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Biomedical subjects

E J Andrews

Publications and source records attributed to E J Andrews.

At least 19 recordsLinked to original sources
PubMed2006

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

Disease Progression↗
PubMed2006

Haemoglobin A1c (HbA1C) in non-diabetic and diabetic vascular patients. Is HbA1C an independent risk factor and predictor of adverse outcome?

BACKGROUND: Plasma Haemoglobin A1c (HbA1c) reflects ambient mean glycaemia over a 2-3 months period. Reports indicate that patients, with and without diabetes, with an elevated HbA1c have an increased risk of adverse outcome following surgical intervention. Our aim was to determine whether elevated plasma HbA1c level was associated with increased postoperative morbidity and mortality in patients undergoing vascular surgical procedures. METHODS: Plasma HbA1c was measured prospectively in 165 consecutive patients undergoing emergency and elective vascular surgical procedures over a 6-month period. Patients were categorized into four groups depending on whether their plasma HbA1c was < or =6%, 6.1-7%, 7.1-8% or >8% and clinical data was entered into a prospectively maintained database. Patients were also classified by diabetic status with suboptimal HbA1c in a patient without diabetes being >6 to < or =7% and suboptimal HbA1c in a patient with diabetes being >7%. Patients with plasma HbA1c >7% were reclassified as having undiagnosed diabetes mellitus. Composite primary endpoints were all cause 30-day morbidity and mortality and all cause 6-month mortality. Composite secondary endpoints were procedure specific complications, adverse cardiac events, stroke, infection and mean length of hospital stay. RESULTS: Of the 165 patients studied, 43 (26.1%) had diabetes and the remaining 122 (73.9%) did not. The mean age was 72 years and 59% were male. Suboptimal HbA1c levels were found in 58% patients without diabetes and in 51% patients with diabetes. In patients without diabetes those with suboptimal HbA1c levels (6-7%) had a significantly higher incidence of overall 30-day morbidity compared to patients with HbA1c levels < or =6% (56.5 vs 15.7%, p<0.001). Similarly, for patients with diabetes those with suboptimal HbA1c levels (HbA1c >7%) had a significantly higher incidence of 30-day morbidity compared to those with HbA1c levels < or =7% (59.1% vs 19%, p=0.018). Multivariate analysis revealed that a plasma HbA1c level of >6 to < or =7% was a significant independent predictor of overall 30-day morbidity in patients without diabetes undergoing vascular surgical procedures. No difference in mortality, composite secondary endpoints, procedure specific complications, stroke or mean length of hospital stay was observed between any of the groups in the study. CONCLUSION: Suboptimal HbA1c levels may hold prognostic significance in patients without diabetes undergoing vascular surgery.

Aged↗
PubMed2004

A review of clinical guidelines.

BACKGROUND: Clinical guidelines are increasingly used in patient management but few clinicians are familiar with their origin or appropriate application. METHODS: A Medline search using the terms 'clinical guidelines' and 'practice guidelines' was conducted. Additional references were sourced by manual searching from the bibliographies of articles located. RESULTS AND CONCLUSION: Clinical guidelines originated in the USA in the early 1980s, initially as a cost containment exercise. Significant improvements in the process and outcomes of care have been demonstrated following their introduction, although the extent of improvement varies considerably. The principles for the development of guidelines are well established but many published guidelines fall short of these basic quality criteria. Guidelines are only one aspect of improving quality and should be used within a wider framework of promoting clinical effectiveness. Understanding their limitations as well as their potential benefits should enable clinicians to have a clearer view of their place in everyday practice.

Evaluation Studies as Topic↗
PubMed2001

Tumor cell adhesion to endothelial cells is increased by endotoxin via an upregulation of beta-1 integrin expression.

BACKGROUND: Recent studies have demonstrated that metastatic disease develops from tumor cells that adhere to endothelial cells and proliferate intravascularly. The beta-1 integrin family and its ligand laminin have been shown to be important in tumor-to-endothelial cell adhesion. Lipopolysaccharide (LPS) has been implicated in the increased metastatic tumor growth that is seen postoperatively. We postulated that LPS increases tumor cell expression of beta-1 integrins and that this leads to increased adhesion. METHODS: The human metastatic colon cancer cell line LS174T was labeled with an enhanced green fluorescent protein (eGFP) using retroviral transfection. Cell cultures were treated with LPS for 1, 2, and 4 h (n = 6 each) and were subsequently cocultured for 30 or 120 min with confluent human umbilical vein endothelial cells (HUVECs), to allow adherence. Adherent tumor cells were counted using fluorescence microscopy. These experiments were carried out in the presence or absence of a functional blocking beta-1 integrin monoclonal antibody (4B4). Expression of beta-1 integrin and laminin on tumor and HUVECs was assessed using flow cytometric analysis. Tumor cell NF-kappaB activation after incubation with LPS was measured. RESULTS: Tumor cell and HUVEC beta-1 integrin expression and HUVEC expression of laminin were significantly (P < 0.05) enhanced after incubation with LPS. Tumor cell adhesion to HUVECs was significantly increased. Addition of the beta-1 integrin blocking antibody reduced tumor cell adhesion to control levels. LPS increased tumor cell NF-kappaB activation. CONCLUSIONS: Exposure to LPS increases tumor cell adhesion to the endothelium through a beta-1 integrin-mediated pathway that is NF-kappaB dependent. This may provide a target for immunotherapy directed at reducing postoperative metastatic tumor growth.

Cell Adhesion↗
PubMed2001

Influence of ferrous iron and ph on carbon tetrachloride degradation by Methanosarcina thermophila.

The influence of environmental conditions on the biological transformation of a contaminant must be well understood to optimize remediation processes. One factor that impacts the biological transformation of carbon tetrachloride (CT) is elemental iron (Fe0). Previous research has shown that Fe0 increases the methanogenic CT degradation rate by providing H2 for cell growth and dechlorination. As Fe0 oxidizes it also increases the pH and Fe2+ levels, which may also impact the biological transformation of CT. Experiments were performed with Methanosarcina thermophila to investigate the influence of these factors on CT degradation. The transformation of CT and CF was greatly influenced by pH, with the rate of CT and CF degradation increasing with increasing pH. After 6 h, > 90% of the CT had been degraded in the treatments containing cells at a pH of 8.5, whereas only about 51% of the CT had been degraded in similar treatments at a pH of 5.5. Fe2+ did not significantly influence the degradation of CT; however, 60% less CF was formed in systems containing cells+Fe2+ than in systems containing cells only. In addition. Fe2+ promoted rapid transformation of CF when added to treatments containing cells. The product distribution after 9 days in all systems containing cells was very similar, with 98.04 +/- 5.46% (two-sided 95% confidence interval) of the originally fed CT present as soluble products. These results show that pH and Fe2+ influence the degradation of CT and CF, although transiently. Because the residence time of contaminants in Fe0 barriers varies with the thickness of the barrier, it is likely that this influence will be important for some flow-through systems. This implies that a combined Fe0/organism remediation system may have previously unrealized advantages (due to pH and Fe2+ changes).

Biodegradation, Environmental↗
PubMed1991

Transitions in CD45 isoform expression indicate continuous differentiation of a monoclonal CD5+ CD11b+ B lineage in Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) has been hypothesized to be a pleomorphic B-cell malignancy with persistent maturation towards plasma cells in all lymphoid tissue. This proposal is based on detection of a heterogeneous density of monoclonal Ig on peripheral blood B-cells in patients with WM. We now present data derived from 2- and 3-color immunofluorescence and flow cytometric analysis that strongly supports this hypothesis. Abnormally high numbers of B lineage cells, defined by expression of CD19, CD20, and CD24, were found among peripheral blood mononuclear cells (PBMC). These B-cells are monoclonal as defined by light chain expression and by the existence of rearranged Ig genes (Southern blot analysis), although they exhibit heterogeneity in the density of surface light chain. Unlike normal PBMC B-cells, the monoclonal B-cells bear CD5 and CD10 (CALLA), express adhesion and adhesion-related molecules (CD11b, CD9), and appear to be actively differentiating during the course of the disease, based on the pattern of CD45 isoform expression. At any given point in time, the population of monoclonal B-cells is heterogeneous in differentiation stage based on transitions in the expression of CD45 isoforms from expression of CD45RA, the high molecular mass isoforms of CD45, to the low molecular mass isoform CD45R0 which appears only on very late stage B-cells and early plasma cells. For one patient, analysis of CD45 isoform expression over 2 years showed that the monoclonal B-cell population as a whole progressed towards terminal differentiation as defined by loss of CD45RA and acquisition of CD45R0. This indicates a continuously differentiating lineage of an unusual B-cell phenotype, and/or malignant transformation of a distinct lineage of B-cells in WM.

Antigens, CD↗
PubMed1989

Abnormalities in lymphocyte profile and specificity repertoire of patients with Waldenstrom's macroglobulinemia, multiple myeloma, and IgM monoclonal gammopathy of undetermined significance.

The characteristics of T and B lymphocyte profile and B lymphocyte specificity repertoire were compared in patients with Waldenstrom's macroglobulinemia (WM), IgM monoclonal gammopathy of undetermined significance (IgM MGUS), multiple myeloma (MM), and age-matched normal subjects. Patients with MM had both significantly reduced frequency and number of sIg+ (surface Ig) B cells, whereas patients with WM and IgM MGUS had a reduced frequency but normal numbers of sIg+ B cells in circulation as detected in a capping assay. WM was distinguished by the large numbers of cells in the peripheral blood lymphocyte (PBL) pool that expressed CD9 (BA-2) and CD24 (BA-1) and were monoclonal, based on light chain analysis using flow cytometry. The profile of T lineage cells showed that the ratio of CD4:CD8 was significantly reduced in both MM and WM due to a reduction in the CD4 set. The CD4+ cells were qualitatively abnormal as well, with an enriched proportion of the 4B4+ (CDw29) subset and decreased proportion of the Lp220+ (CD45R) subset. This appeared to be an effect of the disease process on the relatively immature Lp220+ set. From clonal analysis, those patients with WM or IgM MGUS (unlike MM patients) did not exhibit enhanced reactivity with auto-Ig determinants, and most WM patients (7/8) and half of the IgM MGUS patients (3/6) did not have enriched proportions of B cells reactive to tetanus toxoid (TT). The TT-specific B cells in both WM and IgM MGUS, in contrast to MM, appeared fully functional in secretion of anti-TT IgM in vivo. We speculate that the more severe immunodeficiency in MM may be controlled or exacerbated by the presence of an anti-Ig network. The absence of this network in WM allows a relatively more effective immune response, but the immunodeficiency that is observed in these patients involves some abnormality in normal lymphocyte differentiation (is also present in MM).

Antibody Formation↗
PubMed1989

Comparative analysis of immunodeficiency in patients with monoclonal gammopathy of undetermined significance and patients with untreated multiple myeloma.

The objectives of this study were firstly, to compare the immunophenotype of patients with monoclonal gammopathy of undetermined significance (MGUS) with that of patients with newly diagnosed, untreated multiple myeloma (Unt. MM). Our second objective was to determine which variables might distinguish patients with MGUS and early MM. The CD4/CD8 ratio in both patient groups differed significantly from normal as a result of a decrease in the proportion of CD4+ cells. Similarly, surface immunoglobulin-positive (Ig+) B cells were significantly reduced in both groups. Also, some impairment of Ig secretion was observed. An in vitro specificity study of B cells showed an enriched proportion of B cells specific for tetanus toxoid (which may be indicative of enrichment for memory B cells) in both MGUS and Unt. MM patients. Further to this, in MM patients but not in MGUS patients, there was an enriched proportion of B cells specific for determinants on the F(ab')2 fragment of Ig. This suggests an anomalous auto-immune reactivity to polyclonal Ig molecules. In one of the two patients studied, who progressed from MGUS to MM, disease progression was accompanied by an increase in this anti-Ig reactivity. In both patients there was a decrease in CD4/CD8 ratio.

Aged↗
PubMed1987

Deficiency of mature B and T lymphocyte subsets in the blood of non-Hodgkin lymphoma patients.

The expression of mature B-cell markers and T markers was determined in lymphocytes isolated from the peripheral blood (PBL) of 20 healthy and 51 patients with non-Hodgkin malignant lymphoma (NHL). The disease was classified as newly diagnosed, in remission, or being treated with chemotherapy and of low-, intermediate-, or high-grade malignancy. To avoid technical problems associated with artifacts involving cytophilic immunoglobulins (Ig), we defined mature B-cells by means of three criteria: a) expression of high surface density of Ig sufficient to allow polar movement of receptors to form a cap in an indirect immunofluorescence (IF) assay, b) expression of high density of the human leukocyte antigens DR (HLA-DR) under capped conditions, and c) expression of a 41H.16 marker exclusive to surface Ig+ B-cells. Percentages of PBL able to cap surface Ig (sIg) (lambda, K), HLA-DR (7H.3), and 41H.16 markers were significantly reduced (p less than 0.001) in all of the patients, regardless of treatment status, and the numbers of sIg+-capping cells were similarly reduced in the patients, regardless of the grade of malignancy. Studies with ring fluorescence showed mean percentages of cells expressing OKT3 and OKT4 determinants significantly reduced (P less than 0.001) but OKT8+ cells not significantly different from control. The OKT4/OKT8 ratio was reduced in all patients and did not differ significantly in relation to the degree of malignancy. We conclude that, in NHL, essentially all patients have severe abnormalities in the number of B- or T-cells needed for normal immune responses.

Adult↗
PubMed1986

Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function.

Patients with multiple myeloma are generally immunodeficient, with pronounced depression in primary antibody responses. We have attempted to delineate the reasons for the humoral immunodeficiency by analyzing the specificity repertoire of the surface immunoglobulin (Ig)-positive B cells in patients with multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS), in comparison with normal donors. B lymphocytes from 26 patients with multiple myeloma, 12 patients with MGUS, and 8 normal donors were transformed with Epstein-Barr virus (EBV) and cultured at limiting dilution for clonal analysis. The Ig secreted by each clone was analyzed for class and anti-tetanus toxoid (TT) specificity to determine the frequencies of IgM, IgG, anti-TT IgM, and anti-TT IgG antibody-secreting clones. Our objective was to establish whether the inability to mount humoral responses to common environmental pathogens was due to a lack of specific B cells or to inhibition of B-cell function. Our results indicate that the quantitative B-cell deficiency in patients was due to a nonrandom loss of selected sets of B cells. Although most patients had a reduced aggregate number of B cells, the number of TT-specific B cells was normal. There was, on average, a threefold increase in the proportion of the B-cell specificity repertoire devoted to recognition of TT. Forty-four percent of the patients with MGUS were also affected. In addition, the TT-specific B cells in multiple myeloma patients were severely compromised in their ability to secrete antibody or to differentiate to antibody-secreting cells in vivo. This arrest in differentiation appears to be extrinsic to the B cells, as they were fully able to secrete anti-TT antibody after transformation and culture in vitro. We postulate the existence of an autoimmune inhibitory network mediating the arrest in B-cell differentiation and the humoral immune deficiency.

B-Lymphocytes↗
PubMed1982

Scintigraphic measurement of left-ventricular volumes from the count-density distribution.

An experimental model was developed using ellipsoidal balloons of different volumes to derive an empirical formula linking the "normalized" total count rates on gamma-camera images to volume. The normalized total count rate (NTC) is defined as the total count rate divided by the maximum count density. If an object is at a constant distance from the collimator, the NTC is found to be a linear function of volume. This formula was then applied to calculate left-ventricular end-diastolic volume from scintigraphic images obtained by radionuclide ventriculography in 71 consecutive patients. The distance from the left ventricle to the collimator was estimated from the patient's height and weight. The volumes calculated by the radionuclide method were compared with angiographic volumes obtained at cardiac catheterization, and good correlation was found (r = 0.95).

Cardiac Output↗
PubMed1979

Surface charge in foreign body carcinogenesis.

The importance of surface charge in foreign body carcinogenesis was evaluated by implanting in C3H/HeJ male mice, bipolar polystyrene thermoelectrets formed in variously charged electrical fields. Charged electrets had tumor rates similar to control groups. The cumulative probability of tumor development was highest in the charged electret group being 0.58 at 133 weeks after implantation. The tumor rate for all charged electrets was 27% as compared to 17% and 6% for the control groups. The latent period of tumor induction varied little between groups and averaged approximately 700 days. No conclusions regarding the tumorigenic effect of electropositive versus electronegative sides of the electret were made although the majority of tumors arose on the electronegative (body) side of the electrets. An occasional tumor (2/25) arose on both sides of a single electret. The antigenicities of tumors tested by excise and challenge techniques were weak. The immunologic relationship between top and bottom growing tumors on a single electret could not be adequately determined because of the weak antigenicity.

Animals↗
PubMed1978

Accumulation of mercury and selenium in tissues of kittens fed commercial cat food.

Six kittens, three males and three females, were fed exclusively for one hundred days a commercially canned red meat tuna found to contain elevated concentrations of Mercury (Hg) and Selenium (Se). A similarly sized control group was fed for the same period a dry commercial cat food comparatively low in the concentration of these elements. At the end of the feeding trial, concentrations of Hg Se were markedly higher in blood, bone, brain, kidney, liver, muscle and spleen of the kittens fed the tuna diet as compared to the corresponding controls. No behavioral abnormalities or pathological lesions were detected in any of the kittens.

Animal Feed↗