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Biomedical subjects

D C Carter

Publications and source records attributed to D C Carter.

At least 55 records · Page 3Linked to original sources
PubMed1994

Three-dimensional structure of Schistosoma japonicum glutathione S-transferase fused with a six-amino acid conserved neutralizing epitope of gp41 from HIV.

The 3-dimensional crystal structure of glutathione S-transferase (GST) of Schistosoma japonicum (Sj) fused with a conserved neutralizing epitope on gp41 (glycoprotein, 41 kDa) of human immunodeficiency virus type 1 (HIV-1) (Muster T et al., 1993, J Virol 67:6642-6647) was determined at 2.5 A resolution. The structure of the 3-3 isozyme rat GST of the mu gene class (Ji X, Zhang P, Armstrong RN, Gilliland GL, 1992, Biochemistry 31:10169-10184) was used as a molecular replacement model. The structure consists of a 4-stranded beta-sheet and 3 alpha-helices in domain 1 and 5 alpha-helices in domain 2. The space group of the Sj GST crystal is P4(3)2(1)2, with unit cell dimensions of a = b = 94.7 A, and c = 58.1 A. The crystal has 1 GST monomer per asymmetric unit, and 2 monomers that form an active dimer are related by crystallographic 2-fold symmetry. In the binding site, the ordered structure of reduced glutathione is observed. The gp41 peptide (Glu-Leu-Asp-Lys-Trp-Ala) fused to the C-terminus of Sj GST forms a loop stabilized by symmetry-related GSTs. The Sj GST structure is compared with previously determined GST structures of mammalian gene classes mu, alpha, and pi. Conserved amino acid residues among the 4 GSTs that are important for hydrophobic and hydrophilic interactions for dimer association and glutathione binding are discussed.

Amino Acid Sequence↗
PubMed1994

Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa.

Photoaffinity labelling (PAL) with [32P]8-azido-cAMP and polyacrylamide gel electrophoresis (PAGE) has been used to identify three specific cAMP-binding proteins (cAMP-BPs) within cytosols derived from the centre and periphery of 32 human colorectal cancers and from related adjacent (less than 5 cm from the tumour) and distant (more than 5 cm from the tumour) microscopically benign mucosa. By immunoprecipitation with specific anti-RI and anti-RII antibodies these proteins have subsequently been characterised as a single form of RI (48 kDa) and two forms of RII (50 and 52 kDa). The relative expression of isoforms in each specimen has been quantified by laser densitometry. There was significantly more RI expressed in both tumour centre and periphery than in either adjacent or distant mucosa (P < 0.008 by Wilcoxon signed-rank test). There was no significant difference in relative RI expression between tumour centre and periphery, or between adjacent and distant mucosa. There was no association between relative RI expression and Dukes' stage. Poorly differentiated tumours expressed significantly more RI than those that were either moderately or well differentiated (P = 0.016 by Mann-Whitney U-test). This study is the first to have characterised cAMP-BPs within human colorectal tissues and has demonstrated that colorectal cancers, and in particular those of poor histological grade, relatively overexpress RI when compared with related benign mucosa.

Affinity Labels↗
PubMed1994

Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines.

A number of polyunsaturated fatty acids have been shown to inhibit the growth of malignant cells in vitro. To investigate whether fatty acids modify the growth of human pancreatic cancer, lauric, stearic, palmitic, oleic, linoleic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic and eicosapentaenoic (EPA) acids were each incubated with the cells lines MIA PaCa-2, PANC-1 and CFPAC at concentrations ranging from 1.25 microM to 50 microM and the effect of each fatty acid on cell growth was examined. All the polyunsaturated fatty acids tested had an inhibitory effect, with EPA being the most potent (ID50 2.5-5 microM). Monounsaturated or saturated fatty acids were not inhibitory. The action of EPA could be reversed with the anti-oxidant vitamin E acetate or with oleic acid. The cyclo-oxygenase inhibitors indomethacin and piroxicam had no effect on the action of EPA. The action of EPA appeared to be associated with the generation of lipid peroxides, although the level of lipid peroxidation did not always appear to correlate directly with the extent of cell death. The ability of certain fatty acids to inhibit significantly the growth of three human pancreatic cancer cell lines in vitro at concentrations which could be achieved in vivo suggests that administration of such fatty acids may be of therapeutic benefit in patients with pancreatic cancer.

Cell Division↗
PubMed1994

A trial of elective versus on demand sclerotherapy in "poor risk" patients with variceal haemorrhage.

A prospective randomised trial of "planned" chronic injection sclerotherapy (at three weekly intervals) versus "demand" injection sclerotherapy (after variceal bleeds only) was performed in 40 patients who had endoscopically proven variceal bleeding, and who were either graded as modified Child's grade C or were more than 65 years of age. 45% of patients survived for one year and 37% for two years. There was no significant difference in survival between the groups at either one or two years (p < 0.5; p < 0.1). In the "planned" sclerotherapy group 24 gastrointestinal bleeds occurred in 11 patients over the first nine months after study entry. In the "demand" group 35 bleeds occurred in 13 patients over the first 18 months after study entry. In this small group of "poor risk" patients, planned chronic injection sclerotherapy was not associated with improved survival.

Esophageal and Gastric Varices↗
PubMed1994

Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer.

OBJECTIVE: To determine whether resting energy expenditure (REE) is increased in cachectic patients with pancreatic cancer and to define the relation of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production to the acute-phase response and to REE. METHODS: Measurement of REE (indirect calorimetry) and assessment of body composition (bioelectrical impedance analysis) were done in 21 patients with unresectable pancreatic cancer and on 16 age-related controls. The systemic inflammatory response in peripheral blood of the cancer patients was assessed using the acute-phase protein, C-reactive protein, and the cytokines TNF and IL-6. Production of these cytokines by peripheral blood mononuclear cells in vitro was also measured. RESULTS: Patients with pancreatic cancer had an elevated REE when compared with controls (73.4 +/- 5.0 vs. 53.5 +/- 1.6 kcal/kg body cell mass; p < 0.003). Resting energy expenditure was significantly greater in cancer patients with an acute-phase response (C-reactive protein > 10 mg/L) than in those who did not have such a response (85.5 +/- 10.0 [n = 9] vs. 64.3 +/- 3.0 [n = 12] kcal/kg body cell mass; p < 0.04). Tumor necrosis factor was not detected in the serum of any of the cancer patients. Serum IL-6 was detected but levels were not significantly different among cancer patients with or without an acute-phase response. In contrast, spontaneous production of TNF and IL-6 by isolated peripheral blood mononuclear cells was significantly greater in cancer patients with an acute-phase response that in those without (TNF: 1231 +/- 244 vs. 210 +/- 54 pg/ml/10(5) cells; p < 0.001; IL-6: 11.5 +/- 1.7 vs. 3.6 +/- 1.4 ng/mL/10(5) cells; p < 0.003). CONCLUSIONS: In pancreatic cancer at least a component of weight loss is due to increased REE. Furthermore, the presence of an acute-phase response identifies a group of patients who are markedly hypermetabolic. The serum concentration of TNF of IL-6 does not correlate with the presence of an acute-phase response, whereas rates of cytokine production by peripheral blood mononuclear cells are significantly greater in patients with such a response. This suggests that local rather than systemic cytokine production may be important in regulating the acute-phase response.

Acute-Phase Proteins↗
PubMed1994

Glutamine-supplemented total parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection.

OBJECTIVE: The authors determined the effect of glutamine-supplementation of TPN on postoperative peripheral blood T-cell response and proinflammatory cytokine production in patients undergoing colorectal resection. SUMMARY BACKGROUND DATA: Several vital tissues, including the immune system, are very dependent on glutamine; however, this amino acid, which may be essential in conditions of stress, only now is becoming formulated suitably for incorporation into TPN. The effects of such supplementation on the immune function of stressed surgical patients is unknown. METHODS: Patients (n = 20) were randomized to receive conventional TPN (0.2 g nitrogen/kg/d) or an isonitrogenous/isocaloric regimen with 0.18 g of glutamine/kg/d from days 1 to 6 postoperatively. T-cell DNA synthesis and interleukin (IL)-2 production and peripheral blood mononuclear cell IL-6 and tumor necrosis factor (TNF) production were measured in vitro preoperatively and on days 1 and 6 postoperatively. RESULTS: T-cell DNA synthesis after 5 days of TPN was increased compared with preoperative values in the glutamine-supplemented group (median preoperative tritiated thymidine uptake: 78.3 x 10(3) cpm, day 6: 95.0 x 10(3) cpm, p < 0.05). There was no such increase in the control TPN group (preoperative: 89.0 x 10(3) cpm, day 6: 69.4 x 10(3) cpm, p > 0.05). Glutamine supplementation did not influence IL-2 production or the production of TNF or IL-6. CONCLUSIONS: Glutamine supplementation may be a method of enhancing T-cell function in the surgical patient receiving TPN.

Adolescent↗
PubMed1994

Splanchnic haemodynamics and vasoactive agents in experimental cirrhosis.

It is well known that portal hypertension is associated with a hyperdynamic systemic circulatory state. This study measures systemic and splanchnic haemodynamics in an experimental rat model of hepatic cirrhosis. It also investigates the association between haemodynamic changes in cirrhotic animals and circulating levels of the vasoactive hormones glucagon and vasoactive intestinal polypeptide (VIP). Splanchnic blood flow was significantly increased in the cirrhotic group (13.2 +/- 1.3 vs. 9.2 +/- 1.6 ml/min, P < 0.05). Circulating levels of glucagon and VIP were two and five fold increased respectively in cirrhotic animals compared to controls. There was a strong correlation between portal pressure and glucagon levels in the cirrhotic group (r = 0.85). Raised splanchnic blood flow is partly responsible for elevated portal pressure in this model and this rise may be humorally mediated.

Animals↗
PubMed1993

X-ray and primary structure of horse serum albumin (Equus caballus) at 0.27-nm resolution.

The amino-acid sequence and three-dimensional structure of equine serum albumin have been determined. The amino-acid sequence was deduced from cDNA isolated from equine liver. Comparisons of the primary structure of equine serum albumin with human serum albumin and bovine serum albumin reveal 76.1% and 73.9% sequence identity, respectively. The three-dimensional structure was determined crystallographically by the molecular-replacement method using molecular coordinates from the previously determined structure of human serum albumin, to a resolution of 0.27 nm. In accordance with the primary structure, the three-dimensional structures are highly conserved. There is a root-mean-square difference between alpha-carbons of the two structures of 0.201 nm. The association constants (Ka) for the binding of 2,3,5-triiodobenzoic acid were determined by ultrafiltration methods for equine and human serum albumins to be approximately 10(4) M-1 and 10(5) M-1, respectively. Crystallographic studies of equine serum albumin reveal two binding sites for 2,3,5-triiodobenzoic acid identical with those previously reported for human serum albumin which are located within subdomains in IIA and IIIA. Details and comparisons of the binding chemistry are discussed.

Amino Acid Sequence↗
PubMed1993

Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups.

Neutrophils have been implicated in the pathogenesis of the adult respiratory distress syndrome (ARDS). We have measured concentrations of the neutrophil attractant interleukin-8 in blood and bronchoalveolar lavage fluid (BAL) from patients at risk of ARDS. We studied 29 patients from three groups at risk of developing ARDS: multiple trauma (n = 16), perforated bowel (n = 6), and pancreatitis (n = 7). ARDS developed in 7 of these patients. Interleukin-8 in BAL and blood samples taken on initial hospital presentation was measured by a sandwich enzyme-linked immunosorbent assay. The mean BAL interleukin-8 concentration was significantly higher for the patients who subsequently progressed to ARDS than for the non-ARDS group (3.06 [SE 2.64] vs 0.053 [0.010] ng/mL, p = 0.0006). There was no difference between the groups in plasma interleukin-8 (6.23 [2.60] vs 5.12 [2.22] ng/mL, p = 0.31). Immunocytochemistry suggested that the alveolar macrophage is an important source of interleukin-8 at this early stage in ARDS development. This study provides evidence of a relation between the presence of interleukin-8 in early BAL samples and the development of ARDS. The early appearance of interleukin-8 in BAL of patients at risk of ARDS may be an important prognostic indicator for the development of the disorder and reinforces the likely importance of neutrophils and the effects of their accumulation and activation in the pathogenesis of many cases of ARDS.

Adolescent↗
PubMed1993

Role of serum endotoxin and antiendotoxin core antibody levels in predicting the development of multiple organ failure in acute pancreatitis.

It has been proposed that endotoxin contributes to the development of multiple organ failure (MOF) in acute pancreatitis. Endotoxaemia is transient and may not be detected by intermittent blood sampling. By contrast, not only can changes in the patient's endogenous antiendotoxin core antibody pool persist for many days, but depletion of this pool may be a key event in determining the physiological significance of endotoxaemia. A series of 33 patients with acute pancreatitis had daily measurement of Acute Physiology Score (APS) and levels of C-reactive protein, interleukin 6, endotoxin, immunoglobulin (Ig) G and IgM antiendotoxin core antibodies, and prospective documentation of complications. Endotoxin was detected in the serum of 13 patients, while a significant change in levels of endogenous antiendotoxin core antibodies was detected in all those with severe pancreatitis and in 28 overall. MOF developed in seven patients, five of whom died. The combination of a rising APS over the first 48 h of admission and a significant fall in endogenous IgG antibody level was observed in all patients who developed MOF (seven of seven), but in only one of 16 without MOF (P = 0.00003; overall predictive value 91 per cent). This study suggests that measuring the initial trend in APS and the concentration of endogenous IgG antiendotoxin core antibody provides a means of identifying patients with acute severe pancreatitis who are at high risk of developing MOF. This group might benefit from passive immunotherapy with antiendotoxin antibodies.

Acute Disease↗
PubMed1993

Genetic linkage analysis applied to unaffected women from families with breast cancer can discriminate high- from low-risk individuals.

Up to 20 per cent of cases of breast cancer diagnosed in women under the age of 45 years may be caused by an autosomal dominant gene. A present difficulty is differentiation of mutation carriers from non-mutation carriers in high-risk families. Genetic linkage analysis has been used to localize a susceptibility gene (BRCA1) on chromosome 17q12-21 between markers 42D6 and MFD188, a region 5-10 million base pairs in length. Odds in favour of linkage to this region were greater than 100,000:1 in 15 families with breast cancer. In eight families in which the probability of linkage was above 75 (range 79.2-99.9) per cent, 19 women were identified who were at high lifetime risk of breast cancer (range 80.6-87.2 per cent) and 37 whose risk was similar to that for the general population (range 9.8-16.4 per cent). Genetic risk prediction of this kind may enable high-risk screening clinic resources to be concentrated on those most likely to benefit.

Adult↗
PubMed1993

Changing trends in the management of extrahepatic cholangiocarcinoma.

A series of 107 patients with cholangiocarcinoma diagnosed between January 1980 and December 1991 is reported. Changing patterns of investigation and treatment in the periods 1980-1985 and 1986-1991 are analysed. There was a decrease in the use of percutaneous transhepatic cholangiography in the second period (86 versus 51 per cent of patients) but increased use of endoscopic retrograde cholangiography (19 versus 71 per cent) and computed tomography (8 versus 59 per cent). The overall resectability rate (17 per cent) was similar to those of other reported series but greater in the second period (8 versus 21 per cent). Palliation by endoscopic and percutaneous stenting was associated with a high incidence of recurrent cholangitis (55 per cent) and jaundice (35 per cent). During the second 6-year period, more effective palliation was achieved by segment III cholangiojejunostomy with a lower incidence of recurrent cholangitis (19 per cent) and jaundice (19 per cent). Overall prognosis for patients with this condition is grim and efforts must usually be aimed at providing the most appropriate palliation.

Adenoma, Bile Duct↗
PubMed1993

Phase I and pharmacokinetic trial of liposome-encapsulated doxorubicin.

A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m2 per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m2 per week x 3. The single patient treated at 37.5 mg/m2 weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m2 per week, three of eight patients had grade > or = 3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m2 per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75 +/- 8.80 microM h (mean +/- SD) and 3.07 +/- 1.45 microM, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92 +/- 2.47 microM h and 2.75 +/- 2.70 microM, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42 +/- 11.23 l/h after the infusion of LED and 31.21 +/- 15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65 +/- 5.16 h for LED and 7.46 +/- 5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%-105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin.

Adult↗
PubMed1993

Macrophage prostaglandin E2 and oxidative responses to endotoxin during immunosuppression associated with anaesthesia and transfusion.

The widespread use of blood transfusion in major surgical procedures has led to concern about the immunosuppressive effect of transfusion on patients with underlying malignancy. Transfusion may also suppress the host response to infection. The cellular mechanisms of transfusion-associated immunosuppression may involve macrophage prostaglandin E2 (PGE2) in modulating the host response to cancer and infection. We previously observed that the transfusion of blood increased PGE2 production by unstimulated macrophages. To investigate this PGE2 associated immunosuppression, we studied the effect of transfusion of rats using a physiological stimulus of macrophage PGE2 production, bacterial endotoxin. In the same macrophages, we analysed intracellular oxidative activity. Both allogeneic and syngeneic blood transfusion were associated with increased PGE2 release by macrophages. This stimulation of PGE2 increased with duration of storage of blood. A similar effect of serum indicated that a humoral factor was involved. Endotoxin (50 ng/ml-500 micrograms/ml) stimulated PGE2 production in all transfused subjects. The lowest endotoxin concentration gave proportionately the greatest stimulation. Oxidative activity was down-regulated in macrophages of transfused rats, supporting an immunosuppressive role of PGE2 within the macrophage. An effect of surgery on the oxidative response was also detected.

Anesthesia↗