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Biomedical subjects

G Lowe

Publications and source records attributed to G Lowe.

At least 37 records · Page 2Linked to original sources
PubMed2000

Blood rheology, cardiovascular risk factors, and cardiovascular disease: the West of Scotland Coronary Prevention Study.

The West of Scotland Coronary Prevention Study (WOSCOPS) showed that pravastatin reduced the risk of coronary heart disease (CHD) events in 6,595 middle-aged hypercholesterolaemic men aged 45-64 years without prior myocardial infarction followed for an average of 4.9 years. We hypothesised prospectively (a) that baseline levels of haemorheological variables were related to baseline and incident CHD and to mortality; and (b) that reduction in lipoproteins by pravastatin would lower plasma and blood viscosity, a potential contributory mechanism to CHD events. We therefore studied plasma and blood viscosity, fibrinogen, haematocrit, and blood cell counts at baseline and 1 year. At baseline, plasma and blood viscosity were related to risk factors, CHD measures, and claudication. On univariate analysis, baseline levels of all rheological variables (except platelet count) were related to incident CHD; CHD mortality; and total mortality. On multivariate analysis including baseline CHD and risk factors, plasma and blood viscosity, haematocrit and white cell count each remained significantly associated with incident CHD; while fibrinogen remained an independent predictor of mortality (all p < 0.03). After one year, lipoprotein reduction by pravastatin was associated with significant reductions (about one quarter of a standard deviation) in plasma viscosity (mean difference 0.02 mPa.s, p <0.001) and in blood viscosity (mean difference 0.06 mPa.s, p<0.001), but was not associated with significant changes in other rheological variables. We therefore suggest that pravastatin therapy, which reduces elevated lipoproteins in hypercholesterolaemic men, may lower risks of CHD and mortality partly by lowering plasma and blood viscosity. Further studies are required to test this hypothesis.

Anticholesteremic Agents↗
PubMed2000

Transfer of 4'-chloro-2,2':6',2"-terpyridine platinum(II) between human serum albumin, glutathione and other thiolate ligands. A possible selective natural transport mechanism for the delivery of platinum(II) drugs to tumour cells.

The antitrypanosomal and antitumour activities of (2,2':6',2"-terpyridine)platinum(II) complexes have been postulated to be due to their ability to inhibit irreversibly the NADPH/FAD redox enzymes trypanothione reductase and human thioredoxin reductase respectively. Here we show that these platinum(II) complexes metallate recombinant human albumin (rHA) at the single free thiol group (Cys-34). Moreover, the (2,2':6',2"-terpyridine)platinum(II) complex can be transferred from rHA to other thiols, such as 2-hydroxyethanethiol or glutathione. Human serum albumin could therefore provide a natural transport mechanism for the selective delivery of these agents to tumor cells by the enhanced permeability and retention (EPR) mechanism.

2,2'-Dipyridyl↗
PubMed1999

Catalytic mechanism of phosphorylase kinase probed by mutational studies.

The contributions to catalysis of the conserved catalytic aspartate (Asp149) in the phosphorylase kinase catalytic subunit (PhK; residues 1-298) have been studied by kinetic and crystallographic methods. Kinetic studies in solvents of different viscosity show that PhK, like cyclic AMP dependent protein kinase, exhibits a mechanism in which the chemical step of phosphoryl transfer is fast and the rate-limiting step is release of the products, ADP and phosphoprotein, and possibly viscosity-dependent conformational changes. Site-directed mutagenesis of Asp149 to Ala and Asn resulted in enzymes with a small increase in K(m) for glycogen phosphorylase b (GPb) and ATP substrates and dramatic decreases in k(cat) (1.3 x 10(4) for Asp149Ala and 4.7 x 10(3) for Asp149Asn mutants, respectively). Viscosometric kinetic measurements with the Asp149Asn mutant showed a reduction in the rate-limiting step for release of products by 4.5 x 10(3) and a significant decrease (possibly as great as 2.2 x 10(3)) in the rate constant characterizing the chemical step. The date combined with the crystallographic evidence for the ternary PhK-AMPPNP-peptide complex [Lowe et al. (1997) EMBO J. 6, 6646-6658] provide powerful support for the role of the carboxyl of Asp149 in binding and orientation of the substrate and in catalysis of phosphoryl transfer. The constitutively active subunit PhK has a glutamate (Glu182) residue in the activation segment, in place of a phosphorylatable serine, threonine, or tyrosine residue in other protein kinases that are activated by phosphorylation. Site-directed mutagenesis of Glu182 and other residues involved in a hydrogen bond network resulted in mutant proteins (Glu182Ser, Arg148Ala, and Tyr206Phe) with decreased catalytic efficiency (approximate average decrease in k(cat)/K(m) by 20-fold). The crystal structure of the mutant Glu182Ser at 2.6 A resolution showed a phosphate dianion about 2.6 A from the position previously occupied by the carboxylate of Glu182. There was no change in tertiary structure from the native protein, but the activation segment in the region C-terminal to residue 182 showed increased disorder, indicating that correct localization of the activation segment is necessary in order to recognize and present the protein substrate for catalysis.

Catalysis↗
PubMed1999

Slice blotting: a method for detecting the release of immunoreactive substances from living brain tissue.

The intricate circuitry of the CNS forms highly organized structures containing a multitude of transmitters, modulators and other chemical signals expressed in specific patterns and pathways. Anatomical studies with immunohistochemical and molecular biological techniques have mapped in fine detail the distribution of these substances in fixed tissue. However, the release of neuroactive substances is often under precise spatial control and is regulated by numerous physiological factors. Understanding such complex intercellular signaling systems will require the development of new spatially resolved methods for detecting secretion in living systems. A simple but powerful method is described here for visualizing and quantifying the time-integrated spatial pattern of release of chemical signals from living neural tissue. The method combines the in vitro brain slice preparation with immunostaining protocols used for antigen detection on Western blots. It has widespread potential application in biological research because it can map in vitro patterns of release of cytokines, growth factors, chemoattractants, chemorepellents, morphogens, enzymes, and other paracrine signals in spatially organized systems, subject to a variety of stimuli and conditions.

Animals↗
PubMed1999

Cytotoxicity of 2,2':6',2' '-terpyridineplatinum(II) complexes against human ovarian carcinoma.

2,2':6',2''-Terpyridineplatinum(II) complexes are shown to possess cytotoxicity against a number of human ovarian tumor cell lines. Many of the complexes show similar activity against cisplatin- and doxorubicin-resistant cell lines as the parental cells suggesting that there is little or no cross-resistance with cisplatin or doxorubicin. The cytotoxicity of bis[2,2':6',2''-terpyridineplatinum(II)] complexes is strongly dependent on the nature of the linker. Bis[2,2':6',2''-terpyridineplatinum(II)] complexes with a flexible linker at the 4'-position show poor cytotoxicity; by contrast bis[2,2':6',2''- terpyridineplatinum(II)] complexes with rigid and short linkers at platinum(II) are strikingly effective. Several of the compounds show greater cytotoxicity against human ovarian cell lines than carboplatin, the therapeutic agent currently advocated for the treatment of human ovarian cancers.

Antineoplastic Agents↗
PubMed1999

Cytotoxicity of (2,2':6',2''-terpyridine)platinum(II) complexes to Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei.

A range of (2,2':6',2''-terpyridine)platinum(II) complexes are shown to possess antiprotozoal activity in vitro against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei,the causative organisms of tropical diseases leishmaniasis and trypanosomiasis. The best compounds caused 100% and 78% inhibition of growth of the intracellular amastigote forms of L. donovani and T. cruzi, respectively, at a concentration of 1 microM and 100% inhibition of growth of the bloodstream trypomastigote forms of T. brucei at a concentration of 0.03 microM. The results obtained with complexes in which the fourth ligand to platinum(II) is capable of being substituted with a substitution inert hydroxyethanethiolate complex are compared. The ammine complexes show high antiprotozoal activity suggesting that the trans influence of the 2,2':6',2''-terpyridine ligand has a profound effect on the ease of displacement of the fourth ligand in (2,2':6',2'' -terpyridine)platinum(II) complexes, although nonbonded interaction between the ammine ligand and the 6 and 6' ' hydrogens probably also weakens the ligation to Pt(II).

Animals↗
PubMed1999

Influence of age-related maculopathy on visual functioning and health-related quality of life.

PURPOSE: To describe the influence of age-related maculopathy on visual functioning and health-related quality of life. METHODS: A prospective, cross-sectional, observational cohort sample of 201 persons with various stages of age-related maculopathy was recruited from the Massachusetts Eye and Ear Infirmary as part of a longitudinal study of age-related macular degeneration. Persons were considered to have age-related maculopathy if one or more of the following clinical characteristics were present: drusen, retinal pigment epithelial changes, geographic atrophy, or evidence of exudative disease. Median corrected visual acuity for this sample was 20/25 in the better eye, with all subjects having 20/200 or better visual acuity in at least one eye at baseline. All participants underwent a comprehensive ophthalmologic examination with a dilated pupil. In addition to the usual clinical data collection, severity of age-related maculopathy was graded by an ophthalmologist who used standard clinical criteria and was masked to the participants' descriptions of visual functioning and health-related quality of life. All participants completed an interview that included the Activities of Daily Vision Scale, a survey designed to assess difficulties with routine daily activities that require vision, and the Short Form-36 Health Survey, a generic measure of multidimensional health-related quality of life. RESULTS: Severity of age-related maculopathy was associated with poorer scores of the Activities of Daily Vision Scale. This association was most significant for near vision and driving activities. In this sample, the SF-36 Health Survey scales were not significantly correlated with severity of age-related maculopathy. CONCLUSIONS: Reported visual functioning is significantly associated with the clinical severity of age-related maculopathy. However, once visual acuity is taken into consideration, clinical grading of age-related maculopathy did not explain a significant portion of the variation in visual functioning. The lack of significant correlation between severity of age-related maculopathy and the SF-36 Health Survey may have resulted from the small number of participants in our sample with severe bilateral age-related maculopathy.

Activities of Daily Living↗
PubMed1999

Pleasure, guilt and secretory immunoglobulin A.

Before producing saliva samples for Immunoglobulin A assay, 30 subjects listed their pleasurable activities and rated them in terms of pleasure and guilt. Levels of Immunoglobulin A were higher in those subjects with high ratios of pleasure-guilt scores.

Adult↗
PubMed1998

Evaluation of resins for on-bead screening: a study of papain and chymotrypsin specificity using PEGA-bound combinatorial peptide libraries.

TentaGel, ArgoGel and PEGA resins were evaluated for on-bead biological screening, using a fluorescently-labelled peptide attached to each and assayed for papain activity. Peptide attached to PEGA was cleaved in near quantitative yield at the expected sites, whilst an identical sequence on TentaGel and ArgoGel beads was hydrolysed in very low yields and nonspecifically on ArgoGel. The compatibility of PEGA with enzymes was further demonstrated by the determination of subsite specificities of papain and chymotrypsin using PEGA-bound peptide libraries, which proved to be similar to those observed in free solution.

Chymotrypsin↗
PubMed1998

Aberrant processing of wild-type and mutant bovine pancreatic trypsin inhibitor secreted by Aspergillus niger.

Bovine pancreatic trypsin inhibitor (BPTI) was secreted by Aspergillus niger at yields of up to 23 mg l-1 using a protein fusion strategy. BPTI was linked to part of the fungal glucoamylase protein (GAM) with a dibasic amino acid (KEX2) processing site at the fusion junction. Electrospray ionisation mass spectrometry and N-terminal protein sequencing revealed that, although biologically active in vitro, the purified products from a number of independent transformants consisted of a mixture of BPTI molecules differing at the N-terminus. Approximately 35-60% of this mixture was processed correctly. Aberrant processing of the GAM-BPTI fusion protein by the A. niger KEX2-like endoprotease was the most likely cause of this variation although the involvement of other fungal endoproteases could not be ruled out. In vitro studies have highlighted a weak interaction between BPTI and the Saccharomyces cerevisiae KEX2 endoprotease, suggesting that BPTI is not a potent inhibitor of KEX2p. A small proportion of the recombinant BPTI (10%) showed 'nicking' of the K15-A16 bond, indicating an interaction with a fungal trypsin-like enzyme. Mutant BPTI homologues designed to have anti-elastase activity, BPTI(K15V), BPTI(K15V,P13I) and BPTI(K15V,G12A), have also been expressed and secreted by A. niger. They also showed a similar spectrum of aberrant N-terminal processing but no 'nicking' of the K15-V16 bond was observed. Comparison of A. niger with other expression systems showed that it is an effective system for producing BPTI and its homologues, although not all molecules were correctly processed. This variation in processing efficiency may be useful in understanding the important determinants of protein processing in this fungus.

Amino Acid Sequence↗
PubMed1998

Clear-cell carcinoma of the ovary in a 19-year-old woman.

The risk of inadvertently treating an ovarian malignancy is always present regardless of the patient's age, clinical history, ultrasound features, serum tumour markers, menopausal status and intraoperative findings. This risk can be minimized by paying particular attention to high-risk characteristics in any of the above assessment criteria and by obtaining an intraoperative frozen section if there is any suspicion of malignancy. The same approach should be used whether the initial treatment is by laparotomy or laparoscopy. We present a case of clear-cell carcinoma of the ovary in a 19-year-old woman where there was delay in diagnosis and treatment as a result of an incorrect initial histopathology assessment. This appears to be the youngest patient reported in the literature with a clear-cell carcinoma of the ovary.

Adenocarcinoma, Clear Cell↗
PubMed1998

The use of cultured dermis in the treatment of diabetic foot ulcers.

The aim of this open, non-comparative study was to assess the potential benefit of tissue-engineered human dermis (Dermagraft) in healing long-standing, difficult-to-heal diabetic foot ulcers, and the practicality of its use in the UK. Six patients with full-thickness neuropathic diabetic foot ulcers which extended into subcutaneous tissue and had an area > 1 cm2 were included. The treatment was applied weekly for eight weeks and the patients were followed for a total of 24 weeks. Four patients completed the study, showing improvement ranging from a reduction of 26% in ulcer area to complete healing. Two patients were withdrawn after developing complications not associated with the treatment. We conclude that this tissue-engineered human dermis has a role in the treatment of diabetic foot ulcers as part of a comprehensive treatment package. A study to confirm effectiveness in a comparative trial and optimise patient selection is indicated.

Adult↗