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Biomedical subjects

M Whittaker

Publications and source records attributed to M Whittaker.

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

The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.

Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.

Administration, Oral↗
PubMed1998

Discovery of protease inhibitors using targeted libraries.

There continues to be considerable effort towards the construction of compound libraries targeted for the inhibition of protease enzymes. New tag-encoding methods for library deconvolution have been applied to this problem and there has been particular interest in novel solid-phase linkers for the introduction of key pharmacophore groups required for protease inhibition. Recent reports have tended to focus on nonpeptidic libraries, and, notably, structure-based design methods are now being applied to direct library design.

Chemistry, Organic↗
PubMed1998

Ultrasound-guided unilateral neck exploration for sporadic primary hyperparathyroidism: is it worthwhile?

The role of preoperative localisation tests before initial neck exploration for primary hyperparathyroidism (PHP) remains controversial, as does the optimal surgical approach. We report our experience with preoperative ultrasound (US) and the operative management of sporadic PHP between 1990 and 1995. Preoperative US was carried out by an experienced radiologist. Three surgeons adopted a policy of 'selective' US-guided unilateral neck exploration (UNE); the fourth surgeon performed routine bilateral neck exploration (BNE). There were 72 patients: 26 men and 46 women, with a mean age of 57.4 +/- 12.5 years (range 21-80 years). All patients underwent initial neck exploration for 'sporadic' PHP, of whom 63 had preoperative US. This was positive in 52 patients; 27 of whom underwent a UNE, 23 had a BNE, and two patients had a UNE converted to a BNE. Patients with 'negative' US (n = 11), and those receiving no preoperative localisation test (n = 90) underwent a BNE. The sensitivity, specificity and accuracy of US were 80% (52/65), 100% (61/61), and 90% (113/126), respectively. Comparable success rates were achieved (BNE: 97% (33/34) vs UNE: 93% (27/29), P < 0.05), with very low morbidity. Failures with the scan-guided UNE were caused by missed contralateral adenomas. An experienced radiologist and a low incidence of multiglandular disease (MGD) are essential prerequisites for the scan-guided unilateral approach. An experienced surgeon, on the other hand, is the only prerequisite for the 'gold standard' bilateral approach.

Adenoma↗
PubMed1998

Self-mutilation: culture, contexts and nursing responses.

Few papers address the issue of deliberate self-mutilation other than from clinical perspectives. This paper advocates a user-perspective and discusses some of the issues which might attend such a change. The occurrence of self-mutilation is placed within a cultural framework so as to enlarge the debate beyond the confines of medical/nursing responses. It is suggested that nurses abrogate their attachment to such responses and embrace more collaborative approaches to care. In particular, nurses are asked to review their (moral) responses to self-mutilation, an activity which, too often, has been responded to with scorn and derision.

Adolescent↗
PubMed1997

A model for the microtubule-Ncd motor protein complex obtained by cryo-electron microscopy and image analysis.

Kinesin motors convert chemical energy from ATP hydrolysis into unidirectional movement. To understand how kinesin motors bind to and move along microtubules, we fit the atomic structure of the motor domain of Ncd (a kinesin motor involved in meiosis and mitosis) into three-dimensional density maps of Ncd-microtubule complexes calculated by cryo-electron microscopy and image analysis. The model reveals that Ncd shares an extensive interaction surface with the microtubule, and that a portion of the binding site involves loops that contain conserved residues. In the Ncd dimer, the microtubule-bound motor domain makes intimate contact with its partner head, which is dissociated from the microtubule. This head-head interaction may be important in positioning the dissociated head to take a step to the next binding site on the microtubule protofilament.

Adenosine Triphosphatases↗
PubMed1997

Conformational changes due to calcium-induced calmodulin dissociation in brush border myosin I-decorated F-actin revealed by cryoelectron microscopy and image analysis.

Brush border myosin I (BBMI) is a single-headed molecular motor. Its catalytic domain exhibits extensive sequence homology to the catalytic domain of myosin II, while its tail lacks the coiled-coil nature of myosin II. The BBMI tail domain contains at least three IQ motifs and binds calmodulin. Addition of calcium removes one of these calmodulin light chains, with effects on ATPase activity and motility in in vitro assays. Using the techniques of cryoelectron microscopy and helical image analysis we have calculated three-dimensional (3D) maps of BBMI-decorated actin filaments prepared in the presence and absence of calcium. The 3D maps describe a BBMI catalytic domain that is strikingly similar to the catalytic domain of myosin II subfragment 1 (S1), with the exception of a short amino-terminal region of the heavy chain, which is absent from BBMI. The tail domains of BBMI and S1 are highly divergent in structure, continuing on from their respective motor domains with very different geometries. Addition of calcium to BBMI, and the concomitant loss of a calmodulin light chain, results in an extensive reorganization of mass in the tail domain.

Actins↗
PubMed1997

emScope: A Tool Kit for Control and Automation of a Remote Electron Microscope

We have developed a portable and extensible set of tools and applications for control of a remote transmission electron microscope (TEM). These tools will be used to develop a system for automatically acquiring large numbers of high quality images from a TEM in a routine, robust, and efficient manner. In particular we plan to develop applications that allow for data collection from specimens preserved in vitreous ice. Copyright 1997 Academic Press. Copyright 1997 Academic Press

Journal Article↗
PubMed1997

The influence of quality of care upon contraceptive use in rural Bangladesh.

Efforts to develop quantitative indicators of quality of care for family planning services, and to evaluate its role in contraceptive behavior, remain at an early stage. The present study, based upon an analysis of prospective data from a sample of 7,800 reproductive-aged rural Bangladeshi women, provides empirical evidence on the importance of quality of care for contraceptive practice. The results demonstrate that the perceptions of women regarding the quality of field-worker care were significantly related to the probability of subsequent adoption of a family planning method. Women who were not using a method and who scored high on an index of perceived quality of care were 27 percent more likely to adopt a method subsequently, compared with women with a low score. Effects were even more pronounced for contraceptive continuation; high quality of care was associated with a 72 percent greater likelihood of continued use of any method of contraception.

Adult↗
PubMed1996

Characterisation of refractory wastes at hydrocarbon-contaminated sites-II. Screening of reference oils by stable carbon isotope fingerprinting.

The preliminary evaluation of stable carbon-isotope ratio mass spectrometry (IRMS) as a novel, alternative method for screening residual heavy or weathered petroleum wastes is presented. Seven well-characterised middle-to high-boiling range oils (predominant boiling range: 150-600 degrees C) and their isolated class fractions were analysed by IRMS. Whole oil delta13C values (which express the ratio of (13)C to (12)C within each sample) showed a small but significant decrease with decreasing oil asphaltene content, from -26.8% for heavier oils to -28.8% for lighter, predominantly paraffinic oils. In agreement with the conventionally observed trend, delta13C values of isolated class fractions were found to increase in the following order: delta13Csat (congruent with delta13Coil) < delta13Caro < delta13Cpol < delta13Casp, delta13Csat up to 2.5% more negative than delta13Cpol and delta13Casp. However, this variation was much less pronounced for the heavier oil samples. As a result, isotope type curves exhibited a clear distinction between heavier oils, which produced much flatter type curves, and lighter oils, for which type curves were characteristically sloping. From these preliminary results, IRMS would appear to have application as a potential method for identifying a predominance of asphaltene class fractions in residual hydrocarbon wastes and for distinguishing between heavy and light oily contaminants.

Journal Article↗
PubMed1996

The Depth of the Pneumoperitoneum Determines the Safety of Primary Cannula Insertion

We assessed the anterior-to-posterior depth of pneumoperitoneum at various volumes and pressures, and the actual depth when a standard force was applied to the primary cannula in the umbilicus (equivalent to the normal force used). A 5-mm laparoscope was inserted through a suprapubic port and a depth gauge through the 10-mm intraumbilical port. All gas was initially removed from the abdomen, and the depth of the pneumoperitoneum was measured, with and without the standard force applied to the umbilical port, at incremental volumes and pressures up to 25 mm Hg. Our data strongly suggest that a 2- to 3-L pneumoperitoneum is inadequate in most cases, as the anterior abdominal wall will lie directly against bowel or omentum as soon as any force is applied to the umbilical port. The data also suggest that the pneumoperitoneum should be pressure limited and not volume limited. The pressure should be set at 25 mm Hg, as this gives an adequate pneumoperitoneum depth when the primary cannula is inserted, and hence a greater margin of safety.

Journal Article↗
PubMed1996

Lexipafant (BB-882), a platelet activating factor receptor antagonist, ameliorates mucosal inflammation in an animal model of colitis.

OBJECTIVE: To assess the anti-inflammatory action of lexipafant (BB-882), a platelet activating factor antagonist, in an animal model of acute colitis. DESIGN: An animal intervention study. METHODS: Following the rectal instillation of formalin 0.75% into male New Zealand White (NZW) rabbits, 0.85 ml of aggregated immunoglobulin was administered i.v. Treatment groups (0.8 mg/kg, n = 6; 2.4 mg/kg, n = 13; 3.2 mg/kg, n = 10) were given bolus doses of BB-882 two-hourly i.v. (control group, n = 25). Rectal dialysis was performed before induction of colitis and sacrifice. Dialysate leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were determined. Tissue was saved for histology and measurement of myeloperoxidase content. RESULTS: There was a dose-dependent improvement in macroscopic scores (2.4 and 3.2 mg/kg: P < 0.02, P < 0.001) and myeloperoxidase levels (3.2 mg/kg: P < 0.04). Dialysate LTB4 levels fell (2.4 and 3.2 mg/kg: P < 0.03, P < 0.02) as did PGE2 levels. TXB2 concentrations remained unaffected. CONCLUSION: The PAF receptor antagonist BB-882 shows efficacy in treating inflammation in an animal model of acute colitis as evidenced by a dose-dependent fall in macroscopic mucosal damage, neutrophil infiltration and reduced generation of inflammatory mediators.

Animals↗
PubMed1995

A 35-A movement of smooth muscle myosin on ADP release.

Myosin II crossbridges interact with F-actin producing powerstrokes of around 100 A (refs 1, 2), during which the products of ATP hydrolysis are released. This has been postulated to involve an articulation of the myosin head (S1) on actin, or substantial conformational changes in S1 itself. Small movements of the regulatory light chain have been detected (see, for example, refs 9, 10), but most data suggest that the bulk of S1 does not move on actin during crossbridge cycling. Here we present three-dimensional maps of S1-decorated F-actin in the presence and absence of MgADP. The myosin motor domain is similar in both states but there are major orientational differences in the light-chain-binding domain. This domain acts as a rigid level arm pivoting about the end of the motor domain and swinging approximately 23 degrees, resulting in a approximately 35-A step. Small, nucleotide-mediated conformational changes in the motor domain may thus be converted by the light-chain domain into large movement steps.

Adenosine Diphosphate↗
PubMed1995

PHOELIX: a package for semi-automated helical reconstruction.

We describe a set of procedures and algorithms which have been developed to provide an efficient and reliable method for reconstructing a three-dimensional density map from specimens with helical symmetry. These procedures build on the original MRC helical processing suite, with extensions principally developed using the SUPRIM image processing package. Actomyosin is used as a model specimen to demonstrate the utility of this repackaged and expanded set of routines. The time required to complete a three-dimensional map has been reduced from several weeks using traditional manual techniques to a few days. The increased signal/noise provided has allowed for the extraction of additional layer lines not previously identified by manual techniques.

Actomyosin↗
PubMed1994

Structural characterization of the copper site in galactose oxidase using X-ray absorption spectroscopy.

X-ray absorption spectroscopy has been used to characterize the local structural environment of the Cu ion in the reductively inactivated, oxidatively activated, and active+substrate oxidation state derivatives of galactose oxidase. In all three cases, the local environment of the Cu is best modeled by a single shell of low-Z (N or O) scatterers. This is generally consistent with the structure determined crystallographically, although the EXAFS bond lengths are slightly, but significantly, shorter than those found crystallographically. The best-fit average bond lengths are 1.97, 1.95, and 1.98 A for inactive, active, and active+substrate, respectively. The CuII ion in the active and inactive derivatives has an apparent coordination number of 4, consistent with the equatorial ligation seen crystallographically. The CuI ion in the reduced+substrate derivative appears to have either a lower coordination number or a significantly more distorted local environment. The observed CuI-(N/O) bond length favors a model where the Cu become 3-coordinate in the substrate-reduced complex.

Copper↗