earlier in 73%. Operative mortality was 11.5% among patients who had a single definitive operative procedure and 15.4% among those whose treatment involved reoperation after prior exploration elsewhere. Overall survival rates at two, five, and ten years were 56%, 34%, and 20% respectively. Factors associated with favorable survival were histologic differentiation (Broders grades 1 and 2), absence of nodal metastasis, and papillary histologic characteristics. Noteworthy is the fact that no patient having resection of an undifferentiated carcinoma (Broders grade 3 or 4) survived four years.

Pancreatic hormone response to neuropeptide Y (NPY) perifusion in vitro.

Available data on the effect of neuropeptide Y (NPY) on insulin release are conflicting and little data exist regarding the effect of NPY on glucagon secretion. The purpose of the present study, therefore, was to characterize the direct effect of NPY on the release of these pancreatic hormones and to examine the role of glucose on these interactions. Using a perifused mouse islet system, we found that NPY suppressed both basal and glucose-stimulated insulin secretion. Thus, basal insulin release assessed as mean integrated area under the curve/20 min (AUC/20 min) decreased from 1446 +/- 143 pg to 651 +/- 112 pg (P less than 0.05) with the addition of 2 x 10(-8) M NPY and the AUC/20 min for glucose stimulated insulin output decreased from 1973 +/- 248 pg to 1426 +/- 199 pg (P less than 0.05). In both cases, this inhibitory effect was followed after removing NPY by a stimulation of insulin secretion which was typical of a 'rebound off-response'. In contrast, NPY exerted a stimulatory effect on basal glucagon release and significantly reversed the suppressive effect of high glucose on glucagon output. The basal glucagon AUC/20 min increased from 212 +/- 103 pg to 579 +/- 316 pg (P less than 0.05), while glucagon secretion in the presence of 27.7 mM glucose increased from 75 +/- 26 pg to 255 +/- 28 pg (P less than 0.01). In conclusion, we have shown that the direct effect of NPY on the endocrine pancreas is to suppress insulin but stimulate glucagon secretion. These data are compatible with a role for NPY in the regulation of pancreatic hormone output.

Rectal ejaculation and prostatic carcinoma.

A case of carcinoma of the prostate causing fistulous communication between the rectum and the prostatic ducts is presented. The patient's initial symptoms included gradual onset of inability to ejaculate and the complaint of ejaculation per rectum. Appropriate urologic studies demonstrated a fistulous connection between the area of the ejaculatory duct and the rectum. Microscopic studies of rectal discharge confirmed that semen was exiting through his rectum. All genitourinary symptoms in patients with carcinoma of the prostate warrant thorough investigation.

Defective glucose-stimulated insulin release from perifused islets of C57BL/6J mice.

Previous work has shown that the C57BL/6J (BL/6) mouse strain develops type 2 diabetes after being fed a high-fat, high-simple carbohydrate (HFHSC) diet. In contrast, the AJ mouse strain does not. The aim of the present study was to determine if differences in the insulin secretory characteristics of isolated perifused islets of these animals could help explain why the BL/6 mouse develops diet-induced diabetes. Insulin secretion was assessed as mean integrated area under the curve during 20 min of stimulation with 27.7 mM glucose or 5 mM lauric acid. We found that both glucose- and laurate-stimulated insulin secretions were significantly less in euglycemic BL/6 mice than in the euglycemic AJ mice. The defect in insulin response to glucose, but not laurate, in islets from the BL/6 mouse was exacerbated when the animals were fed the HFHSC diet. These data suggest that the BL/6 mouse has a defective insulin response to glucose, which is exacerbated by a diabetogenic diet.

Anterior resection for adenocarcinoma of the distal large bowel.

Among 400 patients with adenocarcinoma of the distal large bowel, anterior resection resulted in more anastomotic leaks, postoperative urinary retention and diarrhea when used for lesions of the mid-rectum than when used for lesions of the proximal rectum or sigmoid colon. However, the operative mortality, long-term morbidity and 2 year survival were similar among patients with lesions at all three locations.

Effect of L-glutamine supplementation on impaired glucose regulation during intravenous lipid administration.

In contrast to L-glutamine, lipid emulsions are routinely administered to patients receiving nutritional support. The provision of fat during intravenous feeding is essential, but the potentially toxic byproducts of fatty acid oxidation may have adverse metabolic consequences. In the present study, we have examined the effect of L-glutamine, an inhibitor of fatty acid oxidation, on the development of defective blood glucose regulation caused by a 48-hour infusion of 10% intralipid in rats. Male Sprague-Dawley rats (200-290 g) were anesthetized with sodium pentobarbital, the right femoral vein cannulated, and baseline blood samples were taken. Each rat was placed in a metabolic cage with access to water, in the presence or absence of rodent chow. Two hours after waking, the rats were infused with 10% intralipid with either saline (control), 2% L-glutamine, or 2% L-alanine. After 48 hours, all animals were sacrificed and blood samples were again obtained. The mean +/- SEM plasma glucose levels before and after lipid infusion at the rate of 1 mL/hr in control rats fed ad libitum, were 125 +/- 13 and 170 +/- 5 mg/dL (p < 0.01, n = 7). Similarly, plasma free fatty acids (FFA) in these animals rose from 0.74 +/- 0.11 to 1.34 +/- 0.32 mmol/L (p < 0.05). Plasma insulin levels also increased from 337 +/- 44 to 1278 +/- 88 pg/mL (p < 0.01). Reduction of intralipid dose infusion did not prevent insulin resistance characterized by hyperglycemia and hyperinsulinemia. However, addition of L-glutamine to the high-dose lipid infusion with chow feeding prevented changes in plasma glucose, insulin levels, and FFA but not triglyceride levels. Also, glutamine but not alanine supplementation in intralipid infused rats without chow feeding prevented changes in plasma glucose, insulin, and malondialdehyde levels. In conclusion, these data show that glutamine supplementation during intravenous lipid administration in rats prevents the development of impaired glucose regulation associated with hyperlipidemia.

Painful palmar and plantar erythema associated with hepatic artery infusion of 5-fluoro-2'deoxyuridine.

Painful palmar and plantar erythema is an uncommon systemic complication of chemotherapy and has been reported in association with methotrexate, cystosine arabinoside, doxorubicin, and 5-fluorouracil. The authors report a case in which the syndrome was precipitated by hepatic artery infusion of 5-FUdR. The previous recommendation that treatment of patients developing painful palmar-plantar erythema from other drugs may be successfully resumed using intrahepatic arterial infusion of FUdR must be reconsidered in light of the present report.

Myoelectric and motor patterns of continent pouch and conventional ileostomy.

Our aim was to compare the myoelectrical and motor properties of the continent ileal pouch of 19 patients with those of the terminal ileum of six patients with Brooke ileostomy. The undistended ileum in both types of ileostomy exhibited pacesetter potentials at a mean frequency of 9.1 cycles per minute during fasting upon which were superimposed the cyclic bursts of action potentials and attendant contractions characteristic of the interdigestive state. Both types of ileostomy also accommodated to distention, with intraluminal pressure being kept low as the ileum filled. However, the amplitudes of the changes in intraluminal pressure present in the pouch were less than those present in the Brooke ileum both before and during distention, and the volumes to which the ileum could be distended were far greater in the patients with ileal pouches than in those with the Brooke ileostomy. Feeding did not alter the responses to distention of either type of ileostomy. We conclude that the electrical and motor patterns of the undistended ileum are similar in both types of ileostomy, but that the anatomic and motor properties of the pouch allow it to accept far larger intraluminal volumes both during fasting and after feeding.

Glutathione-mediated preservation and enhancement of isolated perifused islet function.

It has been shown that myocardial tissue function may be better preserved if antioxidants are incorporated into the reoxygenation medium at the end of the ischemic period following isolation of the organ. Although isolated pancreatic islets are prone to ischemic-reperfusion injury, it is not clear if antioxidants have a role in the preservation of their function. The purpose of the present study, therefore, was to examine the effect of the addition of glutathione (GSH) to a physiologic incubation medium on pancreatic islet response to glucose stimulation. Islets isolated by microdissection were preperifused at the rate of 1 ml/min for 1 hr at 37 degrees C, with Krebs-Ringer bicarbonate (KRB) buffer containing 1% albumin, 5.5 mM (basal) glucose without (control) or with 10 mM glutamine or 10 mN GSH and maintained at pH 7.4 by continuous gassing with 95/5% O2/CO2. After preperifusion, basal effluent samples were taken on ice for 20 min. The perifusion was then continued for 20 min with the KRB containing 27.7 mM glucose alone, followed by another 20 min of basal glucose washout. Solutions were changed using a stopcock and all effluent perifusate samples obtained were stored frozen at -20 degrees C until radioimmunoassay for insulin. Total insulin output in the control group increased from a basal 11.45 +/- 3.18 to 29.23 +/- 7.08 ng/6 islets/20 min (P < 0.001, n = 5) when the glucose concentration was raised to 27.7 mM. During a 20-min washout, insulin secretion was still significantly raised and did not return to the prestimulation basal rate. In the glutamine-treated islets, insulin output increased from 7.23 +/- 0.94 to 16.83 +/- 2.25 ng/6 islets/20 min (P < 0.001, n = 5) with 27.7 mM glucose stimulation and the significantly raised washout basal rate of secretion did not return to the prestimulation level. GSH treatment not only caused an enhanced 27.7 mM glucose stimulation (8.46 +/- 1.99 to 38.72 +/- 11.51 ng/6 islets/20 min, P < 0.001, n = 6) of insulin output but also completely restored the basal rate of insulin secretion to the prestimulation level within the 20-min washout perifusion. In conclusion, these data show that incubation of isolated islets with GSH enhanced their secretory response to glucose stimulation and preserved their functional integrity.

Splenectomy for primary and recurrent immune thrombocytopenic purpura (ITP). Current criteria for patient selection and results.

Of 565 patients with thrombocytopenia admitted to Duke University Hospital between 1975 and 1985, 100 had splenectomy. Ninety-eight patients had failed chronic immunosuppressive therapy and three patients had acute intracranial bleeding or total absence of platelets in the peripheral blood smear, and had urgent splenectomy. At primary splenectomy, accessory spleens were identified and resected in 18% of patients. There was no operative mortality. Fifty-eight patients had an excellent response to splenectomy and their steroids were tapered off within 3 weeks. Thirteen patients had a poor response to primary splenectomy of whom eight remitted spontaneously and five required accessory splenectomy resulting in complete remission in three patients. Twenty-nine patients were considered nonresponders, 25 of whom had radionuclide scanning for accessory spleens. Seven of these patients had accessory spleens identified but only four consented to accessory splenectomy. In three of the four patients, a complete remission was achieved. Neither platelet antibody titers nor measurements of platelet survival or turnover predicted platelet response to splenectomy. However, immune thrombocytopenic purpura (ITP) in older patients was significantly less likely to respond to splenectomy. These data support continuing use of splenectomy in selected patients with ITP and an aggressive search for accessory spleens in patients who relapse since they are easily localized at operation by hand-held isotope detector probe.

A reversible enteropathy complicating continuous hepatic artery infusion chemotherapy with 5-fluoro-2-deoxyuridine.

This article describes two patients with hepatic metastases from colorectal cancer in whom a reversible enteropathy developed during the administration of hepatic artery infusion chemotherapy with 5-fluoro-2-deoxyuridine (5-FUdR) via an Infusaid Series 400 pump (Infusaid Corp., Sharon, MA). Both patients had severe diarrhea and signs that suggested small bowel obstruction. Barium studies revealed a distinctive radiologic appearance of severe narrowing of the ileum associated with complete loss of normal mucosal patterns. Results of an extensive evaluation for an infectious or toxin-related enterocolitis were negative. Perfusion studies confirmed the appropriate position of the catheters and revealed no extrahepatic perfusion. Systemic shunting of the 5-FUdR through the liver or tumor bed is postulated as the primary event, with the small bowel manifesting the major toxicity.

Computed tomographic detection of gas within spontaneously necrotic tissue.

Computed tomography (CT) is a widely accepted modality for the detection, localization, and potential therapeutic drainage of abdominal abscesses. The CT demonstration of extraluminal gas within the abdomen usually signifies the presence of an abscess. We report two cases of nonpurulent spontaneous tissue necrosis which simulated a gas containing abscess on CT. The significance of a gas-containing mass detected by CT must be interpreted cautiously since this appearance is not necessarily pathognomonic of a drainable abscess. Confirmation of purulent material within a suspected abscess collection requires documentation by percutaneous aspiration or surgery.