Biomedical subjects
Publications and source records attributed to M S Nussbaum.
Duplications of the genitourinary tract are uncommon and may be a source of confusion in the early diagnosis of ureteral trauma when their presence is not suspected. We present a case of delayed diagnosis of a penetrating injury to a duplicated ureter and its management.
The hepatic toxicity of TPN that is seen clinically appears to be multifactorial in origin. Most patients develop a combination of hepatic steatosis with evidence of cholestasis and abnormalities in liver function. The model that we have studied is one of pure hepatic steatosis since, on repeated study, these rats do not develop any liver function abnormalities. It is unclear whether this is related to the fact that these are short-term experiments, that rat livers respond differently from humans, or that rats do not have gallbladders. It has not been possible to carry these experiments out beyond 3 weeks since the rats develop bacterial colonization of the central lines as well as evidence of line sepsis. thus confounding the issue of hepatic toxicity being due to the TPN or to sepsis. One hypothesis is that hepatic steatosis is an early marker of liver toxicity and that prevention or reversal of hepatic steatosis may protect the liver from further abnormality. Insulin and glucagon seem to play a critical role in the development of TPN-associated hepatic steatosis. Specifically, an elevated portal venous insulin-glucagon molar ratio appears to be the primary stimulus and any treatment that lowers this ratio should diminish hepatic steatosis. The use of glucagon as a treatment modality is new. We have found no evident side effects of low dose glucagon in rats when it is added to the TPN solution. Glutamine has received much attention recently as a nutritional pharmacological agent in ameliorating some of the intestinal complications of parenteral nutrition and is well tolerated when administered appropriately. Intravenous lipid administration is an important nonprotein calorie source, especially when a high dextrose base cannot be used, and plays a role as well in preventing the development of hepatic steatosis. Thus, it is suggested that the clinical treatment of hepatic steatosis during TPN can be safely performed using any one, or a combination, of these modalities and without having to discontinue the TPN infusions. Since we observed no deterioration of liver function in rats receiving TPN for up to 2 weeks, we cannot completely relate these findings and recommendations to the hepatic dysfunction seen clinically with the use of TPN. Additional study will be required before this can be conclusively determined.
Infusion of total parenteral nutrition (TPN) with excess carbohydrate calories leads to hepatic steatosis in rats and is associated with an elevated portal insulin/glucagon molar ratio. Previously we have shown that adding glucagon to TPN prevents and reverses hepatic steatosis in rats, possibly by increasing hepatic lipid export. It has been reported that steatosis is eliminated in rats by the addition of L-glutamine to TPN. In this study, we examined the effect of glutamine on portal insulin and glucagon levels and the development of hepatic steatosis. Adult rats (n = 19) received internal jugular catheters: Group 1 (n = 6), saline (3 cc/hr) and chow ad libitum; Group 2 (n = 7), 25% dextrose base TPN; Group 3 (n = 6), 25% dextrose base TPN with 2% glutamine. The infusion rate of TPN was 1.2 cc/100 g body wt/hr. Daily nitrogen balance was determined and at 7 days, portal venous blood was drawn for insulin and glucagon radioimmunoassay, livers were removed for histology and lipid content determination, and the small intestines were removed for mucosal protein and DNA content determination. Panlobular vacuolization of the hepatocytes was noted on histology in Group 2 (TPN) while Group 1 (chow) and Group 3 (TPN + glutamine) showed normal liver morphology. Hepatic lipid content was significantly elevated in Group 2 (P less than 0.05). The portal insulin/glucagon molar ratio was increased because of excessive portal venous insulin in Group 2 (TPN). In contrast, portal glucagon was significantly elevated while the insulin/glucagon ratio and hepatic lipid content did not increase above control levels in the glutamine-supplemented Group 3 rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Peptide YY (PYY), a homolog of pancreatic polypeptide, has been shown to be released after stimulation of colonic mucosa with bile and fatty acids. In this study proximal jejunal and biliary involvement in the regulation of circulating PYY and the distribution of PYY-containing cells in rat intestine was evaluated. Six rats underwent proximal jejunal bypass, six rats had Roux-en-Y cholangiojejunostomies, and six sham-operated rats were used as controls. Three months after surgery feeding studies using either a mixed meal or a pure fat meal were performed in unanesthetized animals and venous blood was collected for plasma PYY radioimmunoassays. After the feeding studies, fresh specimens were taken from multiple areas of the intestine for immunohistochemical analysis. The surgical procedures did not significantly affect basal PYY plasma levels. Both mixed and fat meals significantly increased circulating PYY in control animals. Exclusion of the proximal jejunum resulted in inhibition of postprandial PYY release. The PYY response in rats with Roux-en-Y cholangiojejunostomies was blunted after a mixed meal and delayed after a fat meal. The incidence of PYY-containing cells increased along the functional gut in all rats. The bypassed jejunum in both experimental groups of animals contained fewer PYY-staining cells than sham-operated rats. Our results suggest that the exclusion of a segment of proximal jejunum from gastrointestinal continuity in rats leads to an inhibition of postprandial PYY release. PYY release may be controlled in part by stimulatory neural and/or endocrine signals originating from the proximal jejunum.
Neuropeptide Y (NPY), a 36-amino-acid peptide, was measured in the peripheral circulation and ileal lumen of conscious dogs using a sensitive radioimmunoassay. Fasting NPY concentrations averaged 448 +/- 15 pg/ml in the peripheral blood and 364 +/- 23 pg/ml in the ileal effluent. Following a mixed meal, circulating NPY levels rose to 499 +/- 37 pg/ml (P less than 0.05), whereas recoverable quantities of ileal intraluminal NPY fell to 257 +/- 19 pg/ml (P less than 0.05). Neither fat nor glucose meals significantly changed circulating or ileal intraluminal NPY recovery. These results demonstrate release of NPY into the blood and ileal lumen for the first time and support NPY as a candidate gut hormone.
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The objective of this study was to investigate the roles of the proximal jejunum and endogenous bile within the proximal jejunum on the enteroinsular axis. Twelve Sprague-Dawley rats underwent proximal jejunal bypass, 11 rats underwent Roux-en-Y cholangiojejunostomies, and 12 rats underwent sham operations. After 3 months, oral glucose tolerance tests were performed in unanesthetized animals and venous blood was collected for plasma glucose and insulin measurements. The surgical procedures did not significantly affect the basal glucose and insulin levels compared with sham-operated animals. The insulin response in rats with excluded proximal jejunal segments was inhibited. The decreased insulinogenic index seen in these animals indicates a possible diabetogenic effect of this procedure. An oral glucose challenge resulted in significant hyperinsulinemia, with an increased insulinogenic index in animals that had undergone Roux-en-Y cholangiojejunostomies. These findings suggest that bile is a potential mediator in the proximal jejunal involvement in the enteroinsular axis.
Neuropeptide Y (NPY) is a 36 amino acid peptide amide isolated from porcine brain. The NPY analog, 4-norleucine-NPY was synthesized by a solid-phase method and purified to homogeneity in 20% yield by reverse-phase chromatography. Investigation of the biological properties indicated that the analog is an agonist of NPY. Secondary structural analyses revealed that NPY and the analog exhibited predominantly alpha-helical and beta-sheet structures, respectively; however, experiments in trifluoroethanol indicated that the analog has the potential of assuming an alpha-helical structure. Based on circular dichroism (CD), Raman spectroscopy and Chou-Fasman analyses, a model has been proposed for the secondary structure of NPY.
We examined 29 patients without stone disease or pancreatic ductal ectasia who underwent transduodenal sphincteroplasty and transampullary septotomy for symptoms of biliary colic or pancreatitis. The combination of biliary symptoms and a fibrotic ampulla of Vater portends a favorable surgical outcome in virtually all such patients. Patients with pancreatitis did worse overall, perhaps due to the existence of unappreciated subclinical parenchymal disease not related to sphincter dysfunction. Although endoscopic retrograde cholangiography was sensitive in demonstrating abnormalities of the pancreaticobiliary system, its specificity as a predictor of good results was poor. It seems prudent to temper one's enthusiasm for sphincteroplasty in the patient with pancreatitis, whereas patients with biliary symptoms, the postcholecystectomy syndrome, or both will usually benefit significantly from this procedure.
Infusion of total parenteral nutrition (TPN) with excess carbohydrate calories leads to hepatic steatosis in rats that is associated with an elevated portal insulin/glucagon molar ratio. Previously we have shown that adding glucagon to TPN prevents hepatic steatosis in rats. In this study we attempted to reverse the steatosis by adding glucagon to TPN after 1 week of TPN alone. Adult rats (n = 28) received internal jugular catheters: Group 1 (n = 7), saline (3 cc/h) and chow ad libitum; Group 2 (n = 7), 25% dextrose base TPN solution for 1 week; Group 3 (n = 7), 25% dextrose base TPN for 2 weeks; Group 4 (n = 7), 25% dextrose base TPN for 1 week and then glucagon (15 micrograms/100 g/day) added to TPN for the second week. The infusion rate of TPN was 1.2 ml/100 g/hr (40% kcal greater than control). At 7 days (Group 2) and 14 days (Groups 1, 3, and 4) portal and peripheral venous blood levels were drawn for insulin and glucagon radioimmunoassay, blood glucose determination, and liver function tests; livers were removed for histology and lipid content determination. Blood glucose was equivalent among all groups. Liver function tests were within normal limits. Panlobular vacuolization of the hepatocytes was noted on histology in Groups 2 and 3. Hepatic lipid content was significantly elevated in Group 3. The portal insulin/glucagon molar ratio was increased because of excessive portal venous insulin in Groups 2 and 3 (P less than 0.05 by ANOVA). In contrast, portal venous insulin and the insulin/glucagon molar ratio did not increase in Group 4 and hepatic lipid infiltration was absent when glucagon was added to the TPN solution after 1 week of TPN solution alone. The results suggest that the addition of glucagon to hypertonic dextrose TPN is not only protective in preventing hepatic steatosis, but may reverse steatosis, possibly by increasing hepatic lipid export.
Peptide YY (PYY) is a recently discovered polypeptide found in the endocrine cells of the distal small intestine, colon, and rectum. This study was designed to evaluate the postprandial release of PYY into the peripheral blood and the ileal lumen in response to different ingested nutrients. Six adult conditioned mongrel dogs had 25-cm distal ileal Thiry-Vella segments surgically constructed. After a 2-week postoperative recovery period the animals were fed meals consisting of protein (2 g/kg), fat (5 g/kg), or glucose (1.5 g/kg). Circulating and ileal intraluminal PYY concentrations were measured by a sensitive radioimmunoassay developed in our laboratory. Significant increases in circulating PYY levels were seen only after the fat meal in dogs. Ileal intraluminal PYY concentrations were significantly greater than those concentrations seen in the peripheral blood. A significant rise in ileal intraluminal PYY was seen only after the glucose meal without concomitant changes in circulating PYY. These findings document independent release mechanisms of PYY into the circulation and ileal lumen of the awake dog. We believe that the release of PYY into the canine circulation and into the ileal lumen after feeding may be dependent on the type of nutrient ingested and may serve to regulate the diverse physiologic roles of PYY in the gastrointestinal tract.
A specific, precise and sensitive double-antibody radioimmunoassay for Neuropeptide Y (NPY) has been developed. There was no appreciable cross-reactivity with the structurally related peptides, peptide YY (PYY) and pancreatic polypeptide (PP). The minimum detectable plasma NPY level was 3 nM. Application of radioimmunoassay to canine models revealed that portal and systemic NPY levels increased significantly following a standard meal.
Hepatic steatosis is an ongoing problem in total parenteral nutrition (TPN). The etiology of this deranged hepatic morphology is unclear, but lack of enteral stimulation and excess carbohydrate calories have been suggested as altering the intestinal hormone profile. In this study, adult male Sprague-Dawley rats (n = 28) received internal jugular catheters: group 1 (n = 7) received saline (3 cc/hr) and chow ad libitum; groups 2, 3, and 4 (n = 7) received 15, 20, and 25% dextrose-base TPN solutions, respectively, in quantities matching the caloric intake of paired ad libitum animals. At 7 days portal and peripheral venous blood samples were drawn for insulin and glucagon radioimmunoassay, and livers were removed for histologic examination and determination of total hepatic lipid content. Portal and peripheral insulin levels rose in a linear fashion with increasing dextrose concentration. Lipid content increased with elevated portal venous insulin/glucagon ratio in groups 3 and 4. Periportal fatty infiltration increased with increasing dextrose concentrations. The results suggest that the liver's response to altered portal insulin/glucagon ratio may play an important role in changes of hepatic morphology associated with TPN.
Hepatic steatosis is one of the two principal hepatic complications of total parenteral nutrition (TPN), the other being cholestasis. While the cause is uncertain, an excess of carbohydrate calories in rats leads to an elevated portal insulin/glucagon (I/G) molar ratio, periportal fatty infiltration, and increased total hepatic lipid content. Insulin causes fatty acid biosynthesis, whereas glucagon causes hepatic release and inhibition of fatty acid synthesis. Thus we attempted to add glucagon to lower the I/G to see if this would affect the degree of hepatic fatty infiltration by encouraging hepatic fat mobilization. Adult rats (n = 21) received internal jugular catheters; Group 1 (n = 7) was given saline solution (3 ml/h) and chow ad libitum; Group 2 (n = 7), 25% dextrose-base (D25W) TPN solution; Group 3 (n = 7), D25W TPN + 33 micrograms/100 gm/day glucagon. At 7 days portal and peripheral venous blood samples were drawn for insulin and glucagon radioimmunoassay and blood glucose determination; livers were removed for histologic study and lipid determination. Blood glucose did not differ in any group. Hepatic lipid and peripheral and portal venous I/G were increased and periportal fatty infiltration was extensive in Group 2, whereas hepatic lipid and I/G were decreased and periportal fatty infiltration was absent in glucagon-infused rats (Group 3). An abnormally high I/G ratio in portal blood elicited by high-glucose TPN may be responsible, at least in part, for hepatic steatosis. By increasing hepatic lipid export, addition of glucagon to TPN may play a major role in decreasing hepatic steatosis.
A series of 27 patients with generalized myasthenia gravis is presented. All patients were treated by a sternal split and extended thymectomy and radical mediastinal dissection. The overall drug-free remission rate was 63%, although three additional patients are likely to achieve drug-free remission in the near future, with the total drug-free remission rate then being 74%. Of the remaining patients, all but three improved and require decreased medication, for an improvement rate of approximately 90%. One patient who has not improved had an invasive malignant thymoma. Drug-free remission was achieved in 46% of the male patients and in 82% of the female patients despite that the mean duration of disease was greater than 3.5 years. There was one serious complication, that of sterile sternal dehiscence. There was no mortality. The results suggest that an aggressive, radical surgical approach to myasthenia gravis, even in a group of patients considered somewhat less favorable because of a relatively long duration of disease, can result in a high percentage of drug-free remissions. Radical surgery for myasthenia gravis appears to be the treatment of choice, with medical therapy being reserved for those patients who are not likely to survive operation.
Giant duodenal ulcer is a variant of peptic ulcer that is 2 cm in diameter or greater and essentially replaces the duodenal bulb. Diagnosis by upper gastrointestinal series is often missed, due to the large size of the ulcer, which causes it to look like a scarred duodenal bulb or duodenal diverticulum. This study reviews our experience with 32 patients who presented with giant duodenal ulcer between 1963 and 1982. Seventy-five percent of the patients were men between 30 and 81 years of age (mean age 59 years). Gastrointestinal hemorrhage was a presenting symptom in 75 percent of the patients and free perforation in 9 percent. Diagnosis was made by upper gastrointestinal series (24 patients), and endoscopy (11 patients), alone or in combination. Three patients were diagnosed at surgery and one at necropsy. Mean size of the ulcer was 3.5 cm in diameter, range 2 to 6 cm. Twenty-four patients were initially managed medically (mean length of treatment 41 months), with 2 deaths (hemorrhage) and 20 recurrences (83 percent). Twenty-seven operations were required in 25 patients. In 17 of the 25, medical treatment had failed. Seven of these patients required emergency surgery. Eight patients were managed primarily by surgery, of whom five presented emergently. There were three deaths in the surgical group after emergency surgery. In two of these patients, medical treatment had failed. There were no deaths among the elective surgery group. Twenty-five of the 27 operative procedures were definitive, acid-reducing operations (15 vagotomy and antrectomy and 10 vagotomy and drainage). Two patients underwent emergency exploration and oversewing of a giant perforated ulcer alone, and both patients required subsequent surgery because of symptoms. The results indicate that giant duodenal ulcer should be primarily surgically managed and that an acid-reducing procedure should be performed during primary surgery. These patients do very poorly with medical therapy, and the mortality rate is increased if emergency surgery is required for hemorrhage. Medical treatment alone is associated with a high morbidity (92 percent). Should operation be required, a definitive acid reduction operation is the procedure of choice.
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