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Biomedical subjects

D C Carter

Publications and source records attributed to D C Carter.

At least 19 recordsLinked to original sources
PubMed1992

Structure of a human monoclonal antibody Fab fragment against gp41 of human immunodeficiency virus type 1.

The three-dimensional structure of a human monoclonal antibody (Fab), which binds specifically to a major epitope of the transmembrane protein gp41 of the human immunodeficiency virus type 1, has been determined by crystallographic methods to a resolution of 2.7 A. It has been previously determined that this antibody recognizes the epitope SGKLICTTAVPWNAS, belongs to the subclass IgG1 (kappa), and exhibits antibody-dependent cellular cytotoxicity. The quaternary structure of the Fab is in an extended conformation with an elbow bend angle between the constant and variable domains of 175 degrees. Structurally, four of the hypervariable loops can be classified according to previously recognized canonical structures. The third hypervariable loops of the heavy (H3) and light chain (L3) are structurally distinct. Hypervariable loop H3, residues 102H-109H, is unusually extended from the surface. The complementarity-determining region forms a hydrophobic binding pocket that is created primarily from hypervariable loops L3, H3, and H2.

Amino Acid Sequence↗
PubMed1992

Atomic structure and chemistry of human serum albumin.

The three-dimensional structure of human serum albumin has been determined crystallographically to a resolution of 2.8 A. It comprises three homologous domains that assemble to form a heart-shaped molecule. Each domain is a product of two subdomains that possess common structural motifs. The principal regions of ligand binding to human serum albumin are located in hydrophobic cavities in subdomains IIA and IIIA, which exhibit similar chemistry. The structure explains numerous physical phenomena and should provide insight into future pharmacokinetic and genetically engineered therapeutic applications of serum albumin.

Amino Acid Sequence↗
PubMed1992

p53 allele losses, mutations and expression in breast cancer and their relationship to clinico-pathological parameters.

The p53 locus on the short arm of chromosome 17 at 17p 13.1 was examined for loss of heterozygosity, mutation, mRNA and protein expression in 60 primary breast cancers. Allele loss around the p53 locus was detected in 19/45 informative tumours (42%). p53 mutations in the evolutionarily conserved exons 5 to 9 were detected in 17/60 (28%) by amplification mismatch and confirmed by direct DNA sequencing. p53 mRNA expression was detected by Northern blot in 36/59 (61%) of tumours, and p53 protein expression using antibody 1801 on frozen-tissue sections in 13/44 of the tumours examined. p53 mutation was significantly associated with oestrogen-receptor-poor tumours (p less than 0.01) and hence with poor prognosis, but not with other clinical or pathological parameters. There was no statistical correlation between loss of heterozygosity around the p53 locus at 17p13.1 and p53 mutation. Furthermore, p53 mutation was not associated with p53 expression detected by immunohistochemical staining with antibody 1801 or as p53 mRNA. In addition, events on 17p (allele losses, p53 mutation, p53 expression) were independent of c-erbB-2 expression. In breast cancer, by contrast with colorectal, lung and ovarian cancer, there appears to be no clear association between p53 DNA abnormalities and p53 expression.

Alleles↗
PubMed1992

Regulation of tumor necrosis factor production in healthy humans and in patients with cancer.

To study the factors that influence cytokine release, the effect of endotoxin on in vitro tumor necrosis factor production by monocytes from debilitated patients with cancer (n = 6) was compared with that from healthy controls (n = 5). Spontaneous and endotoxin-stimulated monocyte tumor necrosis factor production was similar in patients with cancer and controls. However, with total peripheral blood mononuclear cells, enhancement of tumor necrosis factor production by endotoxin in patients with cancer (46 +/- 12, mean +/- SEM) was greater than in controls (0% +/- 7%). This enhanced response correlated with reduced peripheral blood mononuclear cell blastogenesis in response to phytohemagglutinin (r = .66) and could be partially reversed in vitro by addition of exogenous interleukin 2. Thus, a component of total peripheral blood mononuclear cells (probably T cells) seems to influence monocyte cytokine production in response to endotoxin. Moreover, this regulatory component is decreased in patients with cancer, correlates with decreased peripheral blood mononuclear cell blastogenesis, and can stimulated with interleukin 2.

Adult↗
PubMed1992

Balloon tamponade and vasoactive drugs in the control of acute variceal haemorrhage.

Successful pharmacological arrest of haemorrhage might avoid the risk of aspiration associated with tamponade and early studies have suggested that the vasoactive agent somatostatin may be as effective and perhaps safer than tamponade in controlling variceal haemorrhage. In our view, vasopressin has not established a role in management but we retain an open mind regarding the potential use of terlipressin in combination with nitroglycerin. It is unlikely that any of these agents can improve significantly our ability to control variceal haemorrhage when compared to balloon tamponade but they may reduce the incidence of pulmonary complications and thereby reduce subsequent mortality. Tamponade has proved successful in controlling acute haemorrhage from oesophageal varices in our hands. Late complications continue to give cause for concern but until effective safe alternatives to tamponade are developed, we continue to advocate its use for emergency control of acute variceal haemorrhage. Our own studies have shown that the high mortality seen in this patient population may reflect the severity of the underlying liver disease rather than failure of a management policy employing oesophageal tamponade for the initial control of acute variceal haemorrhage.

Antihypertensive Agents↗
PubMed1992

Plasma concentrations of endogenous heparinoids in portal hypertension.

Bleeding as a complication of liver disease can occur in the absence of recognised haemostatic defects. It is now possible to measure the concentration of endogenous heparinoid substances in the blood using a competitive binding assay. One such substance, heparan sulphate (normal range < 600 ng/ml) was assayed in the plasma of 49 patients admitted because of oesophageal varices. In 27 patients with recent upper gastrointestinal bleeding the median plasma heparan sulphate value was 1700 ng/ml (interquartile (IQ) range 900-3900) compared with 390 ng/ml (IQ range 256-800) in 22 patients with no recent bleed (p < 0.01). As heparan sulphate is metabolised by the same route as exogenous heparin, an attempt to establish a cause for the raised heparan concentrations was made by measuring the clearance of exogenous heparin in 10 portal hypertensive patients and 10 controls. The median half life of heparin in plasma in the portal hypertensive patients (25.5 minutes; IQ range 22-34) was significantly longer (p < 0.007) than the median half life in the controls (18.7 minutes; IQ range 17-21.5). Thus, there is evidence of raised concentrations of endogenous heparin like substances in portal hypertensive patients after gastrointestinal bleeding. These high concentrations may result from reduced hepatic clearance.

Esophageal and Gastric Varices↗
PubMed1992

A prospective trial of endoscopic sclerotherapy v oesophageal transection and gastric devascularisation in the long term management of bleeding oesophageal varices.

In a prospective three centre study oesophageal transection and gastric devascularisation have been compared with endoscopic sclerotherapy in the long term management of bleeding oesophageal varices. Cirrhotic patients (Child's A or B grade) with documented bleeding oesophageal varices were treated initially with emergency sclerotherapy, and after five days stability, were allocated to one of the two treatment regimes. The endoscopic sclerotherapy group underwent regular sclerotherapy until variceal obliteration while those undergoing surgery were not endoscoped unless bleeding recurred, when they were treated by sclerotherapy if appropriate. Ninety two patients were eligible for analysis (68% alcoholic cirrhosis; mean age 50.1 years) and follow up was achieved for a mean of 52.5 months (range 17-83). Mortality in the first three months was greater in the oesophageal transection and gastric devascularisation group (20% v 1%) but by two years the survival curves were the same and thereafter there was no difference in mortality. Rebleeding occurred in 13/41 (31%) patients, undergoing oesophageal transection and gastric devascularisation. The costs incurred during the first year of oesophageal transection and gastric devascularisation treatment were significantly greater than with endoscopic sclerotherapy (4369 pounds v 1067 pounds, p < 0.0001) and the high rate of rebleeding in the surgical group meant that no cost savings occurred in subsequent years. It is concluded that oesophageal transection and gastric devascularisation confers no benefit over endoscopic sclerotherapy in terms of long term survival and that it is not cost effective as judged by the current health care costs in the United Kingdom.

Adult↗
PubMed1992

Taurocholate induced gastric mucosal injuries in experimental portal hypertension.

The susceptibility of the gastric mucosa to injury by topical sodium taurocholate (40 mmol/l) in hydrochloric acid (150 mmol/l) was studied in prehepatic and cirrhotic rat models of portal hypertension. Portal venous pressure was increased in rats who had undergone partial portal vein ligation compared with rats that had undergone sham operation on days 3, 7, and 28 after operation (20.6 (0.9), 14.8 (0.8), and 11.3 (0.5) mm Hg v 7.3 (0.7), 7.3 (0.6), and 8.2 (0.2) mmHg respectively (mean (SEM)). At day 3 gastric mucosal injuries were increased in rats with partial portal vein ligation compared with sham operated rats (55.3 (9.4) vs 22.3 (10.5) mm2, p = 0.006), but at the later time intervals there was no significant difference in injuries between the two groups. In rats with carbon tetrachloride induced hepatic cirrhosis, portal pressure was increased (15.6 (1.0) v 6.7 (0.6) mmHg), but again there was no significant difference in mucosal injuries relative to control animals. We conclude that gastric mucosal defence mechanisms are impaired in acute but not chronic experimental portal hypertension.

Acute Disease↗
PubMed1992

A study of regional gastric mucosal blood flow in a rat model of hepatic cirrhosis.

There is controversy surrounding the effects of portal hypertension on the level of perfusion to the gastric wall. This study maps the regional distribution of gastric mucosal and muscle blood flow measured using quantitative autoradiography in a carbon tetrachloride-induced rat model of hepatic cirrhosis. There was a significant increase in both corpus mucosal (124.3 +/- 13.8 vs. 84.8 +/- 4.2 ml.100 g-1.min-1) and muscle blood flow (50.9 +/- 3.6 vs. 33.4 +/- 2.3 ml.100 g-1.min-1) in animals with experimental cirrhosis compared with controls. There was no significant difference in the ratio of blood tracer concentration between the basal and luminal aspects of corpus mucosa in cirrhotic and control groups. We conclude that experimental cirrhosis is associated with gastric mucosal hyperperfusion and that "active" rather than "passive" congestion of the stomach wall may be a more appropriate description of the basic hemodynamic change in this model.

Animals↗
PubMed1992

Erosive gastritis and portal hypertension.

There is conflicting evidence concerning the effects of portal hypertension on the gastric mucosa. This paper summarises the histological and haemodynamic alterations which are present in both human and experimental portal hypertension. Despite the fact that histological studies suggests that the gastric mucosa is an oedematous plethoric structure in portal hypertension, haemodynamic studies show that gastric mucosal blood glow is at least maintained if not increased in portal hypertension. The term "active" rather than "passive" congestion is a more appropriate description of the basic change present in the gastric mucosa in portal hypertension.

Animals↗
PubMed1992

Fibronectin as a prognostic indicator in portal hypertension.

Plasma fibronectin levels were measured in 33 patients with portal hypertension and compared with modified Child's grading and a previously described prognostic index. Outcome at one year from blood sampling was recorded. Mean plasma fibronectin level was 304.1 mg/ml (sem 24.3) and significantly lower levels were found in patients who had had a variceal bleed within the previous seven days. Plasma fibronectin levels tended to be lower in patients with poor liver function as assessed by modified Child's grading but this did not achieve statistical significance. Plasma fibronectin alone was not an accurate predictor of one year survival in these patients but only one of seven patients who had a plasma fibronectin level below 300 mg/l in association with a poor prognostic index survived for one year.

Esophageal and Gastric Varices↗
PubMed1992

A comparison of SMS 201-995 and oesophageal tamponade in the control of acute variceal haemorrhage.

Forty endoscopically proven active variceal bleeds were entered in a prospective trial comparing oesophageal tamponade with SMS 201-995 infusion. Oesophageal tamponade controlled 19 of 20 bleeds over the first four hours and 14 of 18 bleeds over 48 hours. SMS 201-995 infusion controlled 18 of 20 bleeds over the first four hours and 10 of 20 bleeds over 48 hours (p = 0.15). No significant differences between the groups were seen in time to control of bleeding, amount of blood transfused or number of patients crossed over to the opposite treatment. Complications in the oesophageal tamponade group were discomfort due to the tube (17 patients) and chest infection (10 patients), while in the SMS 201-995 group 7 chest infections and one episode of hyperglycaemia occurred, with no symptomatic complaints. The patient survived the admission in 15 of the oesophageal tamponade bleeds and all of the SMS 201-995 bleeds (p = 0.047). An intravenous infusion of SMS 201-995 appears to have comparable efficacy to oesophageal tamponade in variceal bleeding.

Acute Disease↗
PubMed1991

Injection sclerotherapy for bleeding varices: risk factors and complications.

Risk factors for complications after injection sclerotherapy were studied in 163 patients undergoing 667 treatments for bleeding oesophageal varices. The overall mortality rate was 7 per cent per injection sclerotherapy session; 16 per cent per acute session and 2.4 per cent per elective session. Acute variceal bleeding was controlled by injection sclerotherapy in 91 per cent of patients. Complications occurred after 16 per cent of injection sclerotherapy sessions. Deaths and complications were significantly associated with poor modified Child's grading (P less than 0.001), the first variceal bleed (P less than 0.001), acute injection sclerotherapy (P less than 0.001) and the use of the rigid oesophagoscope (P less than 0.001).

Esophageal and Gastric Varices↗
PubMed1991

Cyclic adenosine 3',5'-monophosphate binding proteins in human colorectal cancer and mucosa.

Cyclic AMP Binding Proteins (cAMP-BP) levels have been measured by means of a competitive binding assay in the cytosols of 50 human colorectal cancers. These levels have been related to those in mucosa both adjacent to and distant from the tumour in the same patients. Cyclic AMP-BP were higher in tumour than in either adjacent (P less than 0.000001) or distant mucosa (P less than 0.00001). Binding of cAMP in adjacent mucosa was lower than that in distant mucosa (P less than 0.0001). There was no significant difference in the level of binding between tumours arising from different sites in the colon and binding was not related to age or sex of the patient. However, binding was higher in Dukes' B than Dukes' C cancers (P less than 0.005). There was also a trend for cAMP binding levels to be higher in moderately differentiated than in poorly differentiated cancers (P = 0.07). Thus cAMP-BP appear to be over-expressed in human colorectal cancers and levels are related to the stage and grade.

Aged↗
PubMed1991

The effect of the somatostatin analogue SMS 201-995 on experimental pancreatic carcinogenesis in the Syrian golden hamster.

Somatostatin analogues have been suggested as possible therapy for human pancreatic cancer. This paper investigates the effect of the somatostatin analogue SMS 201-995 (Sandoz) in the Syrian golden hamster model of nitrosamine-induced pancreatic carcinogenesis. Step-wise increasing doses of i.v. SMS 201-995 suppressed pancreatic juice output from a median basal value of 212 mg/kg body wt/h (Q1:Q3 = 121:334) to a median basal value of 70 mg/kg body wt/h during infusion of 5 micrograms/kg body wt/h of SMS 201-995 (Q1:Q3 = 64:102, P less than 0.05). Chronic s.c. injection of 5 and 10 micrograms/kg body wt SMS 201-995 twice daily for 3 days each week, did not affect pancreatic wet wt or pancreatic total DNA content after 1 or 6 weeks of treatment when compared to controls. The most interesting and unexpected finding in our study was that SMS 201-995 seemed to promote pancreatic carcinogenesis when administered in low dosage. More SMS 201-995 treated animals receiving 5 micrograms/kg body wt developed invasive pancreatic adenocarcinoma than controls after 15 weeks of carcinogen (4/10 animals versus 0/10, P less than 0.05, Fisher's exact test) and pancreatic involvement by tumour was more extensive (17/75 pancreatic blocks affected versus 0/71, P less than 0.001). When carcinoma in situ and microcarcinomata were analysed with invasive lesions, animals injected with 5 micrograms/kg body wt SMS 201-995 were still significantly more affected than controls (33/75 blocks versus 9/71, P less than 0.001). Hamsters injected with the higher SMS 201-995 dose (10 micrograms/kg body wt) did not show any increase in malignancy over the controls. These results suggest that the effect of SMS 201-995 on pancreatic carcinogenesis in the Syrian hamster is complex and varies with dose administered. Further work is required before its use on man can be justified.

Animals↗