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Biomedical subjects

D C Carter

Publications and source records attributed to D C Carter.

At least 37 records · Page 2Linked to original sources
PubMed1996

Metabolic disturbance and sensitivity to endotoxin in patients with advanced cancer: relationship to lymphocyte reactivity, tumour necrosis factor (TNF) production and survival.

Increased TNF production and impaired lymphocyte function have been individually linked with metabolic disturbance, endotoxaemia and mortality in humans. The inter-relationship between these observations was investigated in humans with cancer. In 13 patients with metastatic colorectal cancer and seven healthy volunteers, observations (n = 23) included peripheral blood mononuclear cell (PBMC) TNF production, IL-2 production and phytohaemagglutinin (PHA) response; the acute-phase protein response (APPR) (serum C-reactive protein (CRP), albumin, CRP/albumin ratio), and survival. APPR correlated with survival (CRP, r = -0.689, P = 0.006; CRP/albumin, r = -0.758, P = 0.002; albumin, r = 0.655, P = 0.011), but not with TNF production. TNF production in response to in vitro endotoxin correlated with impaired lymphocyte function in patients (r = 0.567, P = 0.043) and in the whole group (r = 0.65, P = 0.001). The ratio (basal PBMC TNF production)/(lymphocyte function) correlated with CRP (r = 0.569, P = 0.042), CRP/albumin (r = 0.617, P = 0.025), endotoxin sensitivity (r = 0.567, P = 0.043) and survival (r = -0.545, P = 0.038) in patients, and the whole group (P < 0.002). Impaired lymphocyte function may influence TNF production, endotoxin sensitivity and metabolic disturbance in humans with cancer. (r = Spearman correlation coefficient.)

Adult↗
PubMed1996

Report on consensus conference on colorectal cancer: Royal College of Surgeons of Edinburgh 1993.

Colorectal cancer is the second commonest cause of death from cancer in Scotland. Recent developments in molecular biology, pre-symptomatic diagnosis, surgery and adjuvant treatment suggest that a substantial reduction in mortality is achievable. Some fear that major changes to the organisation of the NHS could undermine future attempts to coordinate major cancer screening studies or multicentre adjuvant trials. In contrast, others argue that a sharp focus on cost and benefits could encourage the development of clear guidelines based on a consensus of good practice. Thus, the time seems right for a consensus conference and this article summarises the outcome of such a recent conference held in Scotland. A group of 80 surgeons, radiation oncologists and medical oncologists were invited as a representative cross-section of clinicians with an interest in colorectal cancer. Seventy per cent of those attending were surgeons. A series of expert presentations were used to lead discussion in four sessions devoted respectively to epidemiology and screening, influence of surgical factors and outcome, the role of adjuvant therapy and planning for the future. Full discussion from delegates was encouraged and computer-collated, key-pad responses allowed documentation of the opinions of the audience in respect of pre-defined questions. For statistical purposes we have assumed that a consensus had been reached when there was a statistically significant difference (Chi-square) between the observed response from clinicians and the null hypothesis, i.e. a 50/50 split.

Aftercare↗
PubMed1995

Acute-phase protein response and survival duration of patients with pancreatic cancer.

BACKGROUND: Current methods to predict survival duration of patients with pancreatic cancer are limited. The aim of this study was to determine whether certain nutritional indices and the acute-phase protein response are prognostic factors independent of disease stage for patients with unresectable pancreatic cancer. METHODS: Variables at the time of diagnosis of 102 patients with unresectable pancreatic cancer were entered into a Cox's proportional hazards model. Included in the analysis were the serum concentration of C-reactive protein (CRP) and albumin, the extent of weight loss, age, sex, and disease stage (International Union Against Cancer criteria). RESULTS: A multivariate analysis in which each factor was adjusted for the influence of the other factors revealed the patient age, disease stage, serum albumin, and serum CRP to be independent predictors of survival. The presence of an acute-phase protein response was the most significant independent predictors of survival duration. The median survival of those with an acute-phase protein response (CRP > 10 mg/L, n = 45) was 66 days compared with 222 days for those with no acute-phase protein response (n = 57, P = 0.001, Mann-Whitney U test). CONCLUSION: The acute-phase protein response is a useful prognostic indicator for patients with unresectable pancreatic cancer. Moreover, the metabolic disturbances associated with an acute-phase protein response of patients with pancreatic cancer may be a worthwhile therapeutic target.

Acute-Phase Proteins↗
PubMed1995

Effect of ibuprofen on the acute-phase response and protein metabolism in patients with cancer and weight loss.

The aim of this study was to determine whether administration of the non-steroidal anti-inflammatory agent ibuprofen might attenuate the acute-phase response in patients with colonic cancer. Cytokines and acute-phase proteins were measured before administration of ibuprofen and again 3 days later, when protein synthesis was measured using 15N-glycine. In patients with cancer, ibuprofen caused a significant reduction in the plasma concentration of all five acute-phase proteins studied. Although interleukin 6 levels were raised, they did not change following administration of ibuprofen. Unlike the situation in patients with cancer who did not receive ibuprofen, whole-body protein kinetics were similar to those of control subjects in patients with cancer who received ibuprofen. Whether or not ibuprofen had been administered, non-export hepatic protein synthesis rates were significantly lower in patients with than in those without cancer. These results suggest that short-term administration of ibuprofen can attenuate accelerated whole-body protein kinetics and the acute-phase response in patients with advanced cancer.

Acute-Phase Proteins↗
PubMed1995

Ibuprofen reduces energy expenditure and acute-phase protein production compared with placebo in pancreatic cancer patients.

The aim of this study was to investigate the effect of the cyclo-oxygenase inhibitor ibuprofen on the acute-phase protein response and resting energy expenditure (REE) of weight-losing patients with pancreatic cancer. Patients with irresectable pancreatic cancer (n = 16) were treated with either ibuprofen (1200 mg day-1 for 7 days (n = 10) or placebo (n = 6). A group of 17 age-related non-cancer subjects were also studied. Indirect calorimetry, anthropometry, multifrequency bioelectrical impedence analysis and serum C-reactive protein (CRP) estimation were performed immediately before and after treatment. Before treatment, total REE was significantly elevated in the pancreatic cancer patients compared with healthy controls (1499 +/- 71 vs 1377 +/- 58 kcal) (P < 0.02). Following treatment the mean REE of the ibuprofen group fell significantly (1386 +/- 89 kcal) compared with pretreatment values (1468 +/- 99 kcal) (P < 0.02), whereas no change was observed in the placebo group. Serum CRP concentration was also reduced in the ibuprofen-treated group (pre-ibuprofen, 51 mg l-1; post-ibuprofen, 29 mg l-1; P < 0.05). These results suggest that ibuprofen may have a role in abrogating the catabolic processes which contribute to weight loss in patients with pancreatic cancer.

Acute-Phase Proteins↗
PubMed1995

Interleukin-4 and interleukin-10 increase endotoxin-stimulated human umbilical vein endothelial cell interleukin-8 release.

The aim of this study was to determine the effect of interleukin-4 (IL-4) and interleukin-10 (IL-10) on interleukin-8 (IL-8) release from endothelial cells. Confluent monolayers of human umbilical vein endothelial cells (HUVECs) were incubated in the absence or presence of 10 ng/ml of bacterial lipopolysaccharide (LPS), with 5% human AB serum and recombinant human IL-4 or IL-10 over a dose range from 50 fg/ml to 50 ng/ml (final concentration). IL-4 and IL-10 had no effect on HUVEC IL-8 release in the absence of LPS. In the presence of LPS, IL-4 and IL-10 enhanced IL-8 release by approximately 300% compared with LPS-stimulated cells alone, IL-8 release increasing from 2594 +/- 493 pg/ml (no IL-4 or IL-10) to 7892 +/- 320 pg/ml (IL-4, 5 pg/ml; p = 0.001) and 8359 +/- 712 pg/ml (IL-10, 50 pg/ml; p = 0.002). IL-8 release in response to IL-4 or IL-10 plateaued above 5 and 50 pg/ml, respectively. This study suggests that IL-4 and IL-10 may be involved in the complex regulation of endothelial cell cytokine production during the response to endotoxin.

Cells, Cultured↗
PubMed1995

Interaction between a Fab fragment against gp41 of human immunodeficiency virus 1 and its peptide epitope: characterization using a peptide epitope library and molecular modeling.

The molecular interaction of the Fab fragment of the human monoclonal antibody 3D6, directed against the transmembrane protein gp41 of human immunodeficiency virus (HIV) 1, with its peptide epitope is characterized by a panel of overlapping peptides, a peptide epitope library and molecular modeling techniques. The sequence CSGKLICTTAVPW, corresponding to amino acids 605-617 of gp41, was identified as the best binding peptide (KD = 1 x 10(-8) mol/l). This peptide served as a starting point to prepare a cellulose-bound peptide epitope library in which each residue of the epitope is substituted by all L- and D-amino acids, resulting in 494 epitope peptide variants which were subsequently analyzed for binding 3D6. The library was synthesized to identify residues critical for binding and to obtain information about the molecular environment of the epitope peptide bound to 3D6. Both cysteine residues, as well as isoleucine 6, threonine 8 and proline 12, of the epitope were highly sensitive to substitution. Using the data obtained from the epitope characterization, as well as a low-resolution electron density map of a 3D6 Fab-peptide complex, a 3-D model of the Fab-peptide complex was generated by molecular modeling. The modeling experiments predict binding of the peptide, which is cyclized via the two cysteine residues, to a pocket formed dominantly by the hypervariable loops complementarity determining regions CDR3L, CDR2H and CDR3H.

Amino Acid Sequence↗
PubMed1995

Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography.

OBJECTIVE: The authors performed a prospective evaluation of staging laparoscopy with laparoscopic ultrasonography in predicting surgical resectability in patients with carcinomas of the pancreatic head and periampullary region. SUMMARY BACKGROUND DATA: Pancreatic resection with curative intent is possible in a select minority of patients who have carcinomas of the pancreatic head and periampullary region. Patient selection is important to plan appropriate therapy and avoid unnecessary laparotomy in patients with unresectable disease. Laparoscopic ultrasonography is a novel technique that combines the proven benefits of staging laparoscopy with high resolution intraoperative ultrasound of the liver and pancreas, but which has yet to be evaluated critically in the staging of pancreatic malignancy. METHODS: A cohort of 40 consecutive patients referred to a tertiary referral center and with a diagnosis of potentially resectable pancreatic or periampullary cancer underwent staging laparoscopy with laparoscopic ultrasonography. The diagnostic accuracy of staging laparoscopy alone and in conjunction with laparoscopic ultrasonography was evaluated in predicting tumor resectability (absence of peritoneal or liver metastases; absence of malignant regional lymphadenopathy; tumor confined to pancreatic head or periampullary region). RESULTS: "Occult" metastatic lesions were demonstrated by staging laparoscopy in 14 patients (35%). Laparoscopic ultrasonography demonstrated factors confirming unresectable tumor in 23 patients (59%), provided staging information in addition to that of laparoscopy alone in 20 patients (53%), and changed the decision regarding tumor resectability in 10 patients (25%). Staging laparoscopy with laparoscopic ultrasonography was more specific and accurate in predicting tumor resectability than laparoscopy alone (88% and 89% versus 50% and 65%, respectively). CONCLUSIONS: Staging laparoscopy is indispensable in the detection of "occult" intra-abdominal metastases. Laparoscopic ultrasonography improves the accuracy of laparoscopic staging in patients with potentially resectable pancreatic and periampullary carcinomas.

Adenocarcinoma↗
PubMed1995

Factors influencing morbidity and mortality in acute pancreatitis; an analysis of 279 cases.

Of 279 patients admitted to a specialist unit with acute pancreatitis, 210 were admitted directly and 69 were transferred for treatment of local or systemic complications. Outcome was assessed in terms of mortality and morbidity and in relation to aetiology, predicted severity of disease (modified Glasgow score), organ failure (modified Goris multiple organ failure score), and need for surgical intervention. The death rate was 1.9% in patients admitted directly but was 18.8% in those transferred from other units. Mortality in gall stone related pancreatitis was 3% compared with 15% (p = 0.03) in pancreatitis of unknown aetiology and 27% (p = 0.01) in post-endoscopic retrograde cholangiopancreatography pancreatitis. Mortality was related to age (mortality > 55 years old 11% v 2%; p = 0.003) and Goris score (score 0, mortality 0% v score 5-9, mortality 67%; p = 0.001). In patients transferred from other units, mortality was 11% in those transferred within a week of diagnosis and 35% when transfer was delayed (p = 0.04). Thirty six patients had pancreatic necrosis on dynamic computed tomography of whom 29 underwent pancreatic necrosectomy with a 34% mortality. Mortality was related to the modified Goris score (median score 2 in survivors v 6 in non-survivors; p = 0.005) and was higher when necrosectomy was performed within the first two weeks of admission (100% vs 21%; p = 0.004). In conclusion, mortality in acute pancreatitis is influenced by age, aetiology of the disease, and presence of organ failure. Patients transferred for specialist care have a 10-fold greater mortality than those admitted directly and mortality is greatest when transfer is delayed. Early necrosectomy carries a prohibitively high mortality.

Acute Disease↗
PubMed1995

Insulin and counterregulatory hormones influence acute-phase protein production in human hepatocytes.

After trauma or sepsis, the liver undergoes a reprioritization of export protein synthesis with elevated production of some acute-phase reactants and reduced production of others. We have examined the effects of combinations of insulin and the counterregulatory hormones (dexamethasone, glucagon, and epinephrine), in the presence or absence of interleukin (IL)-6, on the production by isolated hepatocytes of the positive acute-phase proteins C-reactive protein, alpha 1-antichymotrypsin, alpha 1-acid glycoprotein, and haptoglobin, and the negative acute-phase proteins prealbumin and transferrin. The effect of IL-6 on the production of the above proteins was influenced significantly by insulin and all of the counterregulatory hormones. Significant three-way interactions as well as higher order interactions between the stress hormones and insulin were seen in the case of C-reactive protein. The results indicate that both positive and negative acute-phase proteins respond differently to insulin and the counterregulatory hormones and that the potential exists for the regulation of synthesis of individual acute-phase reactants by interaction between the cytokine network and the classical endocrine hormones.

Acute-Phase Proteins↗
PubMed1994

Preliminary crystallographic studies of four crystal forms of serum albumin.

Several crystal forms of serum albumin suitable for three-dimensional structure determination have been grown. These forms include crystals of recombinant and wild-type human serum albumin, baboon serum albumin, and canine serum albumin. The intrinsic limits of X-ray diffraction for these crystals are in the range 0.28-0.22 nm. Two of the crystal forms produced from human and canine albumin include incorporated long-chain fatty acids. Molecular replacement experiments have been successfully conducted on each crystal form using the previously determined atomic coordinates of human serum albumin illustrating the conserved tertiary structure.

Animals↗
PubMed1994

Role of selectins in development of adult respiratory distress syndrome.

The acute lung injury of adult respiratory distress syndrome (ARDS) is characterised by inflammatory cell accumulation and activation in the lung. Selectins are a family of adhesion molecules implicated in leucocyte-endothelial adhesion, whose receptors can exist in a cleaved, soluble form. We investigated whether circulating soluble selectin adhesion molecules, obtained from ARDS at-risk patients, were associated with subsequent ARDS development. 82 patients, at risk of ARDS, were enrolled from three well-defined groups (multiple trauma, pancreatitis, perforated bowel). Plasma samples were obtained on hospital presentation and soluble L, E, and P, selectins were quantified with a sandwich enzyme-linked immunosorbent assay (ELISA). 14 patients subsequently developed ARDS. Initial plasma soluble L-selectin (sL-selectin) levels were significantly lower in patients who progressed to ARDS compared to those who did not (p = 0.0001; 95% Cl for mean in ARDS patients as percent of that in non-ARDS patients, 27-61%). Moreover concentrations were lower than in 62 normal volunteers (range 0.37-6.55, median 1.83 micrograms/mL, n = 62), suggesting that a selective reduction of sL-selectin correlates with susceptibility. In addition, a significant correlation was found between low values of sL-selectin and indices of subsequent lung injury including requirement for ventilation (p = 0.0001) and degree of respiratory failure (p = 0.0001). A significant correlation was also found between low values of sL-selectin and patient mortality (p = 0.002). These results elucidate the inflammatory cell endothelial interactions in the early stages of ARDS and may be of prognostic value.

Acute Disease↗
PubMed1994

Chemotherapy prolongs survival in inoperable pancreatic carcinoma.

Forty-three patients with irresectable advanced pancreatic cancer were randomized to receive chemotherapy using a combination of 5-fluorouracil, Adriamycin and mitomycin or no chemotherapy. Groups were well matched with regard to age, extent of disease and performance status on entry. Chemotherapy was well tolerated and, although common, side-effects were usually mild. Psychological measurements based on the Hospital Anxiety and Depression score were made in 31 patients. These showed significantly less depression but not anxiety in the treated group immediately after randomization and following 2 months of chemotherapy. Median survival in the treated group was 33 (range 9-80) weeks compared with 15 (range 1-62) weeks in the untreated group (P < 0.002). Chemotherapy should be considered in all patients presenting with advanced inoperable pancreatic cancer.

Adult↗
PubMed1994

Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12-21.

Eight breast cancer pedigrees with a high probability of containing individuals with the BRCA1 gene mutation (odds 79.2-99.9 per cent) were identified through genetic linkage analysis using probes located within q12-22 on the long arm of chromosome 17. Some 102 female relatives were successfully typed with one or both of adjacent markers D17S588 and D17S579, and 41 were probable non-BRCA1 mutation carriers. Of the remaining 61 women classified as probable BRCA1 carriers, breast cancer was diagnosed in 35. As expected from epidemiological segregation analysis studies, 13 of these had bilateral disease. Approximately two-thirds of women unaffected by malignancy and alive at the time of observation were non-BRCA1 carriers. Lifetime disease penetrance of the BRCA1 gene was 88 per cent and this plateau was reached earlier (by age 65 years) than that estimated in segregation analysis. The survival curve of patients with breast cancer was less steep in BRCA1 gene carriers than that in the general population; 5-, 10- and 20-year survival rates unadjusted for non-cancer deaths were 83, 63 and 41 per cent respectively. The 5-year survival rate was significantly higher in BRCA1 carriers than that in an age-matched Scottish population (P < 0.05).

Adult↗
PubMed1994

Segment III cholangiojejunostomy for palliation of malignant hilar obstruction.

Between 1984 and 1992, 26 patients with obstructive jaundice due to malignancy at the liver hilum were treated by segment III Roux-en-Y cholangiojejunostomy. Twenty-two patients had hilar cholangiocarcinoma, one carcinoma of the gallbladder, one pancreatic carcinoma, one recurrent gastric carcinoma and one lymphoma. Seventeen patients had no complications in the postoperative period and six had complications; there were three postoperative deaths. Eighteen of the 23 surviving patients experienced complete resolution of jaundice for at least 3 months. Four developed recurrent jaundice and three had episodes of cholangitis before death. Segment III cholangiojejunostomy offers effective palliation for most patients with irresectable hilar malignancy.

Adult↗