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A W Harris

Publications and source records attributed to A W Harris.

At least 37 records · Page 2Linked to original sources
PubMed1998

A test of lymphoma induction by long-term exposure of E mu-Pim1 transgenic mice to 50 Hz magnetic fields.

E mu-Pim1 transgenic mice expressing a dysregulated Pim1 oncogene in their lymphoid cells were used to test whether exposure to 50 Hz magnetic fields can increase the frequency of malignant lymphoma in mice of a strain predisposed to develop such tumors spontaneously at low incidence. Specific-pathogen-free female mice were allocated randomly into groups of approximately 100 at 6-8 weeks of age and then exposed for 20 h/day for up to 18 months to sinusoidal magnetic fields of 0, 1, 100 or 1000 microT, or 1000 microT pulsed 15 min on and 15 min off. Additional E mu-Pim1 mice were injected with ethylnitrosourea (50 mg/kg body weight) as positive controls for enhanced lymphomagenesis; these yielded a cumulative incidence of lymphoma of 60% in 9 months. A lethal, transgene-dependent renal glomerular disease occurred at a frequency that varied from 9% to 19% among the groups, but the increase was statistically significant only at the 1000-microT exposure. Lymphoblastic and non-lymphoblastic (predominantly follicular) lymphomas were seen in 26 to 35% of the exposed mice, but at no significantly higher incidence than the 29% found in the sham-exposed mice. Hence we conclude that the lymphoma-prone mice did not reveal any tumorigenic effect of long-term exposure to 50 Hz magnetic fields.

Animals↗
PubMed1998

Effect of a bcl-2 transgene on production and localization of precursor B cells in mouse bone marrow.

Many B cell precursors die while differentiating in mouse bone marrow. To ascertain the mechanisms involved in this process, populations of B lineage cells and their tissue localization were analyzed in bone marrow of transgenic mice overexpressing the apoptosis inhibitor, Bcl-2. Immunofluorescence labeling and mitotic arrest were used to quantitate the number and proliferative activity of mu- pro-B cells (terminal deoxynucleotidyl transferase [TdT]+B220-, TdT+B220+, and TdT-B220+); pre-B cells (cmu+); and B cells (smu+). Mature B cells (IgM+IgD+) were increased 16- to 20-fold. In addition, immature B lymphocytes (IgM+IgD-/low), representing newly formed cells, were increased three- to sixfold, whereas pre-B cells and late pro-B cells were increased 30 to 60% in production rate. Earlier pro-B cells expressing TdT were unaffected. In spleen, both mature and immature B cells were greatly increased, but cells of precursor phenotype were few and TdT+ cells were absent. The in vivo location of B cells was examined by autoradiography using light and electron microscopy after intravenous injection of 125I-labeled antibodies. B lineage cells (B220+) were increased throughout bone marrow, often within dilated venous sinusoids, particularly in subosteal regions. Many intravascular and perisinusoidal cells were IgDhigh mature B lymphocytes. In contrast, many other IgM+ and IgDlow immature B lymphocytes clustered extravascularly around the central venous sinus. Plasma cells with distended endoplasmic reticulum were numerous. These findings provide evidence that, in addition to expanding the recirculating pool of B cells entering bone marrow from the blood stream, high levels of Bcl-2 can inhibit some of the apoptosis occurring during B cell differentiation, thereby expanding populations of B lymphopoietic precursor cells within the bone marrow parenchyma.

Animals↗
PubMed1997

Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Emu-bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3-83mudelta (anti-Kk,b) Ig Tg mice to H-2(b) mice or to mice expressing transgene-driven Kb in the periphery. In 3-83mudelta/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

Animals↗
PubMed1997

Expression of a bcl-2 transgene reduces proliferation and slows turnover of developing B lymphocytes in vivo.

B lymphocyte differentiation proceeds through a series of alternating stages of proliferative expansion interspersed with noncycling stationary phases during which cells undergo either positive selection or apoptotic cell death. The molecular control of cell cycle progression and that of apoptosis appear to be interconnected. Overexpression of Bcl-2 in lymphocytes or fibroblasts antagonizes apoptosis and delays their transition from the quiescent state into the cell cycle. We have undertaken a systematic analysis of the impact of bcl-2 transgene expression on cell cycle distribution and turnover rate of developing B lymphocytes in normal mice and in mutant animals in which B cell differentiation is arrested at the pro-B/pre-BI or the pre-BII stage. These experiments revealed that overexpression of Bcl-2 reduces proliferation and slows turnover of B cells at all stages of development. This demonstrates that Bcl-2 can retard transition of B cells between the quiescent and the cycling state regardless of the mitogenic stimulus and the differentiation stage. The implications of these results for the normal control of B lymphopoiesis and for lymphomagenesis are discussed.

Animals↗
PubMed1997

Recurrence of duodenal ulcer after Helicobacter pylori eradication is related to high acid output.

BACKGROUND: Helicobacter pylori eradication reduces the recurrence of duodenal ulcers. It is unclear why duodenal ulcers rarely recur in the absence of reinfection with H. pylori or NSAID treatment. METHODS: Basal, gastrin-releasing peptide- and pentagastrin-stimulated peak acid outputs in patients with ulcer relapse after H. pylori eradication were measured, and compared with patients without ulcer relapse after H. pylori eradication. RESULTS: Pentagastrin-stimulated peak acid output was significantly higher in H. pylori-positive patients with duodenal ulcers than in H. pylori-negative controls, and fell significantly after H. pylori eradication. In H. pylori-negative patients with recurrent duodenal ulcers, pentagastrin-stimulated peak acid output was significantly higher than in controls and similar to H. pylori-positive patients with duodenal ulcers. CONCLUSIONS: These findings suggest that duodenal ulcer relapse after eradication of H. pylori may be related to high pentagastrin-stimulated peak acid output. In this subset of patients with duodenal ulcers, maintenance anti-secretory treatment may be necessary to prevent relapse.

Adult↗
PubMed1997

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors.

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro-T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre-TCR, not those stimulated via c-Kit and the IL-7 receptor.

Animals↗
PubMed1997

One week triple therapy for Helicobacter pylori: a multicentre comparative study. Lansoprazole Helicobacter Study Group.

BACKGROUND: Eradication of Helicobacter pylori cures and prevents the relapse of duodenal ulceration and also results in histological resolution of chronic active gastritis. AIM: To compare four treatment regimens lasting seven days of a proton pump inhibitor and two antibiotics in the eradication of H pylori. PATIENTS: Men or women with H pylori positive duodenal ulceration or gastritis, or both. METHODS: A single blind, prospectively randomised, parallel group, comparative, multicentre study. After a positive CLO test, patients underwent histology, H pylori culture, and a 13C urea breath test to confirm H pylori status. Treatment with one of four regimens: LAC, LAM, LCM, or OAM, where L is 30 mg of lansoprazole twice daily, A is 1 g of amoxycillin twice daily, M is 400 mg of metronidazole twice daily, C is 250 mg of clarithromycin twice daily, and O is 20 mg of omeprazole twice daily, was assigned randomly. A follow up breath test was done at least 28 days after completing treatment. RESULTS: H pylori eradication (intention to treat) was 104/121 (86.0%) with LAC, 87/131 (66.4%) with LAM, 103/118 (87.3%) with LCM, and 94/126 (74.6%) with OAM. There was a significant difference (p < 0.001) in the proportion of patients in whom eradication was successful between LAC and LCM when compared with LAM, but no significant difference (p = 0.15) between LAM and OAM. Metronidazole resistance before treatment was identified as a significant prognostic factor with regard to eradication of H pylori. The regimens which contained metronidazole were significantly less effective than those without metronidazole in the presence of pretreatment resistant H pylori. There was no difference among the treatment groups with regard to the incidence and severity of adverse events reported. CONCLUSIONS: All four treatment regimens were safe and effective in eradicating H pylori in the patient population studied. LAC was the most efficacious treatment in patients with pretreatment metronidazole resistant H pylori, and was significantly better than LAM and OAM in this group of patients.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

Lymphomas in E mu-Pim1 transgenic mice exposed to pulsed 900 MHZ electromagnetic fields.

Whether radiofrequency (RF) fields are carcinogenic is controversial; epidemiological data have been inconclusive and animal tests limited. The aim of the present study was to determine whether long-term exposure to pulse-modulated RF fields similar to those used in digital mobile telecommunications would increase the incidence of lymphoma in E mu-Pim1 transgenic mice, which are moderately predisposed to develop lymphoma spontaneously. One hundred female E mu-Pim1 mice were sham-exposed and 101 were exposed for two 30-min periods per day for up to 18 months to plane-wave fields of 900 MHz with a pulse repetition frequency of 217 Hz and a pulse width of 0.6 ms. Incident power densities were 2.6-13 W/m2 and specific absorption rates were 0.008-4.2 W/kg, averaging 0.13-1.4 W/kg. Lymphoma risk was found to be significantly higher in the exposed mice than in the controls (OR = 2.4. P = 0.006, 95% CI = 1.3-4.5). Follicular lymphomas were the major contributor to the increased tumor incidence. Thus long-term intermittent exposure to RF fields can enhance the probability that mice carrying a lymphomagenic oncogene will develop lymphomas. We suggest that such genetically cancer-prone mice provide an experimental system for more detailed assessment of dose-response relationships for risk of cancer after RF-field exposure.

Animals↗
PubMed1997

Deregulation of cell survival in lymphomagenesis.

Because normal lymphoid tissue homeostasis depends on a balance between cell proliferation and cell death, lymphomas can arise from mutations that interfere with the normal cell death process. We here discuss some circumstances in which lymphoid cell overexpression of a cell death antagonist, the Bcl2 protein, in E mu-bcl2 transgenic mice can contribute to the development of lymphomas and plasmacytomas.

Animals↗
PubMed1996

Mutations in the p53 and SCID genes cooperate in tumorigenesis.

DNA damage can cause mutations that contribute to cellular transformation and tumorigenesis. The p53 tumor suppressor acts to protect the organism from DNA damage by inducing either G1 arrest to facilitate DNA repair or by activating physiological cell death (apoptosis). Consistent with this critical function of p53, mice lacking p53 are predisposed to developing tumors, particularly lymphoma. The severe combined immune deficiency (scid) focus encodes the catalytic subunit of DNA protein kinase (DNA-PKcs), a protein complex that has a role in the cellular response to DNA damage. Cells from scid mice are hypersensitive to radiation and scid lymphocytes fail to develop from precursors because they are unable to properly join DNA-coding ends during antigen receptor gene rearrangement. We examined the combined effect of loss of p53 and loss of DNA-PKcs on lymphocyte development and tumorigenesis by generating p53-/- scid mice. Our data demonstrate that loss of p53 promotes T-cell development in scid mice but does not noticeably affect B lymphopoiesis. Moreover, scid cells are able to induce p53 protein expression and activate G1 arrest or apoptosis in response to ionizing radiation, indicating that DNA-PKcs is not essential for these responses to DNA damage. Furthermore, p53-/- scid double mutant mice develop lymphoma earlier than p53-/- littermates, demonstrating that loss of these two genes can cooperate in tumorigenesis. Collectively, these results provide evidence for an unsuspected role of p53 as a checkpoint regulator in early T-cell development and demonstrate that loss of an additional component of the cellular response to DNA damage can cooperate with loss of p53 in lymphomagenesis.

Animals↗
PubMed1996

Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival.

Mice expressing both a bcl-2 and a myc transgene within the B lymphoid cell compartment invariably develop novel immature haemopoietic tumours. The likely cell of origin of these tumours was identified by a common pattern of cell surface marker expression on a subset of cells comprising approximately 1% of normal mouse bone marrow. The bcl-2-myc tumour cells could be induced to differentiate into either B lymphocytes or macrophages in culture with certain cytokines and feeder cells. Analysis of their progression into the B lymphoid lineage revealed that Igk locus transcription can precede Igh as well as Igk rearrangement. Surprisingly, the undifferentiated tumour cells died rapidly in culture, even in the presence of multiple cytokines, but they proliferated on monolayers of stromal cells derived from haemopoietic tissues. Thus, even with Bcl-2 levels that protect more differentiated cells, these immature bi-potential progenitor cells require a stromal-induced signal for survival. These results provide insight into the process of lineage commitment and suggest new levels of control of cell survival during early steps in haemopoietic development.

Animals↗
PubMed1996

Eradication of Helicobacter pylori in patients with duodenal ulcer lowers basal and peak acid outputs to gastrin releasing peptide and pentagastrin.

BACKGROUND: Patients with duodenal ulcer (DU) have high basal (BAO) and peak (PAO) acid outputs. The effect of Helicobacter pylori eradication on these variables is unclear. AIM: To discover if gastric acid hypersecretion in patients with DU is caused by H pylori. PATIENTS AND METHODS: BAO, gastrin releasing peptide (GRP), and pentagastrin stimulated PAO in 10 H pylori negative controls, and in 10 H pylori positive patients with DU was measured before and six months after H pylori eradication. H pylori status was determined by histology, culture, and by the 13C-urea breath test. After collecting a 30 minute basal aspirate, GRP 40 pmol/kg/h was infused for 45 minutes, and after a 30 minute washout, pentagastrin 6 micrograms/kg was injected intramuscularly. RESULTS: Basal and stimulated acid output (PAOGRP and PAOPg) were significantly higher in H pylori positive DU than in H pylori negative controls. Six months after H pylori eradication, basal and stimulated acid outputs were all significantly lower than before H pylori eradication. CONCLUSIONS: This study has shown that BAO, PAOGRP, and PAOPg are higher in H pylori positive DU than in H pylori negative controls. All decreased significantly six months after H pylori eradication, to fall within the range of controls. These results are compatible with a hypothesis that acid hypersecretion in duodenal ulcer disease is caused by H pylori infection.

Adult↗
PubMed1996

Relation between gastric acid output, Helicobacter pylori, and gastric metaplasia in the duodenal bulb.

BACKGROUND: Factors that determine gastric metaplasia in the duodenal bulb are ill defined. It is more common and extensive in the presence of high acid output and possibly in the presence of Helicobacter pylori. However, no quantitative relation between acid output and the extent of gastric metaplasia has been demonstrated and its relation to H pylori is uncertain. AIM: To determine the relation between H pylori infection and acid output and the presence and extent of gastric metaplasia in the duodenal bulb. subjects: H pylori positive and negative patients with duodenal ulcer and healthy controls were studied. METHODS: Quadrantic duodenal bulb biopsy specimens were taken and the presence and extent of gastric metaplasia determined using a computer enhanced image intensifier. Basal and stimulated acid outputs were measured. RESULTS: gastric metaplasia was significantly (p < 0.05 more common and significantly (p < 0.05) greater in extent in patients with duodenal ulcer than in controls. Neither the prevalence or extent of gastric metaplasia was affected by H pylori status. There were significant (p < 0.01) direct correlations between acid output and extent of gastric metaplasia. CONCLUSIONS: Prevalence and extent of gastric metaplasia are not related to H pylori in controls, or in patients with duodenal ulcer. Rather, high acid response to gastrin may be more important.

Adult↗
PubMed1996

Parietal cells in the duodenal bulb and their relation to Helicobacter pylori infection.

AIM: To investigate the prevalence, and relation to Helicobacter pylori, of parietal cells in the duodenal bulb using a monoclonal antibody directed against H+,K(+)-ATPase (HK12.18). METHODS: Twenty six patients with duodenal ulcer disease and 16 healthy controls were studied. H pylori status was determined by gastric histology and culture and by the 13C-urea breath test. Four biopsy specimens were taken from the duodenal bulb and stained with HK12.18. The presence/absence and number of parietal cells in the duodenal bulb were assessed blindly by a histopathologist. RESULTS: The overall prevalence of parietal cells in the duodenal bulb was 31% (13/42) and was similar in patients with duodenal ulcer and in controls, and in H pylori positive and negative subjects. The median (range) number of parietal cells in the duodenal bulb was 7.5 (4-20) parietal cells/subject, and was similar in all four groups. CONCLUSIONS: The prevalence of parietal cells in the duodenal bulb (31%) is notably higher than previously reported in endoscopic studies, and is in keeping with reports from studies on necropsy/operative specimens. There was no difference in the prevalence or number of parietal cells in the duodenal bulb between patients with duodenal ulcer and controls, regardless of H pylori status. These findings suggest that parietal cells in the duodenal bulb do not contribute to the pathogenesis of duodenal ulcer.

Adult↗
PubMed1996

Lessons from bcl-2 transgenic mice for immunology, cancer biology and cell death research.

The protein product of the proto-oncogene bcl-2, originally discovered by virtue of its chromosomal translocation in human follicular centre B cell lymphoma, is a physiological inhibitor of programmed cell death, apoptosis. Initial studies in transgenic mice overexpressing Bcl-2 in B or T lymphocytes demonstrated that Bcl-2 can potently antagonise cell death induced by multiple independent signal transduction routes and can contribute to oncogenesis, particularly in combination with other oncogenes, like c-myc, that promote cell proliferation. Further investigations using crosses between bcl-2 transgenic mice and T cell receptor or immunoglobulin transgenic mice or mutant mice deficient in proper antigen receptor gene rearrangement demonstrated that Bcl-2 can only block death of cells that failed to receive a positive stimulus, "death by neglect', but not activation induced apoptosis. Collectively, these results provide evidence that distinct signalling pathways for apoptosis converge upon a common effector machinery where Bcl-2 acts as an antagonist, but that there also exists a mechanism that can either bypass the Bcl-2 checkpoint or override its protective function. These experimental data are reviewed here and discussed in context of current knowledge of lymphocyte differentiation, tumorigenesis and cell death regulation.

Animals↗
PubMed1996

Lansoprazole, clarithromycin and metronidazole for seven days in Helicobacter pylori infection.

BACKGROUND: This study determines the efficacy and safety of a 1-week triple therapy regimen of lansoprazole, clarithromycin and metronidazole in an area with a high prevalence of pre-treatment metronidazole-resistant strains of Helicobacter pylori. METHODS: Seventy-five H. pylori positive patients with gastritis or duodenal ulcer were entered into an open study of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. H. pylori status was determined by CLOtest, histology, culture and by 13C-urea breath test (repeated > or = 28 days after treatment). RESULTS: Seventy-one patients completed the treatment and returned for follow-up. H. pylori was eradicated in 61 of 71 (86%) patients by per-protocol analysis, and in 61 of 75 (81%) patients by intention-to-treat analysis. H. pylori was eradicated in 12 of 16 (75%) patients with metronidazole-resistant strains compared with 22 of 24 (92%) in patients with metronidazole-sensitive strains of H. pylori (P = 0.14). Fourty-five patients reported at least one adverse event, and three patients stopped treatment due to them (two with headaches and one with diarrhoea). CONCLUSIONS: A 1-week course of lansoprazole 30 mg o.m., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. eradicates H. pylori in up to 86% of patients. It is of proven benefit in patients with pre-treatment metronidazole-resistant strains of H. pylori.

2-Pyridinylmethylsulfinylbenzimidazoles↗