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Biomedical subjects

D P Bentley

Publications and source records attributed to D P Bentley.

At least 19 recordsLinked to original sources
PubMed2000

The apoptotic pathway: a target for therapy in chronic lymphocytic leukemia.

Cell division and apoptosis (programmed cell death) are the two major physiological processes which control the size of cell populations. Chronic lymphocytic leukaemia arises as a result of the clonal expansion of, usually B-, lymphocytes in which a dysregulation of apoptosis leads to prolonged cell survival. The same process becomes exaggerated with increasing drug resistance, the usual cause of treatment failure in this condition. The identification of points in the apoptotic pathway at which dysregulation occurs is beginning to open up new therapeutic opportunities where the conventional cytotoxic chemotherapy approach is found to fail. Although these strategies are still in their infancy they may increase understanding of the pathogenesis of the disorder and overcome the problem of drug resistance.

Animals↗
PubMed1997

Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance.

The bcl-2 gene is overexpressed in the absence of gene rearrangements in most cases of B-cell chronic lymphocytic leukaemia (B-CLL) and the proto-oncogene product Bcl-2 has been shown to be a regulator of apoptosis. The activity of this protein is opposed by Bax, a homologous protein that accelerates the rate of cell death. B-lymphocyte Bcl-2 and Bax protein levels were found to be significantly altered in B-CLL and increased Bcl-2/Bax ratios were observed in both the treated and untreated patients compared with those of normal controls. These alterations were particularly pronounced in those treated patients found to be clinically unresponsive to chemotherapy. In order to determine whether Bcl-2/Bax ratios affected cell survival via an anti-apoptotic mechanism, cell death was induced in B-CLL cells in vitro using chlorambucil, and apoptosis was monitored by Annexin V and propidium iodide staining. Confirmation that the labelled cells were apoptotic was achieved by morphological assessment of cytospin preparations of cell-sorted populations. Drug-induced apoptosis in B-CLL cells was inversely related to Bcl-2/Bax ratios.

Apoptosis↗
PubMed1994

Healing of broken human chromosomes by the addition of telomeric repeats.

We have characterized and compared a series of naturally occurring chromosomal truncations involving the terminal region of the short arm of human chromosome 16 (16p13.3). All six broken chromosomes appear to have been stabilized by the direct addition of telomeric repeats (TTAGGG)n to nontelomeric DNA. In five of the six chromosomes, sequence analysis shows that the three of four nucleotides preceding the point of telomere addition are complementary to and in phase with the putative RNA template of human telomerase. Otherwise we have found no common structural features around the breakpoint regions. These findings, together with previously reported in vitro data, suggest that chromosome-healing events in man can be mediated by telomerase and that a small region of complementarity to the RNA template of telomerase at the end of a broken chromosome may be sufficient to prime healing in vivo.

Base Sequence↗
PubMed1992

Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1.

Reversal of the anticoagulant effect of warfarin in patients with no active haemorrhage can be achieved by administration of intravenous vitamin K1. Currently recommended doses of intravenous vitamin K1, for this purpose often result in subsequent difficulties in anticoagulation. We observed the response to low dose intravenous vitamin K1 in patients requiring reversal of anticoagulant therapy. Ten consecutive patients received 1 mg and 21 further patients received 0.5 mg of intravenous vitamin K1. In 50% of the patients who received 1 mg of vitamin K1 the INR (International Normalised Ratio) fell below 2 at 24 h whereas in patients who received 0.5 mg the INR fell below 5.5 in all subjects after 24 h and in none did it fall below 2.0. No patient had any thrombotic or haemorrhagic complications and no difficulty was encountered in re-establishing anticoagulant control after 24 h. We recommend 0.5 mg of vitamin K1 as an effective and convenient method of predictable and fine control of oral anticoagulant therapy.

Adult↗
PubMed1992

The inhibition of DNA synthesis in chronic lymphocytic leukaemia cells by chlorambucil in vitro.

The inhibition of 3H-thymidine incorporation into the DNA of mitogen-stimulated lymphocytes from patients with chronic lymphocytic leukaemia by chlorambucil was measured in vitro and the results related to clinical drug resistance. The assay proved to be both sensitive and specific showing a clear separation of those patients with responsive disease from those with disease resistant to treatment. There was evidence of primary drug resistance in untreated patients. In almost all patients who received treatment this led to increasing resistance to chlorambucil in vitro. The assay is predictive of clinical responsiveness and provides a potential means whereby new therapeutic agents and treatment modifiers may be investigated.

Chlorambucil↗
PubMed1991

In vitro chemosensitivity testing in chronic lymphocytic leukaemia patients.

Twenty-nine samples from eighteen patients with chronic lymphocytic leukaemia (CLL) were used in a direct comparison of in vitro response to chlorambucil measured in a metabolic (MTT) and dye exclusion (D.Ex) assay. Reduced ability to produce formazan corresponded to a reduced number of dye-excluding viable cells and a significant correlation was found between dose-response measured in the two assays. Initial low absorbance values obtained with untreated control cells in the MTT assay were effectively overcome by increasing both the cell seeding density and MTT exposure time with the consequent increase in assay sensitivity. The MTT assay provided qualitatively similar dose-response data to that obtained in the D.Ex assay. A wide range in in vitro response was seen for both pretreatment and treatment patient groups. In vitro dose-responses were seen to coincide with decreasing or stable white cell counts, taken around the time of sampling, in samples from 4 patients. Less marked dose-responses were observed for 2 patients considered clinically resistant to chlorambucil. The MTT assay would seem, therefore, to be applicable to in vitro assay of cell response in CLL.

Chlorambucil↗
PubMed1990

Is the mdr 1 gene relevant in chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Aplastic anaemia incidence in parts of the United Kingdom in 1985.

This paper describes the distribution of new cases of aplastic anaemia in parts of the UK in 1985. The age, sex and spatial pattern are described. Special attention is given to the investigation of five childhood cases which occurred close in space and time. The results are contrasted with similar data from elsewhere.

Adolescent↗
PubMed1988

A cluster of three cases of aplastic anaemia in children.

During a 2-week period three unrelated children presented with severe aplastic anaemia at a general hospital serving a population of 25,000 children aged 0-15 years. The probability of this occurring by chance alone was 0.00009 (exact probability cluster analysis). Serology for common viral infections including hepatitis A & B and infectious mononucleosis was negative. It was not possible to demonstrate IgM antibodies to human parvovirus (HPV) by radioimmunoprecipitation or HPV virions by DNA hybridization in the patients or any members of their families. Epidemiological investigation failed to demonstrate a common environmental toxin. It did reveal, however, that all three patients had spent time, within the preceding 3 months in a swimming pool and its surrounding area in a region of Cardiff where none of them resided. Pool maintenance was satisfactory and water analysis showed no abnormality. The possibility must remain that the cluster was caused by an undisclosed environmental toxin.

Anemia, Aplastic↗
PubMed1987

A comparison of 3 and 6 weeks' anticoagulation in the treatment of venous thromboembolism.

One hundred hospital in-patients treated for pulmonary embolism (PE) and/or deep vein thrombosis (DVT) were randomly allocated to receive 3 or 6 weeks' anticoagulation with heparin and warfarin. At one year recurrence rates were 12% in the 6 week group and 10% in those treated for 3 weeks. No patient died as a result of recurrence. Our study suggests that 3 weeks' anticoagulation therapy, using intravenous heparin for the first 5 days and warfarin from the third day, is adequate for patients without persisting risk factors.

Adult↗
PubMed1987

Haemoglobinopathy screening in a 'low-risk' area of the United Kingdom: South Glamorgan, Wales.

Figures collected over 2 1/2 years of screening of women attending the antenatal clinics of South Glamorgan, Wales, showed that the percentage of women identified as a risk for haemoglobinopathy trait (7.4%) was almost twice that estimated from the 1981 Census data (4.1%) and that the incidence of a thalassaemia trait in these women (0.38% beta; 0.68% alpha) was similar to that of an area of supposedly greater risk in London (0.46% beta; 0.42% alpha). Figures from one laboratory showed that without a scrutiny of all antenatal clinic blood counts for thalassaemic indices some thalassaemia traits will be missed. The apparent incidence of the HbS trait was 0.13%, and reasons for this being an underestimate are given.

Female↗