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Biomedical subjects

B Bennett

Publications and source records attributed to B Bennett.

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

Tissue plasminogen activator, plasminogen activator inhibitors, and activator-inhibitor complex in liver disease.

AIMS: To identify the relative contribution of plasminogen activators, particularly tissue plasminogen activator (t-PA) and specific plasminogen activator inhibitors (PAI-1, PAI-2), to the fibrinolytic changes associated with various types of liver disease or severe chemical and physical damage to the liver. METHODS: Platelet rich (PRP) and platelet poor plasma (PFP) from patients with alcoholic cirrhosis, primary biliary cirrhosis, hepatic malignancy, or paracetamol overdose, or who were undergoing partial hepatectomy or liver transplantation, were assayed for t-PA, PAI-1, t-PA-PAI-1 complex and PAI-2 antigen values using specific enzyme linked immunosorbent assays (ELISAs) developed in this laboratory. RESULTS: Appreciable increases in the plasma concentration of t-PA, PAI-1, and t-PA-PAI-1 were seen in patients with alcoholic cirrhosis, primary biliary cirrhosis, and hepatic malignancy. Liver damage due to paracetamol overdose and partial hepatectomy both resulted in a striking increase in plasma PAI-1 concentration, although concentrations of t-PA and t-PA-PAI-1 complex were less affected. Concentrations of t-PA, PAI-1, and t-PA-PAI-1 complex returned to near normal values after successful liver transplantation in a patient with chronic active hepatitis. PAI-2 was also detected in several patients with chronic liver disorders. CONCLUSIONS: Haemorrhage due to fibrinolytic bleeding is commonly associated with liver disease. The patients studied here all had appreciable increases in circulating t-PA antigen concentrations. This was associated with increased concentrations of PAI-1 antigen and t-PA-PAI-1 complex and the balance between activator and inhibitor did not result in systemic plasmin generation. Reduced PAI-1 activity in cirrhosis or a critical difference in the ratio of t-PA to PAI-1 concentrations may explain the enhanced plasminogen activator activity previously noted in cirrhosis but not metastatic disease. Reduced hepatic clearance of t-PA and t-PA-PAI-1 complex due to impaired liver function may account for increased concentrations of free and complexed t-PA.

Enzyme-Linked Immunosorbent Assay↗
PubMed1994

Distribution of plasminogen activator inhibitor in normal liver, cirrhotic liver, and liver with metastases.

AIMS: To examine the distribution of PAI-1 antigen in normal and cirrhotic liver and liver with metastases. METHODS: Sections of normal and cirrhotic liver and liver with metastases were stained using the alkaline phosphatase antialkaline phosphatase (APAAP) technique and monoclonal antibody specific for plasminogen activator inhibitor (PAI-1). RESULTS: PAI-1 antigen was identified as discrete granules in the cytoplasm of hepatocytes in normal liver, particularly around portal tracts and central veins of the liver lobule. In cirrhotic liver a striking reduction of PAI-1 antigen was noted. In liver with metastases increased amounts of PAI-1 antigen were concentrated in hepatocytes around the margins of malignant deposits. CONCLUSIONS: Cirrhotic liver contains considerably less PAI-1 antigen than does normal liver, despite raised plasma concentrations of PAI-1. This may reflect release of hepatic PAI-1 into the circulation or decreased clearance of PAI-1 from the plasma. Secondary malignant deposits in the liver seem to stimulate production of PAI-1 in adjacent hepatocytes. This may influence the invasive process and may contribute to the thrombotic tendency associated with malignancy.

Carcinoma, Hepatocellular↗
PubMed1993

Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10.

Recently, we described the cloning and expression of a human cDNA which is the homologue to P600, a gene transcribed by mouse Th2 clones. Based on its activities on human monocytes and B cells this gene was designated IL-13. In the present study we investigated the effects of IL-13 alone or in combination with IL-4, IFN-gamma, or IL-10 on human monocytes. IL-13 induced significant changes in the phenotype of monocytes. Like IL-4, it enhanced the expression of CD11b, CD11c, CD18, CD29, CD49e (VLA-5), class II MHC, CD13, and CD23, whereas it decreased the expression of CD64, CD32, CD16, and CD14 in a dose-dependent manner. IL-13 induced up-regulation of class II MHC Ag and its down-regulatory effects on CD64, CD32, and CD16 expression were prevented by IL-10. IFN-gamma could also partially prevent the IL-13-induced down-regulation of CD64, but not that of CD32 and CD16. However, IL-13 strongly inhibited spontaneous and IL-10- or IFN-gamma-induced ADCC activity of human monocytes toward anti-D coated Rh+ erythrocytes, indicating that the cytotoxic activity of monocytes was inhibited. Furthermore, IL-13 inhibited production of IL-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, IL-12 p35, IL-12 p40, macrophage inflammatory protein-1 alpha, granulocyte/macrophage-CSF, granulocyte-CSF, IFN-alpha, and TNF alpha by monocytes activated with LPS. In contrast, IL-13 enhanced the production of IL-1 ra by these cells. Similar results on cytokine production were observed or have been obtained with IL-4. Thus IL-13 shares most of its activities on human monocytes with IL-4, but no additive or synergistic effects of IL-4 and IL-13 on human monocytes were observed, suggesting that these cytokines may share common receptor components. Taken together, these results indicate that IL-13 has anti-inflammatory and important immunoregulatory activities.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1993

Outcome in colorectal adenocarcinoma: two seven-year studies of a population.

OBJECTIVE: To record every patient with proved colorectal adenocarcinoma presenting from a defined population over two years in 1968-9 and during 1980-2, and to compare treatment and outcome over seven years. DESIGN: Retrospective in 1968-9 and prospective in 1980-2. SETTING: Aberdeen general hospitals. SUBJECTS: Every patient presenting to the four general surgical units with histological proof of colorectal adenocarcinoma. MAIN FINDINGS: On average, one new patient presented each week per 100,000 population. The proportion of patients aged 65 and over rose from 67% to 71%. An operation was performed on 385 patients in 1968-9 and on 399 during 1980-2. At laparotomy the proportion of patients who seemed to be curable and had a radical operation rose slightly, from 56% to 61%, and operative mortality fell from 9% to 5%. In all there were 421 survivors of curative surgery, and seven years later three quarters were either alive (51%) or had died without recurrence (25%). In both studies some 40% of patients were considered incurable when they presented, but the number who had a palliative resection rose from 59% to 85%. CONCLUSIONS: The contribution of radical surgery to the treatment of colorectal adenocarcinoma is substantial, with three quarters of patients so treated showing no evidence of recurrence after seven years. Operative mortality in an elderly population is now low, and improvement in late outcome is more likely to come from developments in adjuvant therapy than in operative technique. A continuing problem is that 40% of patients are not curable when they present, although palliative resection can now be offered to over 80%.

Adenocarcinoma↗
PubMed1993

The roles of alpha 2-antiplasmin and plasminogen activator inhibitor 1 (PAI-1) in the inhibition of clot lysis.

The relative importance of the two major inhibitors of fibrinolysis, alpha 2-antiplasmin (alpha 2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified alpha 2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to alpha 2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 x 10(8)/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, alpha 2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of alpha 2-AP, in such situations.

Blood Platelets↗
PubMed1993

Parvovirus B19 induced red cell aplasia in myelofibrosis.

A 38-year-old female presented with moderate anaemia and a leucoerythroblastic blood film. Subsequent investigation showed myelofibrosis in cellular phase. Her haemoglobin quickly and spontaneously recovered with concurrent serological evidence of recent parvovirus B19 infection. This is the first report in the literature of parvovirus causing red cell aplasia in myelofibrosis.

Adult↗
PubMed1993

Plasminogen activator inhibitors (PAI-1 and PAI-2) in normal pregnancies, pre-eclampsia and hydatidiform mole.

OBJECTIVE: To examine the behaviour of the major inhibitors of fibrinolysis (PAI-1 and PAI-2) in normal pregnancy and pregnancy complicated by either pre-eclampsia or hydatidiform mole. DESIGN: Prospective study. SETTING: Antenatal Clinic and Maternity Hospital. SUBJECTS: Eleven women with established pre-eclampsia and eleven women, matched by age, parity, and duration of pregnancy who were undergoing uncomplicated pregnancy. Two women having surgery for hydatidiform mole. MAIN OUTCOME MEASURE: Plasma levels of PAI-1 and PAI-2 antigens determined by sensitive specific ELISA. Functional identification of PAI-2 by nondenaturing gel electrophoresis with overlay zymography. RESULTS: In pre-eclampsia PAI-2 antigen was significantly lower than in normal pregnancy (105.3 +/- 34.9 versus 187.1 +/- 67.9 ng/ml; P < 0.001). In contrast PAI-1 antigen was significantly higher in pre-eclampsia than in normal pregnancy (170.7 +/- 71.2 versus 113.8 +/- 35.6 ng/ml; P < 0.05). In consequence the ratio of PAI-1/PAI-2 increased markedly in pre-eclampsia (2.5 versus 0.6). No PAI-2 was detected in plasma of women with hydatidiform moles. CONCLUSIONS: PAI-2 levels fell significantly in pre-eclampsia probably as a result of decreased placental mass or function. The raised PAI-1 level in pre-eclampsia may reflect a response to hypertension or renal damage that is not specific to pregnancy or may reflect altered placental function. The use of the ratio of PAI-1/PAI-2 assists in separating normal from abnormal pregnancies.

Enzyme-Linked Immunosorbent Assay↗
PubMed1993

Development of a trehalose 6,6'-dimycolate model which explains cord formation by Mycobacterium tuberculosis.

Trehalose 6,6'-dimycolate (TDM) is a glycolipid of mycobacteria that displays an unusual toxicity and has been reported to be a virulence factor for Mycobacterium tuberculosis. Lack of understanding of the toxicity has impeded acceptance of TDM as a virulence factor. We previously reported that the toxicity of TDM depends on its presentation as a surface monolayer consisting of 30% trehalose and 70% exposed mycolic acid moieties. This paper further investigates the structure of the TDM monolayer. It began with the observation that beads coated with TDM, but not with closely related analogs, aggregate to form organized structures resembling the cords of virulent mycobacteria. This implied that the TDM molecules in the monolayer were arranged in an organized structure. This structure was investigated by real-time kinetic microscopy, scanning electron microscopy, and gross observations of the adhesion patterns of TDM-coated beads. In each of these models, the structures induced by TDM differed from those of analogs or other amphiphiles studied. These observations were used to construct a model of the structure of TDM monolayer which envisions linear arrays of TDM molecules arranged in a circumferential pattern on beads with discontinuities only at the two poles.

Cord Factors↗
PubMed1992

A comparison of commercially available adjuvants for use in research.

We evaluated an adjuvant, TiterMax, as an alternative to complete Freund's adjuvant (CFA) for producing antisera in animals. TiterMax, consists of a microparticulate stabilized water-in-oil emulsion of a metabolizable oil, squalene, with the adjuvant block copolymer CRL89-41. This paper reports two evaluations of TiterMax versus CFA and other commercially available adjuvants. In the first study, mice were immunized with a hapten, trinitrophenol, conjugated to hen egg albumin (TNP-HEA) in one of several adjuvants: TiterMax, CFA, Adjuvax, Ribi adjuvant system (RAS), Alhydrogel or Lipovant. TiterMax induced higher longer lasting titers with fewer injections than any of the other adjuvants. The magnitude of the response to TNP varied with species and route of immunization. In the second study, CFA, TiterMax, Adjuvax and RAS were compared in rabbits, mice and goats. Animals were immunized with luteinizing hormone-releasing hormone (LHRH) conjugated to BSA in each adjuvant using comparable protocols. TiterMax induced titers against the peptide equivalent to CFA in all three species. The inflammatory responses induced by TiterMax were mild and transient compared with those induced by CFA. These data suggest that TiterMax is an effective alternative to CFA in many situations.

Adjuvants, Immunologic↗
PubMed1992

Significance of accessory ductal structures in hernia sacs.

The finding of ductal structures resembling a vas deferens during pathological examination of a hernia sac specimen has significant medical and legal implications. A method of distinguishing these accessory structures from an inadvertently transected vas has been lacking and is needed. Between July 1989 and January 1990 we examined 147 hernia sacs from 105 consecutive prepubertal and adolescent boys to determine the incidence and salient histological features distinguishing these ductal structures from a true vas deferens. Luminal diameters of the ductal structures were compared with published normal age-related established vas deferens diameters and with those measured during hernia repair in 10 of our youngest patients. Among the 147 specimens 6 hernia sacs (4.1%) contained ductal structures. We found that the mean ductal diameter (0.263 mm.) was significantly smaller than that of a normal vas deferens (0.69 to 1.5 mm.). Furthermore, the surrounding mantle of tissue of these ductal structures lacked muscle tissue when studied with Masson trichrome stain. We conclude that duct diameter and trichrome staining are simple ways of differentiating these structures from a true vas deferens.

Adolescent↗
PubMed1992

Management of ventricular arrhythmias: then and now.

OBJECTIVE: To review the changing environment of antiarrhythmic therapy. DATA SOURCES: The majority of articles chosen were written by experts in the field of arrhythmia management. The references include a pilot study, abstracts, original articles and results of study groups. An equal number of sources used in this article were obtained from fellow healthcare professionals and MEDLINE searches. STUDY SELECTION: Large, controlled clinical trials in which patient populations had structural heart disease, prior myocardial infarction and/or frequent ventricular premature beats. All were treated with either antiarrhythmic therapy or devices. DATA SYNTHESIS: Past research in the field of arrhythmia management has indicated that ventricular premature beat suppression is the key to increasing patient survival. After reviewing the results of such pivotal trials as the Cardiac Arrhythmia Suppression Trial, however, the question of whether to initiate therapy remains. CONCLUSIONS: Several trials investigating the efficacy of antiarrhythmic drugs in decreasing sudden death have yielded disappointing results. These trials have been beneficial, however, in classifying arrhythmias and assessing patient risk. The outcomes of these trials, combined with advances in the treatment of heart disease, provide us with a framework for antiarrhythmic therapy. Additional controlled clinical trials are necessary if we are to learn the best means of increasing survival in ventricular arrhythmia patients.

Action Potentials↗
PubMed1991

Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.

Base Sequence↗
PubMed1991

31P ENDOR studies of xanthine oxidase: coupling of phosphorus of the pterin cofactor to molybdenum (V).

31P ENDOR spectra are described for three different molybdenum(V) species in reduced xanthine oxidase samples. The spectra were not affected by removing the FAD from the enzyme, implying that this is located at some distance from molybdenum. Furthermore, in confirmation of the work of J. L. Johnson, R. E. London, and K. V. Rajagopalan [(1989) Proc. Natl. Acad. Sci. U.S.A. 86, 6493-6497], NMR and chemical analysis of the phosphate content of highly purified xanthine oxidase showed there are only three phosphate residues per subunit of the enzyme. It is concluded that the ENDOR features are due to hyperfine coupling of the phosphate group of the pterin cofactor to the molybdenum atom. Evaluation of the dipolar component of the coupling has permitted estimation of the molybdenum-phosphorus distances as 7-12 A. This implies that the cofactor is in an extended conformation in the enzyme molecule. Less detailed 31P ENDOR data on sulfite oxidase are consistent with a similar conformation for the cofactor in this enzyme.

Animals↗
PubMed1991

The receptor for tissue plasminogen activator (t-PA) in complex with its inhibitor, PAI-1, on human hepatocytes.

The binding of t-PA-PAI-1 to human hepatocytes at 4 degrees C reached a maximum at 2 h. Scatchard analysis indicated 74,000 +/- 11,000 high-affinity binding sites for complex per human hepatocyte, with a Kd of 0.87 +/- 0.09 nM. Almost identical results were achieved with the human hepatoma cell line Hep G2. Binding of [125I]t-PA-PAI-1 complex was unaffected by high concentrations of unlabelled t-PA, PAI-1, u-PA or u-PA-PAI-1 complex; only t-PA-PAI-1 complex competed for binding. Hepatocyte-bound t-PA-PAI-1 was internalized and degraded at 37 degrees C. Thus, hepatocytes have a specific t-PA-PAI-1 receptor that participates in clearance of this complex.

Binding, Competitive↗
PubMed1991

Distribution of plasminogen activator inhibitor (PAI-1) in tissues.

Extracts of human tissue were analysed for plasminogen activator inhibitor (PAI-1) antigen and activity. PAI-1 was localised in tissues by an immunochemical method, using monoclonal antibodies. PAI-1 occurred throughout the body; its concentration and activity differed considerably from organ to organ. Extracts of liver and spleen had the greatest abundance of PAI-1, but the activity of the inhibitor was much higher in liver than in spleen: the liver may be a source of plasma PAI-1. Immunochemical staining for PAI-1 was observed in endothelium, platelets and their precursor cells, the megakaryocytes, and locations central to the process of haemostasis. PAI-1 also occurred in neutrophil polymorphs and macrophages, cells important in inflammatory and immune processes, but not in lymphocytes. Other cell types, in particular, vascular smooth muscle cells and mesangial cells, also stained positively for PAI-1 and such cells seem to represent an important reservoir of PAI-1.

Autopsy↗
PubMed1991

Continuation and maintenance treatment of major depression with the monoamine oxidase inhibitor phenelzine: a double-blind placebo-controlled discontinuation study.

Long-term treatment with antidepressant drugs has received little attention until recently. A study is reported comparing the effectiveness of maintenance treatment with phenelzine in responding major depression patients. If they responded initially to nonblind phenelzine treatment and sustained remission for 16 weeks, patients were randomized to 2-year double-blind treatment with phenelzine 60 mg/day, phenelzine 45 mg/day, or placebo. Both doses of phenelzine were significantly better than placebo in preventing relapse of depression. Phenelzine 45 mg/day may be an optimal maintenance dose for many patients.

Adult↗