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Biomedical subjects

E M Copeland

Publications and source records attributed to E M Copeland.

At least 19 recordsLinked to original sources
PubMed1992

Cytokine regulation of intestinal glutamine utilization.

The effects of cytokines on intestinal glutamine metabolism were studied to gain further insight into the regulation of altered glutamine metabolism that occurs during severe infection. One hundred thirteen adult rats were given a single dose of interleukin-1 (IL-1, 50 micrograms/kg), tumor necrosis factor (TNF, 50 micrograms/kg or 150 micrograms/kg), or saline (controls), and flux studies were performed 4 or 12 hours later. Intestinal blood flow was not different between control and cytokine-treated animals at either time point. At the 4-hour time point, arterial glutamine fell by 16% to 21% in the cytokine-treated animals (p less than 0.05); at the 12-hour time point, the arterial glutamine concentration had returned to normal. Intestinal glutamine extraction decreased in the animals treated with IL-1 at both time points (4 hours: 13% +/- 1.3% in IL-1 versus 20% +/- 1.6% in controls, p less than 0.05; and 12 hours: 9% +/- 2% in IL-1 versus 17% +/- 2% in controls, p less than 0.05). Consequently, net intestinal glutamine uptake fell in the animals treated with IL-1 at both time points (p less than 0.05). Similarly, the activity of mucosal glutaminase, the principal enzyme of glutamine hydrolysis in the gut, fell by 50% in the 4-hour study (6.1 +/- 0.6 mumol/h/mg protein in IL-1 versus 9.6 +/- 0.8 mumol/h/mg protein in controls, p less than 0.01) and by 40% in the 12-hour study (5.4 +/- 0.5 mumol/h/mg protein in IL-1 versus 8.8 +/- 0.4 mumol/h/mg protein in controls, p less than 0.05). Concomitant with the aforementioned decrease in gut glutamine metabolism was a 25% incidence of positive blood cultures for gram-negative organisms in IL-1 treated rats studied at the 12-hour time point (p = 0.05 versus controls). In the doses administered and at the time points studied, TNF had no effects on the parameters of gut glutamine metabolism examined. The results indicate that IL-1 is a potential mediator of the alterations in gut glutamine metabolism observed in sepsis and endotoxemia.

Animals↗
PubMed1992

The early response of the jejunal brush border glutamine transporter to endotoxemia.

The early effects of endotoxin (4 hr after a single dose of Escherichia coli LPS, 7.5 mg/kg) on L-glutamine (GLN) transport across the jejunal brush border of rats were studied. Jejunal brush border membrane vesicles (BBMVs) were prepared by a Mg2+ aggregation/differential centrifugation technique. Vesicle purity and integrity were confirmed by a 15-fold enrichment of brush border marker enzymes, osmotic activity, transport overshoots in the presence of sodium, and similar 1- and 2-hr equilibrium values. L-[3H]GLN transport in jejunal BBMVs was measured by a millipore filtration technique. Na(+)-dependent glutamine transport, which accounted for greater than 80% of total transport, was increased twofold in BBMVs from endotoxin-treated rats (67 +/- 5 pmole/mg protein/15 sec vs 38 +/- 3, P less than 0.01). Endotoxin treatment did not alter the activity of the Na(+)-independent carrier. Simultaneously, intestinal extraction of glutamine from the bloodstream fell by 56% (15.1 +/- 2.3% in controls vs 6.6 +/- 1.3% in endotoxin-treated rats, P less than 0.01). This reduction in the uptake of circulating glutamine could not be accounted for by a fall in the arterial concentration. Thus, soon after endotoxemia brush border glutamine uptake is increased while consumption of glutamine across the basolateral membrane is decreased. This increased uptake may support protein synthesis and may provide a biochemical rationale for the use of early enteral nutrition after the onset of critical illness.

Animals↗
PubMed1992

Mechanisms of accelerated hepatic glutamine efflux in the tumour-bearing rat.

The mechanisms potentially controlling the net release of glutamine by the liver that occurs in tumour-bearing rats were investigated. Studies were undertaken when the tumour comprised approximately 7% (15 +/- 2 g) of total body weight. Hepatic glutamine gradient ratios were calculated by dividing hepatic glutamine content by arterial blood glutamine concentration. Both sodium-dependent and sodium-independent hepatocyte carrier-mediated glutamine transport were evaluated employing hepatic plasma membrane vesicles (HPMVs). In TBR the hepatic glutamine gradient ratio doubled (P < 0.001) secondary to a 52% increase in hepatic content (P < 0.005) and a 16% decrease in circulating glutamine (P < 0.001). Sodium-dependent glutamine transport was increased in HPMVs from TBR secondary to a 24 +/- 4% increase in the maximal velocity of transport (Vmax; P < 0.01) without alteration in apparent transporter affinity (Km). Saturable sodium-independent carrier-mediated glutamine transport was increased in HPMVs from TBR over CONT to a much greater relative degree owing to a 2.7-fold increase in transport Vmax (P < 0.05) without a change in transport Km. The accelerated hepatic efflux of glutamine which characterizes malignant growth appears to be the result of both mass-action gradient phenomena and alterations at the level of hepatocyte membrane transport activity.

Animals↗
PubMed1992

Cytokine modulation of Na(+)-dependent glutamine transport across the brush border membrane of monolayers of human intestinal Caco-2 cells.

Previous studies have demonstrated that Na(+)-dependent brush border glutamine transport is diminished in septic patients. To examine the potential regulation of this decreased transport by endotoxin, cytokines, or glucocorticoids, the human intestinal Caco-2 cell line was studied in vitro. Na(+)-dependent glutamine transport across the apical brush border membrane was assayed in confluent monolayers of differentiated cells that were 10 days old. Uptake of 50 microM glutamine was determined after a 12-hour incubation with varying doses (10 to 1000 U/mL) of tumor necrosis factor-alpha, interleukin-1, interleukin-6, interferon-gamma, and various combinations of these cytokines. Studies were also done in cells incubated with E. coli endotoxin (1 micrograms/mL) or dexamethasone (1 and 10 microM). Endotoxin, tumor necrosis factor, interleukin-1, and interleukin-6 alone and in combination did not significantly reduce Na(+)-dependent glutamine transport across the brush border of Caco-2 cells. Dexamethasone decreased glutamine transport by 20%, but this decrease was not apparent for 48 hours. Interferon consistently decreased glutamine transport by 30%; this was due to a reduction in carrier maximal transport velocity (3427 +/- 783 pmol/mg protein/minute in controls versus 2279 +/- 411 in interferon, p less than 0.05) rather than a change in Km (276 +/- 29 microM in controls versus 333 +/- 74 in interferon, p = not interferon + dexamethasone + tumor necrosis factor + interleukin-1 resulted in a 38% decrease in transport activity. Cytokines and glucocorticoids may work independently and synergistically in regulating Na(+)-dependent brush border glutamine transport in human intestinal cells. Whether these signal molecules play a central role in the cause of the diminished brush border glutamine transport that occurs in septic patients requires further study.

Adenocarcinoma↗
PubMed1992

Does preoperative radiation therapy enhance the probability of local control and survival in high-risk distal rectal cancer?

One hundred forty-eight patients were treated with preoperative radiation therapy and surgery for resectable rectal adenocarcinoma at the University of Florida between 1975 and 1986. All patients had at least 5 years' follow-up; no patient was lost to follow-up. Three treatment protocols were used over the study period: 1975 to 1978, 3500 cGy in 20 fractions; 1979 to 1983, 4000 to 5000 cGy at 180 cGy per fraction; and 1984 to 1986, 3000 cGy in 10 fractions. The change was made to 3000 cGy in 10 fractions to reduce the inconvenience and expense associated with preoperative radiation therapy without sacrificing any improvement in local control or complication rates. There were no significant differences in the rates of local control, absolute survival, cause-specific survival, or complications between the three preoperative radiation therapy protocols. The results were compared for the 132 patients who underwent complete resection after preoperative radiation therapy and a series of 135 patients who underwent a complete resection alone for adenocarcinoma of the rectum at the University of Florida between 1959 and 1976. The results at 5 years, calculated by the product-limit method, for preoperative radiation therapy and surgery compared with surgery alone, respectively, were as follows: for local recurrence-free survival, 96% and 67%; for absolute survival, 66% and 40%; and for cause-specific survival, 77% and 50%. All of these differences are significant (p = 0.0001 or less). A subset of 56 patients with locally advanced lesions, based on tethering or circumferential involvement of the rectal lumen, treated with preoperative radiation therapy and surgery were compared with patients treated with surgery alone for stage B2 and C cancers. There was a significant improvement in local control and survival rates in the group irradiated before operation. There was no apparent increase in the incidence of postoperative complications in the patients irradiated before operation.

Adenocarcinoma↗
PubMed1992

Growth hormone regulates amino acid transport in human and rat liver.

Human growth hormone (GH) has been shown to improve nitrogen balance in surgical patients and to decrease urea production. This has been thought to be due primarily to an increase in protein synthesis in skeletal muscle. Little attention has focused on the liver as a possible site where GH may modulate amino acid uptake and thereby divert nitrogen away from urea-genesis. The authors hypothesized that GH regulates amino acid transport in hepatocytes at the plasma membrane level. They studied hepatic amino acid transport in 20 healthy surgical patients that received saline, low-dose GH (0.1 mg/kg/day), or high-dose (0.2 mg/kg/day) GH for 3 days before operation. At operation, a 5- to 10-g wedge biopsy of the liver was obtained, and hepatocyte plasma membrane vesicles were prepared by Percoll density gradient centrifugation. Vesicle transport of [3H]-MeAIB, a highly selective system A substrate, and [3H]-glutamine, a selective system N substrate, was measured, employing a rapid mixing/filtration technique. Hepatocyte plasma membrane vesicles were also prepared from 14 rats treated with saline or one of three different GH treatment regimens: (A) 12 hours after chronic GH treatment (6 mg/kg every 12 hours x 4 doses); (B) 4 hours after acute (1 dose) GH treatment; and (C) 4 hours after chronic GH treatment. In human liver vesicles, low-dose GH resulted in a 13% decrease in system A activity (p = not significant), whereas high-dose GH caused a marked 79% decrease (6.7 +/- 1.7 pmol/mg protein/10 seconds in control patients versus 1.4 +/- 0.7 in GH, p less than 0.05). System N was unaffected. Kinetic analysis of MeAIB transport by vesicles from high-dose GH patients showed the reduction in transport to be due to a 63% decrease in the Vmax (maximal transport velocity) with no alteration in the transport Km (carrier affinity). Vesicles from rats treated chronically with GH using a protocol similar to that used for human subjects exhibited decreased system A transport activity (10.4 +/- 0.4 pmol/mg pro/10 seconds in controls versus 7.5 +/- 0.2 in GH, p less than 0.05) secondary to a 59% reduction in the transport Vmax. Chronic growth hormone treatment decreases the activity of system A in both human and rat hepatocytes. This may be one mechanism by which GH diminishes hepatic urea-genesis and spares amino acids for peripheral protein synthesis.

5'-Nucleotidase↗
PubMed1992

Preoperative irradiation and surgery for initially unresectable adenocarcinoma of the rectum.

Forty-two patients with initially unresectable rectal adenocarcinoma were treated with preoperative irradiation and surgery between March 1970 and March 1986 at the University of Florida (Gainesville, FL). No patient received adjuvant chemotherapy. All patients had follow-up for at least 5 years; 23 (55%) had follow-up for 10 years or more. Five patients (12%) underwent an exploratory laparotomy before irradiation; the remaining 37 patients were clinically thought to have unresectable disease. Eighteen patients had tumor fixation to one structure, and 24 patients (57%) had fixation to two or more structures. Lesions that exhibited impaired mobility but not complete fixation were considered to be clinically resectable and are not included in this series. The dose of preoperative irradiation ranged from 3,500 to 6,000 cGy at 180 cGy per fraction; 30 of 42 patients received 4,500 to 5,000 cGy and only 4 patients received less than 4,000 cGy. Forty-one patients were operated on 1 to 11 (mean 4.6) weeks after the completion of radiotherapy; 1 patient died of aspiration pneumonia after completing irradiation but before the planned resection. Resection of the rectal cancer was accomplished in 37 patients. Four patients were found to have extensive unresectable disease at laparotomy. Twenty-one patients had a complete resection: 11 were stage B2, and 10 were stage C2. Twenty patients had incomplete resection due to positive margins (8 patients), distant metastases with or without positive margins (8 patients), or no resection due to extensive disease (4 patients). Two patients died after the operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1992

Stimulation of hepatocyte System y(+)-mediated L-arginine transport by an inflammatory agent.

BACKGROUND: Arginine participates in several distinct metabolic pathways, including polyamine and nitric oxide biosynthesis. Normally, arginine is effectively sequestered from the hepatocyte intracellular space by the low basal activity of membrane transport system y+. This has implications for the subsequent metabolism of arginine and for hepatic arginine requirements during a septic insult. We investigated the influence of tumor necrosis factor (TNF) on the activity of System y(+)-mediated hepatocyte arginine transport employing hepatic plasma membrane vesicles (HPMVs). METHODS: Rats were treated with a single intraperitoneal injection of TNF (50 or 150 micrograms/kg body weight) for 2, 4, or 24 hours, and HPMVs were prepared by Percoll density gradient centrifugation. Vesicle purity was established by assay of enzyme markers. Vesicle arginine transport activity was evaluated by measurement of tritiated arginine uptake employing a rapid mixing-filtration technique. RESULTS: Arginine transport by HPMVs was entirely independent of sodium and consisted of saturable and nonsaturable components. Prior treatment with TNF resulted in a time- and dose-dependent stimulation of saturable transport within 2 hours and a return to basal levels after 24 hours. Nonsaturable uptake was unchanged. Inhibition analysis indicated that the TNF-induced increase in saturable arginine transport activity was mediated by an increase in System y+. Kinetic analysis revealed that accelerated transport was caused by a 78% increase in the maximal velocity of transport without alteration in transport affinity. CONCLUSIONS: In vivo treatment with TNF results in a rapid stimulation of saturable, System y(+)-mediated arginine transport in the liver. This TNF-induced stimulation of hepatic arginine transport may serve to increase the normally restricted availability of extrahepatic arginine to the hepatocyte intracellular space during a septic insult to support important arginine-dependent pathways in the liver.

Animals↗
PubMed1991

Selective stimulation of brush border glutamine transport in the tumor-bearing rat.

Intestinal extraction of circulating glutamine across the basolateral membrane is diminished in the tumor-bearing rat (TBR). This study was designed to investigate the effects of progressive malignant growth on brush border glutamine transport in order to gain further insight into the adaptive/regulatory changes in intestinal glutamine metabolism that occur in the tumor-bearing rat. Fischer 344 rats (225 +/- 5 g) were implanted with fibrosarcoma cells and were studied at various time points after implantation when the tumors comprised 7%, 20%, and 29% of total body weight. Control and tumor-bearing rats were pair-fed throughout the study. Jejunal brush border membrane vesicles (BBMVs) were prepared by magnesium aggregation/differential centrifugation and transport of radioactively labeled L-glutamine, L-leucine, L-alanine, and D-glucose by BBMVs was measured using a Millipore filtration technique. BBMVs were enriched 15-fold in alkaline phosphatase, indicating brush border vesicle purity. Uptake of all substrates occurred into an osmotically active space, exhibited overshoots, and had similar 1-hr equilibrium values. The rate of glutamine uptake by BBMVs from all tumor-bearing rats was significantly greater than controls, regardless of tumor size. The increase in transport activity was not due to a change in carrier affinity but rather to an increase in maximal transport velocity. In rats with small tumors (7% of body weight), the Vmax was 431 +/- 40 pmole/mg protein/10 sec compared to 259 +/- 30 in control animals (P less than 0.01). In marked contrast, the mean transport of alanine was diminished in BBMVs from TBR (31 +/- 3 pmole/mg protein/10 sec in TBR vs 23 +/- 2 in controls, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Perioperative nutritional support.

In selected malnourished patients, perioperative nutritional support can decrease the morbidity and mortality rates associated with major surgical procedures. Preoperative nutritional support should be delivered via the gastrointestinal tract whenever feasible, generally in the form of enteral diets, which can be given via a feeding tube or as a dietary supplement. Patients with a functional gut who cannot eat because of anorexia or upper gastrointestinal tract obstruction are candidates for preoperative tube feedings. Total parenteral nutrition should be the mainstay of nutritional support when the gastrointestinal tract cannot be used adequately. An improvement in nutritional indices (e.g., serum transferrin, lymphocyte count) may be associated with decreased perioperative morbidity, although the strength of this relation is not clear. In the absence of improvement in such indices, the duration of nutritional support required to decrease operative morbidity is unknown. Postoperatively, enteral tube feedings (delivered via a nasojejunal tube or feeding jejunostomy) should be provided to all preoperatively malnourished patients with a functional gastrointestinal tract who are unable to consume adequate calories orally. Postoperative TPN should be reserved for malnourished patients with a nonfunctional gut or for patients who develop a postoperative complication that precludes enteral feeding. Current nutritional formulas have often neglected the metabolic and nutritional requirements of the intestinal tract. In the future, the combined use of specific nutrients and growth factors may improve nutritional rehabilitation in catabolic patients.

Enteral Nutrition↗
PubMed1991

Rapid analysis of carcinoembryonic antigen levels in gallbladder bile. Identification of patients at high risk of colorectal liver metastasis.

Recently it was found that immunoanalysis of carcinoembryonic antigen (CEA) levels in gallbladder bile may be a sensitive method to detect colorectal liver metastases in humans. Methods used in the past for the detection of CEA in various body fluids were cumbersome and time consuming, requiring acid extraction, extensive dialysis, and column purification. Single-step, solid-phase radioimmunoassays, designed specifically for serum CEA analysis, were developed commercially to replace these methods. Parameters and methodology necessary to adapt these kits for Parameters and methodology necessary to adapt these kits for use with gallbladder bile are presented here. A combination of pretreatment procedures for bile, before radioimmunoassay, permit rapid, reproducible, and accurate measurement of CEA levels in gallbladder bile.

Bile↗
PubMed1991

Nutritional support of the surgical oncology patient.

Malnutrition is a common manifestation of cancer patients and has a significant negative impact on treatment and survival. The metabolic aberrations associated with tumor growth are complex, and nutritional repletion cannot always be accomplished with nutritional support. Ultimate survival depends upon the primary lesion. Oral nutrition should be used whenever patients can eat and are able to take in sufficient calories. Preoperative total parenteral nutrition (TPN) in well-nourished patients appears to be unwarranted at this time, but the efficacy of preoperative TPN in malnourished surgical patients is established. Patients undergoing radiotherapy and chemotherapy can also benefit from nutritional support when the appropriate patient population is selected. In patients who have a potentially treatable disease, their malnourished state should not be a contraindication to therapy, and every effort should be made to nutritionally support such patients.

Cachexia↗
PubMed1990

Accelerated lung amino acid release in hyperdynamic septic surgical patients.

Amino acid flux across the lungs was studied in humans to gain further insight into the altered nitrogen metabolism that characterizes catabolic disease states. Lung flux of glutamine, glutamate, and alanine was determined in three groups of surgical patients with indwelling pulmonary artery catheters: (1) preoperative controls (n = 14), (2) postoperative elective general surgical patients (n = 10, and (3) hyperdynamic septic surgical patients (n = 17). In controls the lung was an organ of amino acid balance. These exchange rates did not change in general surgical patients. In the septic group, glutamine release by the lung increased markedly from a control value of 0.80 +/- 0.99 mumol/kg per minute to 6.80 +/- 1.32 mumol/kg per minute. This accelerated release rate was secondary to both an increase in total pulmonary blood flow and an increase in the pulmonary artery-systemic arterial concentration difference. The lung also became an organ of significant alanine release in septic patients. The lung plays an active metabolic role in the processing of amino acids and may be a key regulator in interorgan nitrogen flux after major injury and infection.

Alanine↗
PubMed1979

Evaluation of nutritional indices as prognostic indicators in the cancer patient.

The nutritional and immunological status of 140 malnourished cancer patients who were to receive intravenous hyperalimentation (IVH) were evaluated prior to treatment with IVH and chemotherapy (CMX), surgery or radiation therapy (XRT). Subsequently, these indices were correlated with responses to treatment. Cell-mediated immunocompetent (CMI+) patients (41%) had lost an average weight of 10 +/- 2.2 lbs., while cell-mediated immunoincompetent (CMI-) patients (59%) had lost an average weight of 31 +/- 2.5 lbs. (p less that 0.05). Total lymphocyte count (TLC) averaged 1290 +/- 250 cells/mm3 in CMI+ patients and 900 +/- 140 cells/mm" in CMI- patients (p less than 0.05). Serum albumin concentration (SA) was 3.6 +/- 0.06 g/dl in CMI+ patients and 3.3 +/- 0.05 g/dl in CMI- patients (p less than 0.05). In the CMI+ group, 49% had a positive response to CMX, whereas only 27% of the CMI-group responded to CMX (p less than 0.01). In the surgery group, 88% of the CMI+ patients, but only 65% of CMI- patients, had uncomplicated postoperative recovery periods. Although nutritional repletion with IVH was undertaken in all patients, those patients with initial CMI- responses had greater body weight loss, lower SA and TLC and either a decreased response to CMX or an increase in postoperative morbidity and mortality when compared with patients who initially had CMI+ responses.

Adolescent↗
PubMed1979

Nutrition, cancer, and intravenous hyperalimentation.

In over 1000 cancer patients treated with intravenous hyperalimentation (IVH), tumor growth has not been identified and catheter-related sepsis has been minimal. Studies in rats demonstrated that the host benefits more than the tumor during nutritional repletion, and any stimulation of tumor growth in the rat-tumor model could be manipulated with DNA specific drugs to benefit the host. A study of 65 malnourished cancer patients undergoing oncologic therapy and treated with IVH indicated that much of the immune suppression in these patients was the result of malnutrition coincident with or secondary to oncologic treatment. Conclusions reached in this study were that nutritional repletion resulted in a return of skin test reactivity, proper wound healing in the surgical patient, and possibly an increase in response to chemotherapy. Certainly, the use of IVH allowed specific oncologic therapy to be administered to a group of malnourished patients who otherwise might not have been acceptable candidates for intensive antineoplastic therapy.

Animals↗
PubMed1979

Enteral and parenteral feeding to evaluate malabsorption in intestinal parasitism.

General evidence of malnutrition such as loss in body weight associated with intestinal parasitism has been attributed to decreased food intake, to intestinal malabsorption, and to change in host basal metabolism. To establish the relative importance of these factors in this regard, rats with trichinosis were studied. The weights of infected and uninfected animals were followed after being placed on one of three feeding regimens for 1 week--stock diet ad libitum, intraduodenal nutrition, and intravenous nutrition. Infected rats on a stock diet lost weight whereas those on the other two regimens maintained the same weight pattern as uninfected counterparts. The maintainance of body weight occurred despite alterations at the level of the intestinal brush border as indicated by a depression of intestinal disaccharidase activities (sucrase and lactase) and by reduction of monosaccharide absorption (measured as accumulation of beta-methyl glucoside) in the proximal, heavily infected region of the small intestine. There was no compensatory increase in enzyme activity nor in the absorptive capacity in the distal gut. Results support the conclusion that inadequate oral food intake rather than changes in basal metabolism or intestinal pathophysiology accounts for weight loss during the intestinal phase of infection.

Animals↗