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Biomedical subjects

D Bowen

Publications and source records attributed to D Bowen.

At least 73 records · Page 4Linked to original sources
PubMed1990

Family studies and prenatal diagnosis in severe von Willebrand disease by polymerase chain reaction amplification of a variable number tandem repeat region of the von Willebrand factor gene.

We have previously demonstrated within intron 40 of the von Willebrand factor (vWF) gene a region of ATCT repeats that was shown to vary in length between two different DNA clones from unrelated individuals. The polymerase chain reaction (PCR) was used to examine the variability in length of this variable number tandem repeat (VNTR) in 53 normal individuals, using primers to DNA sequence flanking the repeat region. Overall, eight different length allelic bands were seen. These were individually sequenced and shown to contain from 6 to 14 ATCT repeats (a nine-repeat band was not seen). Seventy-five percent of individuals were shown to be heterozygous for this vWF.VNTR, and family studies showed Mendelian inheritance with allelic frequencies from 1% (vWF.VNTR [8] and vWF.VNTR [14]) to 39% (vWF.VNTR [7]). In the family of a patient with type III severe von Willebrand disease (vWD), vWF.VNTR results mirrored the phenotypic data and results with previously reported intragenic vWF restriction fragment length polymorphisms (RFLP). The patient was shown to be a compound heterozygote. In a family with a child with severe type III vWD, prenatal diagnosis by vWF.VNTR analysis on DNA obtained by chorionic villus sampling at 10 weeks gestation during a subsequent pregnancy indicated a severely affected fetus. This diagnosis was confirmed by fetal blood sampling at 18 weeks.

DNA↗
PubMed1990

Clonal growth of haemopoietic progenitor cells from myelodysplastic marrow in response to recombinant haemopoietins.

The growth factor requirements of granulocyte-macrophage (GM) and erythroid marrow progenitor cells from 12 myelodysplastic (MDS) patients have been analysed. GM progenitors from two of six patients who grew normal numbers of colonies in response to conditioned medium + erythropoietin (5637CM + Epo) showed defective responses to either GMCSF and/or IL-3. Of all the recombinant factors tested (IL-3, IL-1, GCSF, GMCSF, MCSF), GMCSF was the strongest stimulator of myeloid clonal growth, inducing normal numbers of GM colonies from marrow of six patients (two of whom were neutropenic). Erythroid colonies were low in 5637CM + Epo-supplemented cultures of marrow from all but one patient and remained poor in the presence of any of the haemopoietins. tested. Supraoptimal doses (for normal marrow) of these haemopoietins improved colony growth in only one patient (GM colonies in response to IL-3). Combinations of factors were also largely ineffective at raising myeloid or erythroid colony numbers. These data indicate that the defective response of MDS progenitor cells to growth factors is not amenable to experimental manipulation of recombinant factor levels or combinations. Clonal assays might suggest a role for GMCSF therapy in a subpopulation of neutropenic MDS patients but their potential now needs to be evaluated in association with clinical trials.

Adult↗
PubMed1989

One- and two-dimensional NMR studies of yeast phosphoglycerate kinase.

One- and two-dimensional proton NMR studies have been carried out on yeast phosphoglycerate kinase (Mr approximately 45,000) in order to identify amino-acid spin systems and obtain sequence-specific assignments. A number of sequence-specific assignments have been made using a combination of structural information contained in nuclear Overhauser effect spectra and X-ray crystallographic data. The results of substrate binding studies (both 3-phosphoglycerate and Mg.ATP), which indicate mutual reorientation of certain assigned aromatic residues in the inter-domain region of the protein, are discussed.

Adenosine Triphosphate↗
PubMed1989

Interaction of 5'-deoxy-5-fluorouridine and methotrexate. A basis for reduced methotrexate toxicity.

Methotrexate (MTX) toxicity is reduced significantly by a non-toxic dose of 5'-deoxy-5-fluorouridine (5'dFUr). Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), ileal tissue, and body weight were used as parameters to assess toxicity. MTX treatment alone resulted in: (a) a reduction of body weight; (b) significantly morphological changes in ileal tissue; and (c) a marked decrease in the hematopoietic parameters. Sequential treatment with MTX followed by 5'dFUr resulted in reversal of MTX depression of animal body weight and ileal tissue necrosis, and partial reversal in MTX toxicity to the hematopoietic system. Also, for all parameters studied, there were no significant differences between scheduling of MTX after a priming dose of 5'dFUr, 5'dFUr alone, and control. Hence, this study suggests that 5'dFUr is a pharmacological antidote for MTX toxicity, and, therefore, 5'dFUr in combination with MTX may provide a basis whereby more intense and effective MTX therapy may be given.

Animals↗
PubMed1989

Interval insertion of an intrauterine contraceptive device following cesarean section.

Two previous studies of interval insertion of intrauterine contraceptive devices (IUCD) in women with previous cesarean delivery produced conflicting results. We studied the first and subsequent segment IUCD performance in 215 women with one or more cesarean deliveries. All the insertions were performed by doctors in the outpatient department of the hospital. The follow-up rate at 6 months was over 80%. There was a higher than expected expulsion rate of 19 per 100 insertions in the first 12 months, in both the first and subsequent segments. Other IUCD related problems were in keeping with expectations. The IUCD nonetheless remains a useful contraceptive option for these women.

Adult↗
PubMed1989

Swainsonine: a new antineoplastic immunomodulator.

Swainsonine, an indolizidine alkaloid with immunomodulatory activity, has been found to be effective in inhibiting metastatic dissemination and growth of primary tumors of both murine and human origins. The unique ability of swainsonine to exhibit antimetastatic, anti-proliferative, and immunomodulatory activity imparts this drug a promising future in cancer therapy.

Adjuvants, Immunologic↗
PubMed1989

Experimental approaches for the prevention of hematogenous metastasis.

With improvements in surgical procedures and cure rates, the probable course of cancer for the majority of patients is now largely determined by metastasis rather than growth of the primary tumor itself. Thus, metastasis has received increasing attention over the past decade. These studies have led to the identification of several of the molecular events crucial for metastatic dissemination, information which is now being used to design therapeutic strategies to inhibit metastasis formation. Even though the molecular events involved in the dissemination of malignant disease are only partially known, several promising agents are now being tested for their capacity to limit the spread of cancer. A few clinical trials have shown benefit in prolonging survival and disease-free state, particularly when such therapy is employed on an adjuvant basis.

Antineoplastic Agents↗
PubMed1988

Nucleotide sequence of the phosphoglycerate kinase gene from the extreme thermophile Thermus thermophilus. Comparison of the deduced amino acid sequence with that of the mesophilic yeast phosphoglycerate kinase.

Using oligonucleotide probes derived from amino acid sequencing information, the structural gene for phosphoglycerate kinase from the extreme thermophile, Thermus thermophilus, was cloned in Escherichia coli and its complete nucleotide sequence determined. The gene consists of an open reading frame corresponding to a protein of 390 amino acid residues (calculated Mr 41,791) with an extreme bias for G or C (93.1%) in the codon third base position. Comparison of the deduced amino acid sequence with that of the corresponding mesophilic yeast enzyme indicated a number of significant differences. These are discussed in terms of the unusual codon bias and their possible role in enhanced protein thermal stability.

Amino Acid Sequence↗
PubMed1988

Primary lymphoma of the central nervous system: experience at Addenbrooke's Hospital, Cambridge.

A series of 22 cases of primary intercerebral lymphoma are reported. The clinical presentation and natural history were similar to high grade glioma in adults. There was a male to female ratio of 2.7:1, and a mean age at presentation of 63 years (range 47-72 years). Single masses were present in 77%, and the frontal lobe was the most frequently involved (64%). Treatment regimes included varying combinations of surgical resection and cranial irradiation. Sixteen patients have died, twelve due to recurrent or persistent intracerebral disease. The median survival was ten months. Six patients are still alive at 52, 12, 10, 9, 6 and 4 months. Failure to control the intracranial tumours was the main cause of death. Significant debulking of the tumour was the single most important prognostic factor, although a good initial response to steroids was also favourable. No patient developed spinal deposits. Even when there is a good response to radiation and prolonged survival, the quality of life may be poor: in this series only five out of 22 patients (23%) returned to a normal life. Radiation dosage and the indications for spinal treatment are discussed.

Aged↗
PubMed1988

Insulin-like growth factors and somatomedin B in the cerebrospinal fluid of patients with dementia of the Alzheimer type.

Cerebrospinal fluid levels of radioreceptor assayable insulin-like growth factors (RRA-IGFs) and immunoreactive somatomedin B (SMB) (RIA-B) were determined in apparently healthy individuals and in patients with dementia of the Alzheimer type (AD). The CSF levels of RIA-B and RRA-IGFs did not alter from the healthy controls. After being acidified, the CSF from the controls and from the presenile ADs were separated over a G-50 fine Sephadex . The RRA-IGFs activity eluted in three peaks. The results indicate that the major constituent of CSF RRA in both AD patients and controls is an IGF binding protein. The two minor peaks eluted at approximately 9 K and 6 K, corresponding to the elution positions of "big" IGF-2 and IGF-2.

Aged↗
PubMed1987

Acute pancreatitis in two dogs given azathioprine and prednisone.

Acute pancreatitis was diagnosed in 2 dogs given azathioprine and prednisone. Prednisone and azathioprine had been given as immunosuppressive therapy for pemphigus foliaceus in dog 1 and for polymyositis in dog 2. Azathioprine was discontinued in both dogs. In dog 1, prednisone was reinstituted on day 6 of hospitalization. Prednisone was continued throughout the period of hospitalization in dog 2. Both dogs recovered without complication. Glucocorticoid therapy has been associated with the development of pancreatitis. In human beings, a common side effect of azathioprine is the development of drug-induced pancreatitis. Definitive identification of azathioprine as the cause of pancreatitis in these dogs was not possible; the owners refused to permit retreatment with the drug. Therefore, the synergistic action between these 2 drugs could not be ruled out as the cause of pancreatitis.

Acute Disease↗
PubMed1986

Modulation of high-dose methotrexate toxicity by a non-toxic level of 5-fluorouracil.

High-dose methotrexate (MTX) toxicity is reduced by a non-toxic dose of 5-fluorouracil (FU) when these agents are used in combination. Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, hemoglobin, and hematocrit), ileal tissue, body weight, and mean survival were used as parameters to assess toxicity. For all parameters studied, there were no significant differences between the scheduling of MTX (245 mg/kg) after a priming dose of FU (25 mg/kg), simultaneous MTX and FU, FU alone, and control. However, sequential treatment with MTX followed by FU, and MTX alone resulted in: a marked decrease in the hematopoietic parameters; significant morphological changes in ileal tissue; a reduction of body weight; and increased mortality of animals. Hence, this study suggests that FU, a cytotoxic agent, may protect against MTX toxicity and improve its therapeutic index when FU administration precedes MTX or when these agents are given simultaneously.

Animals↗
PubMed1984

In vitro study of cytotoxic factors against endothelium in childhood dermatomyositis.

In a previous report we showed that leukocytes from a group of patients with childhood dermatomyositis (CDM) were not cytotoxic toward cultured normal human skeletal muscle cells. Blood products from 11 patients with CDM and 12 age- and sex-matched controls were tested for cytotoxicity toward human endothelium using a chromium 51 assay. Mixed lymphocytes, monocytes, and serum alone or in combination did not produce endothelial cell death. The combination of serum and leukocytes, however, did produce some cytotoxic effects in three of 11 patients with CDM. We conclude that those factors tested in vitro are not responsible for the endothelial cell death but together may produce cytotoxic changes in some patients.

Adolescent↗
PubMed1984

Rate-limiting steps in the interactions of fluoropyrimidines and methotrexate.

Rate-limiting steps are defined between methotrexate (MTX) and 5-fluorouracil (FU) or 5-fluorodeoxyuridine (FUdR) and [14C]-formate incorporation into RNA, DNA and protein as a function of the basal rate of dTMP synthesis. When Ehrlich cells are incubated with 0.1 microM FU dR, 1 microM FU and 50 microM MTX for 1-35 min. [3H]-deoxyuridine (UdR) incorporation into DNA is maximally inhibited within 1, 10 and 15 min respectively. The delay in suppression of [3H]-UdR incorporation into MTX-exposed cells compared to cells exposed to FU or FUdR is related to the slow transport of MTX and the increasing free intracellular MTX levels. Influx of MTX is 4 and 10 times slower than FU and FUdR respectively. At 2.5, 5, 10 and 15 min the free intracellular MTX levels (nmol/g dry wt) are 5.8, 7.4, 8.7 and 8.8 respectively. Free intracellular FdUMP is identified 1 min after exposure of cells to FU and FUdR. Antagonism to MTX-suppression of [14C]-formate incorporation into RNA, DNA and protein occurs when cells are simultaneously exposed to MTX and FU or FUdR. However, [14C]-formate incorporation into RNA, DNA and protein is maximally inhibited when Ehrlich tumor cells are incubated with 50 microM MTX for 10 min and then exposed to 1 microM FU for 1 min (a time in which free intracellular MTX is maximal and [3H]-UdR incorporation is maximally suppressed). Hence the sequence and time of administration of FU or FUdR and MTX inhibition of formate incorporation into RNA, DNA and protein is related to the rate of (a) FU, FUdR and MTX transport, (b) FU and FUdR metabolism to FdUMP and (c) generation of maximal free intracellular MTX.

Animals↗