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Biomedical subjects

J Welsh

Publications and source records attributed to J Welsh.

At least 127 records · Page 7Linked to original sources
PubMed1987

Studies on the arrangement of DNA inside viruses using a breakable bis-psoralen crosslinker.

We have developed a new DNA-DNA crosslinking strategy based on a cleavable bispsoralen reagent and used this strategy to study the structures of bacteriophage lambda and the animal virus SV40. Our results show that in both lambda and SV40, all restriction fragments examined can be crosslinked to all other restriction fragments. In bacteriophage lambda, the crosslinking data are consistent with a random packaging model, while in SV40 there is some deviation from the random model. These results imply that the structures of DNA inside these viruses are either highly disordered or very complex.

Bacteriophage lambda↗
PubMed1987

Monoclonal antibodies for the depletion of specific subpopulations of lymphocytes.

A number of rat monoclonal antibodies of the IgG2b subclass have been used to deplete mice of T lymphocyte subsets. It has been possible to produce long-term depletion where antibodies are administered to mice thymectomized in their adult life, or short-term depletion in euthymic animals. It is therefore feasible to ablate a T lymphocyte subpopulation at any stage in the course of an immune response and to examine in detail the role of a particular subset in the induction or effector phases of that response. We have used such ablative procedures to define the T cell subsets which participate in graft rejection, graft-versus-host disease, antigenic competition and antiviral and anti-self immunity and have attempted to exploit such knowledge to establish immunological tolerance in an adult animal.

Animals↗
PubMed1986

Ovine fetal adrenal maturation at term and during fetal ACTH administration: evidence that the modulating effect of cortisol may involve cAMP.

Exogenous ACTH1-24 promotes adrenal maturation in fetal sheep, and this effect appears to be modulated in part by cortisol (Challis et al. 1985). We have examined whether similar changes in adrenal metabolism of progesterone occur with ACTH-induced labour as at spontaneous term and whether the site of cortisol modulation is on adrenal steroidogenesis or at the level of cAMP generation. Chronically catheterized fetal sheep were infused in utero for 100 h between days 127 and 131 of pregnancy with P-ACTH, P-ACTH + metopirone, P-ACTH + metopirone + cortisol, or saline. After 100 h the metabolism of [3H]progesterone was measured in adrenal homogenates. Similar incubations were performed with adrenal tissue from fetal sheep at day 130 of pregnancy and at spontaneous labour. In the treatment groups of sheep, cAMP output by dispersed adrenal cells in response to ACTH added in vitro was also determined. Similar qualitative patterns of [3H]progesterone metabolism were found in adrenal homogenates after in vivo ACTH or at term. At both times there was an increase in cortisol and in total 17 alpha-hydroxycorticosteroid accumulation and also evidence for increased activity of 11 beta-hydroxylase enzyme. The formation of total 17 alpha-hydroxycorticosteroids was not affected significantly by concurrent treatment in vivo with metopirone +/- cortisol. The accumulation of cAMP in vitro was increased after in vivo ACTH, attenuated after ACTH + metopirone, but statistical significance over controls was restored after ACTH + metopirone + cortisol treatment. We conclude that ACTH-induced labour and spontaneous parturition in sheep is associated with qualitatively similar changes in progesterone metabolism by the fetal adrenal gland.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxycorticosteroids↗
PubMed1986

Functional and immunologic protein S levels are decreased during pregnancy.

Protein S, is a natural anticoagulant protein which serves as a cofactor for activated protein C. During pregnancy and in the postpartum period, functional protein S levels are significantly reduced (38% +/- 17.3%, mean +/- 1 SD) when compared to nonpregnant females (97% +/- 31.6%) (P less than 0.001). In plasma an equilibrium exists between functionally active free protein S and protein S complexed with C4b-binding protein, which is functionally inactive. As a result of this equilibrium either a decreased level of total protein S antigen or an elevation of C4b-binding protein could lead to reduced protein S activity. C4b-binding protein levels measured by enzyme-linked immunoassay are not significantly different in pregnant women versus nonpregnant controls (103.5% +/- 21.2% v 100% +/- 16.9%). However, during pregnancy and in the postpartum period, total protein S levels are reduced (68% +/- 10.7%) compared to nonpregnant controls (100% +/- 17.0%). This difference is significant at P less than 0.001. These data demonstrated that the reduction in protein S activity observed during pregnancy is a result of reduced total protein S antigen.

Carrier Proteins↗
PubMed1985

Relation between raised concentrations of fucose, sialic acid, and acute phase proteins in serum from patients with cancer: choosing suitable serum glycoprotein markers.

Serum concentrations of fucose, sialic acid, and eight acute phase proteins were measured in single specimens from patients with cancer in order to determine whether the raised concentrations of protein bound sugars commonly found in cancer correlate with increased concentrations of the acute phase proteins. Strong positive correlations were found only with alpha 1-acid glycoprotein, alpha 1-antitrypsin, and haptoglobins. Changes in protein bound sugars and acute phase proteins were also examined in relation to patients' disease states. Serum fucose was raised more often in patients with advanced disease than in those in whom the spread of the tumour was more restricted; increased sialic acid concentrations, however, were found with a similar frequency in both these groups. Combined use of fucose and sialic acid values gave a high degree of marker positivity which could be only slightly improved on by including measurement of acute phase proteins. The combined use of serum fucose and sialic acid concentrations may have value in monitoring patients with cancer: the sialic acid provides an index of the acute phase response and the fucose a measure of the tumour spread.

Acute-Phase Proteins↗
PubMed1984

Low-density lipoprotein metabolism in mice with soft tissue tumours.

This study examines the potential value of low-density lipoprotein (LDL) as a vehicle for directing cytotoxic drugs to tumour cells in mouse model systems. Control and MAC 13 tumour-bearing NMRI mice were injected with tracer doses of 125I-labelled native and cyclohexanedione-modified 131I-labelled LDL. 18 h later the animals were killed and the radioactivities assimilated by various tissues were measured relative to plasma activity at the time of death. These values were used to calculate specific tissue receptor-mediated LDL uptake. All tissues expressed receptors but the liver and adrenal gland were particularly active. In tumour-inoculated animals, the neoplastic lesions were second only to liver in their net assimilation of LDL. CFLP mice bearing virus-induced parotid adenomata gave results similar to those obtained in NMRI animals. In order to improve the selectivity of LDL assimilation we attempted to downregulate LDL receptors in the liver and adrenal gland by administration of the bile acid sodium taurocholate or by subcutaneous injection of hydrocortisone sodium succinate. These manoeuvres together reduced uptake of the lipoprotein into both organs without affecting tumour activity.

Adenoma↗
PubMed1984

The analysis and animal pharmacokinetics of 1,2,4, triglycidyl urazol using a high-pressure liquid chromatographic technique.

This article details a procedure for the analysis of TGU by a simple high-pressure liquid chromatographic (HPLC) method. Linearity is maintained over the range from zero to at least 30 micrograms 1,2,4, triglycidyl urazol (TGU). The sensitivity of the assay is 250 ng/ml. A second peak, as yet unidentified, was detected on the chromatogram and probably represents a metabolite of TGU. The pharmacokinetic profile of TGU in Porton mice shows a first-order elimination process with a half-life (t1/2 alpha) of 1.5 min for the distribution phase and a t1/2 beta of 5 min. The apparent volume of distribution is 0.75 ml and the clearance 0.10 ml/min with a elimination rate constant of 0.14 min.

Animals↗
PubMed1984

The effect of cytotoxic therapy on saliva and oral flora.

Oral complications of cytotoxic therapy result from direct mucosal damage and, indirectly, occur as a consequence of immunosuppression. Such problems are further exacerbated as a result of associated xerostomia and secondary infection. Therefore, the aims of this study were to examine the salivary volume and composition (amylase, IgA, and lysozyme) together with the oral carriage of potential pathogens in patients receiving cytotoxic therapy. A pilot study comparing healthy controls with patients on chemotherapy for malignant conditions indicated that there were differences between the two groups. Therefore, a longitudinal study was initiated and twelve patients were assessed prior to and 4 and 12 weeks after the start of cytotoxic therapy. The 10-minute forced-spitting salivary volume and amylase and IgA levels all declined significantly over the 12-week period. Lysozyme content did not change. A quantitative increase in the oral carriage of Candida species, coliforms, and Staphylococcus aureus was also observed during therapy. Hence, it is concluded that cytotoxic chemotherapy results in a decreased salivary flow, a reduction in salivary amylase and IgA, and an increase in the oral carriage of opportunistic pathogens.

Adult↗
PubMed1984

The treatment of advanced bladder cancer with methotrexate and cis-platinum--a pharmacokinetic study.

As part of a phase III study in advanced bladder cancer, 5 patients received methotrexate (MTX) 50 mg/m2 as a single agent every 2 weeks, and with every alternate dose of MTX (i.e. every 4 weeks) cis-platinum (CDDP) 50 mg/m2 was given simultaneously, together with saline hydration and diuresis. The clearance of MTX was measured in a total of 12 courses by serial serum sampling for up to 72 hr following injection. In 4 patients (with a mean pretreatment creatinine clearance of 97 ml/min) there was no significant difference between the clearance of MTX when given alone [mean t1/2 (beta) 3.2 hr] and when given 2 weeks later with concurrent CDDP [mean t1/2 (beta) 2.9 hr]. In 1 patient with a pretreatment creatinine clearance of 52 ml/min the clearance of MTX when given alone (without hydration) was significantly delayed compared with the clearance of MTX when given 2 weeks later concurrently with CDDP and saline hydration [t1/2 (beta) 19 and 4.5 hr respectively]. Of the 5 patients so far treated with MTX-CDDP, 2 have had a partial objective response and 3 have had stable disease (including 2 with a marked subjective response). These data indicate that in patients with satisfactory renal function, low-dose MTX and CDDP may be given concurrently without risk of enhanced drug toxicity.

Aged↗
PubMed1984

The oral carriage of yeasts and coliforms in patients on cytotoxic therapy.

The oral carriage of yeasts and coliforms in a healthy adult population and a group of patients with malignancies, undergoing cytotoxic therapy was investigated. A quantitative increase in the intra-oral carriage of Candida species and coliforms was observed during cytotoxic therapy. The most frequent yeast and the coliform isolated were Candida albicans and Escherichia coli, respectively. Thus, the oral cavity may constitute a reservoir of potentially pathogenic flora in patients on cytotoxic therapy.

Adolescent↗
PubMed1983

Oral levonantradol in the control of cancer chemotherapy-induced emesis.

A dose-ranging study with oral levonantradol was performed in 20 cancer patients. The optimum oral dose which attenuated vomiting accompanying chemotherapy was 1 mg 4-hourly. Side-effects comprised dizziness, confusion, euphoria, drowsiness, and difficulty in concentrating. There was no cardiovascular toxicity. Overall toxicity appeared to be dose-related and was mild and acceptable.

Antiemetics↗
PubMed1983

Conformation of promoter DNA: fine mapping of S1-hypersensitive sites.

Larsen and Weintraub showed that a feature of active (but not inactive) chromatin is the appearance of S1-nuclease-hypersensitive sites in the 5'-flanking regions of expressing genes. Such sites are also present in supercoiled, but not relaxed, plasmids carrying these gene sequences. We have developed an in vitro approach to map, at the nucleotide level, S1-hypersensitive sites in artificially generated supercoiled circles of naked DNA. In the case of the adult chicken beta-globin gene, our results correlate extremely well with the coarser in vivo mapping. These sites reside in homopurine-homopyrimidine tracts, and, despite their S1 sensitivity, they do not seem to be single-stranded.

Animals↗
PubMed1983

A randomised multicentre single blind comparison of a cannabinoid anti-emetic (levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy.

One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy. The patients were randomly allocated to receive levonantradol (0.5, 0.75 or 1 mg) or chlorpromazine (25 mg) prior to receiving their first course of cytotoxic therapy. The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy, 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr. The extent of anorexia, nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy. In addition, a self-assessment questionnaire was completed by the patients. Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti-emetic. Both were reasonably well tolerated, although at this dose of levonantradol 22% of patients experienced dysphoric reactions. At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50%, but without a concomitant increase in antiemetic activity. Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum. We conclude that levonantradol (0.5 mg) is a more effective anti-emetic than chlorpromazine (25 mg) in patients receiving cytotoxic chemotherapy. However, its use cannot be recommended due to its high incidence of unacceptable central nervous system side-effects.

Adolescent↗
PubMed1983

Improved vascular access for patients receiving chemotherapy.

Indwelling central venous catheters were used for vascular access in 25 oncology patients. The lines were used for sampling, administration of blood products, chemotherapeutic agents, parenteral nutrients and occasionally plasmapheresis. The complication rate was no higher than in reported series in which the catheters were reserved for parenteral nutrition. We believe that a central venous cannula can be safely used as the sole means of vascular access in those patients with consequent psychological and practical benefits.

Adolescent↗