Biomedical subjects
Publications and source records attributed to S E Steinberg.
This article reviews the history of and the authors' experience with endoscopic management of pancreatic pseudocysts. Discussion includes pseudocyst enterostomy and results, the transpapillary method, complications, endoscopic versus surgical and percutaneous therapy, and drainage of infected pseudocysts and pancreatic necrosis.
Intraductal papillary-mucinous tumor (IPMT) of the pancreas is a premalignant lesion that can result in the hypersecretion of mucous and subsequent pancreatitis. In this report, one of the youngest cases of IPMT is described. Initial pancreaticogram was normal. Pathognomonic changes of the pancreatic duct were found only years later; otherwise, the recurrent pancreatitis seen in this patient might have been repeatedly misdiagnosed as idiopathic. Pre- and perioperative evaluation resulted in pancreaticoduodenectomy for what was felt to be a curative resection. However, the patient suffered an aggressive metastatic course. More extensive surgery may be needed in IPMT, such as total pancreatectomy, especially in cases of diffuse ductal dilation of the pancreas.
BACKGROUND: Although ERCP is commonly performed in children, the effect of findings at ERCP on the subsequent management of pediatric pancreatitis is unknown. METHODS: We retrospectively reviewed charts to determine the impact of ERCP on the management of recurrent acute or chronic pancreatitis in 17 consecutive children (3 boys and 14 girls, 3 to 16 years, mean 11.2 years) with recurrent acute (n = 13) or chronic pancreatitis (n = 4) who underwent ERCP. Radiographs were reviewed in a blinded manner, and the effect of ERCP findings on subsequent management was determined. RESULTS: In 16 of 17 patients (94%), the pancreatic duct was successfully visualized. Of the 16 studies, 9 (56%) had abnormal findings. A change in therapy occurred in all 9 patients as a result of the findings at ERCP. Of the 7 patients with a prior abnormal CT or ultrasound, 5 (71%) had an abnormal ERCP, all resulting in a change in therapy. Three of the 9 patients (33%) without radiographic abnormalities had an abnormal ERCP that, in each case, resulted in a change in therapy. Overall, findings at ERCP altered therapy in 52% of pediatric patients studied with recurrent acute or chronic pancreatitis. A prior abnormal CT had a high predictive value with respect to ERCP resulting in a change in management (83%). CONCLUSIONS: ERCP is useful in the management of pediatric recurrent acute or chronic pancreatitis; abnormalities are found at a rate similar to those found in adults.
Cholecystectomy in patients with advanced cirrhosis is associated with excessive morbidity and mortality. Symptomatic cholelithiasis in patients awaiting orthotopic liver transplantation poses unique management issues. Three patients with end-stage liver disease, severe enough to warrant hepatic transplantation, developed symptoms and complications of cholelithiasis requiring intervention. Each underwent placement of a biliary stent from gallbladder to duodenum at endoscopic retrograde cholangiopancreatogram. In each case, biliary symptoms and complications ceased after stent placement. Two patients remained symptom-free until they underwent successful liver transplantation, and the third awaits transplant and is currently free of symptoms of cholelithiasis. Endoscopic placement of gallbladder stents represents a temporizing alternative for the management of patients with symptomatic cholelithiasis awaiting hepatic transplantation.
A 12-year-old male with acute lymphocytic leukemia received donor bone marrow from his histocompatible father whose marrow was harvested 40 minutes postmortem after he suffered a myocardial infarction. The marrow was stored in liquid nitrogen for 17 days prior to infusion into the recipient. Trypan blue viability was greater than 99% for the fresh marrow. Progenitor cell assays revealed that 20% of the CFU-MIX, 16% of the BFU-E, 10% of the CFU-E, and 17% of the CFU-GM were spared during the cryopreservation period. Posttransplantation, the recipient had a leukocyte count greater than 10(3)/microL by day 26. Southern blotting analysis documented the donor origin of the peripheral blood mononuclear cells and granulocytes isolated 46 days posttransplantation. Unfortunately, the patient died of complications relating to graft-v-host disease 67 days following transplantation. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells and is the first reported case of documented leukocyte engraftment in a recipient of cadaveric marrow.
Detailed studies to analyze the early events of erythropoietin (Ep) secretion and clearance were performed in a rat model using a double antibody radioimmunoassay. Ep clearance was determined following intravenous injection of 1 mL of Ep-rich plasma, 1,080 mU/mL, obtained from phlebotomized rats. Analysis revealed a disappearance curve that conformed to a two-compartment model with an alpha half-life t1/2 of 3.6 minutes and a beta t1/2 of 86 minutes. The volume of distribution was similar to the calculated plasma volume. In anephric animals, there was no change in the plasma clearance rate or the volume of distribution. Rapid Ep secretion was elicited by a single 15 mL/kg phlebotomy (hematocrit decrement 45% to 30%), so that levels reached 20 to 30 times baseline (524 +/- 76 v 24 +/- 7 mU/mL) at five hours, whereas they plateaued for at least 33 hours. The increase in the rate of secretion was geometric, from 9.9 mU/h baseline secretion to 429 mU/h. These data identify a very sensitive and rapidly responsive system for Ep modulation in the rat.
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The requirements for factor VIII (AHF) or factor IX (PTC) of hemophilic patients undergoing dental extractions were evaluated to determine the minimum effective regimen. Sixteen patients underwent 19 operative procedures. The mean total dose of factor VIII or IX was 45.8 U/kg for 11 procedures with preoperative replacement therapy and 34.5 U/kg for the 8 without. Four patients received no replacement therapy at all. Our results compared favorably to published studies employing factor replacement alone or in combination with antifibrinolytic agents such as epsilon-amino-caproic acid (EACA), with respect to blood products utilized and duration of hospitalization. However, our patients received less factor replacement than usually suggested. General anesthesia with intubation, a common recommendation, was not required in any patients. Dental extractions can be carried out in hemophiliacs using less replacement therapy than currently recommended. In some circumstances, no replacement therapy may be necessary. The reported efficacy of antifibrinolytic agents in reducing the requirement for replacement therapy is difficult to assess because of the relatively large amount of prophylactic factor replacement used in conjunction with these agents.
Recent work has provided information that allows the delineation of the mechanisms by which folate homeostasis is maintained. Dietary folates are converted to monoglutamates in the gut, absorbed by an active process, and distributed to tissues by the enterohepatic cycle, possibly utilizing folic acid binding proteins. During short periods of dietary deprivation, supply is maintained in the monoglutamate pools in the enterohepatic cycle as well as within cells. A net increase in available folate results from a decrease in tissue uptake and in subsequent polyglutamate synthesis, coupled with a fixed rate of conversion of polyglutamate to monoglutamate and release from the cell. The liver exerts substantial regulatory effect because of its mass, relatively rapid folate turnover, and the large folate flux through the enterohepatic cycle. In addition, there is a substantial, if more long-term, contribution from tissues that die and release folates (e.g., red blood cells), and a pathway exists that is capable of salvaging this folate and returning it to the liver for subsequent redistribution to actively proliferating cells.
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In order to study the generation, factors controlling endogenous folate pools, and their functional importance, Friend erythroleukemia cells were grown in media containing 100; 1,000; and 10,000 ng/ml of tritiated pteroylglutamic acid (3H)PteGlu1 and then studied in unlabeled media with varying amounts of PteGlu1. The intracellular folate pool was directly proportional to the PteGlu1 in which the cells were incubated. At equilibrium, greater than 95% of the labeled intracellular folate pool chromatographed as polyglutamyl folate, regardless of the exogenous folate concentration. The functional importance of the intracellular folate pool was studied by varying the endogenous pool and the exogenous (media) supply. The ability of the cells to replicate in the absence of exogenous folate was directly proportional to the intracellular polyglutamyl folate pool. The maximal rate of replication, however, required exogenous PteGlu1 in addition. The cell doubling time was the most important determinant of intracellular folate turnover; changes in the intracellular pool size and the extracellular folate concentration had no effect on the turnover time. In a rapidly proliferating tissue, the onset of functional folate deficiency will be determined by dilution of intracellular polyglutamates among progeny until a critical level is reached.
To trace the development of folate-deficient abnormalities of morphology and DNA synthesis, Friend erythroleukaemia cells were grown in media containing 10(2), 10(3) and 10(4) ng of [3H]PteGlu1/ml and then transferred to folate-free media. Parameters examined were: intracellular folate levels; growth potential; morphology; dU suppression; and DNA content by flow microfluorimetry. The most sensitive indicators of folate-deficient cell growth were those related to DNA synthesis (dU and flow microfluorimetry). These became abnormal at intracellular folate levels of 0.2-0.5 ng/10(6) cells and markedly so below 0.1 ng/10(6) cells. Morphological criteria were less sensitive. Cells became megaloblastic at intracellular folate levels below 0.06 ng/10(6). The capacity of the cells to replicate in folate-free media was a function of the intracellular folate (ICF): duplications = 4.01 + ln(ICF)/0.67 (r = 0.993, P less than 0.001). These studies demonstrate that regardless of initial intracellular folate levels, cellular stigmata of folate deficiency appear when cellular folate falls below 3 X 10(5) molecules per cell (dU and flow microfluorimetry) and cells lose the capacity for further replication below 7-10 X 10(5) molecules. The intracellular folate level not only predicts early defects, but also determines the replicative capacity.
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The importance of the folate enterohepatic cycle in governing the supply of folate to implants of a rapidly-growing tumour were studied in a new animal model. Following enteric administration of tritiated pteroylglutamic acid, [3H]PteGlu1, tumour uptake of labelled folate was limited to CH3[3H]H4PteGlu1 produced by the gut mucosal cells during absorption or subsequently recirculated through the enterohepatic cycle. 50% of the labelled folate reaching the tumour nodules in the first 6 h after enteric administration first circulated through the enterohepatic cycle. In addition, labelled folate taken up by tumour was immediately incorporated into a polyglutamyl folate pool. There was no evidence for a release of labelled folate from tumour for recirculation to the liver. Therefore the liver and folate enterohepatic cycle appear to play a major role in regulating the supply of folate to rapidly proliferating tissues such as tumour by acutely storing folate from the diet and then secreting it into bile for reabsorption and transport to tissue.
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The pharmacokinetics of the methotrexate enterohepatic cycle were studied in rats in vivo. For plasma levels of methotrexate between 10(-5) and 10(-8) M, biliary levels were directly proportional and concentrated 27-fold. When labeled methotrexate was administered in doses sufficient to achieve plasma levels of 10(-6) M, approximately 50% of methotrexate appeared in the bile in normal animals and up to 80% appeared in anephric animals. In spite of the high percentage of administered methotrexate which appeared in the bile, complete interruption of the enterohepatic cycle in otherwise normal animals did not affect the plasma decay curve of a bolus of methotrexate. The increased biliary excretion which occurred in animals with renal impairment was utilized with possible therapeutic implications. Bile drainage in these animals rapidly decreased plasma methotrexate levels compared to nondrained controls. This suggests that interruption of the methotrexate enterohepatic cycle may provide an alternative for the management of methotrexate toxicity associated with renal insufficiency.
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