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L Howells

Publications and source records attributed to L Howells.

At least 19 recordsLinked to original sources
PubMed2003

Development, reliability and validity of the Diabetes Illness Representations Questionnaire: four studies with adolescents.

AIMS: This article reports on the development and validity of a Diabetes-specific Illness Representations Questionnaire (DIRQ) to assess all five dimensions of an individual's perception of diabetes, for adolescents with Type 1 diabetes mellitus. METHODS: There were two development studies. Study 1: participants (n = 115) completed a questionnaire assessing perceptions of the consequences of diabetes and the effectiveness of treatment, along with a questionnaire assessing self-care. Study 2: participants (n = 79) completed a questionnaire assessing their identity, timeline and causal beliefs, along with a diabetes self-efficacy and barriers to adherence questionnaire. Subsequently there were two validation studies. Study 3: participants (n = 44 adolescents and 28 parents) completed the DIRQ and questionnaires assessing their self-care and psychological well-being. Glycaemic control was assessed through retrieval of routine assay results. Study 4: participants (n = 70) completed the DIRQ and questionnaires to assess their psychological well-being, with glycaemic control assessed through retrieval of routine assay results. RESULTS: The development studies suggest that the perceived consequences of diabetes consist of two subscales, perceived threat and perceived impact, and provide further support for the distinction between treatment effectiveness to control diabetes and treatment effectiveness to prevent complications. Along with the validation studies, the results indicate that the questionnaire scales showed good internal consistency and construct validity through their associations with measures of self-care and psychological well-being. CONCLUSION: The data reported here suggest that the DIRQ has the potential to be a useful tool for clinical assessment and evaluating the impact of psycho-educational and medical interventions.

Adaptation, Psychological↗
PubMed2002

A randomized control trial of the effect of negotiated telephone support on glycaemic control in young people with Type 1 diabetes.

AIM: To evaluate changes in self-efficacy for self-management in young people with Type 1 diabetes participating in a "Negotiated Telephone Support" (NTS) intervention developed using the principles of problem solving and social learning theory. METHODS: One-year RCT with 79 young people (male 39; mean age +/- sd 16.5 +/- 3.2 years, duration 6.7 +/- 4.4 years, HbA(1c) 8.6 +/- 1.5%) randomized into: Group 1 (control group), continued routine management, n = 28; Group 2, continued routine management with NTS, n = 25; Group 3, annual clinic with NTS, n = 26. OUTCOME MEASURES: HbA(1c), self-efficacy, barriers to adherence, problem solving, and diabetes knowledge. RESULTS: There were no differences between the groups at baseline. Participants in Groups 2 and 3 received an average of 16 telephone calls/year (range 5-19), median duration 9 min (2-30), with a median interval of 3 weeks (1-24) between calls. Significant correlations were found between age and average length of call (r = 0.44, P < 0.01) and frequency of contact (r = 0.36, P < 0.05). Social and school topics were discussed frequently. After 1 year, while the participants in the two intervention groups showed significant improvements in self-efficacy (P = 0.035), there was no difference in glycaemic control in the three groups. Barriers to insulin use adherence were a significant predictor of HbA(1c) (P < 0.001) after controlling for baseline. CONCLUSIONS: NTS is an effective medium to deliver a simple theory-based psychological intervention to enhance self-efficacy for diabetes self-management. Reduced clinic attendance, combined with NTS, did not result in a deterioration of HbA(1c). Intensive personal support needs to be combined with intensive diabetes therapy to improve glycaemic control in this age group.

Adolescent↗
PubMed2001

Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production.

Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10(-5) - 10(-4) M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 microM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E2 (PGE2) production in human colonic epithelial cells. Curcumin reduced PGE2 levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE2 inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.

Adult↗
PubMed2001

Miniaturization of a hepatitis C virus RNA polymerase assay using a -102 degrees C cooled CCD camera-based imaging system.

Innovations in detection technologies have allowed us to develop a novel assay in 1536-well plate format and assess the advantages of screen miniaturization compared with conventional high-throughput compound screening in 96- or 384-well plates. An HCV RNA polymerase assay has been miniaturized in 1536-well plates by using a new detection technology known as LEADseeker homogeneous imaging system. It uses a -102 degrees C cooled charge-coupled device (CCD) camera and newly designed scintillation proximity microparticles. The miniaturized assay used europium-doped streptavidin-coated yttrium oxide (YO(x)) or polystyrene (PS) microspheres to capture biotin-labeled [(3)H]RNA product transcripts. Beads in proximity to the radioisotope convert the emitted beta(-) particles into photons having wavelengths in the red region of the visible spectrum, optimal for detection by the CCD camera. Because the camera collects light from all wells of the plate simultaneously, 1536-well plates are imaged as rapidly as 384-well plates, on the order of 10 min per plate. The assay has a signal to background of approximately 20-fold, satisfactory for high-throughput robotics screening. The enzyme kinetics and potency of a known inhibitor were similar to those obtained from the conventional assay using scintillation proximity assay (SPA) beads and a scintillation plate counter. Furthermore, the newly developed microbeads (emitting at 610 to 620 nm) are less prone to quenching effects caused by yellow-colored compounds, than conventional SPA beads or scintillation fluid (emitting at 400 to 480 nm region). Thus, the LEADseeker imaging system is a useful new tool for miniaturization of assays for high-throughput screening.

Cold Temperature↗
PubMed2001

Multi-residue analysis of avermectins and moxidectin by ion-trap LC-MSn.

A multi-residue method was developed and validated for the quantitation and confirmation of avermectins and moxidectin residues in bovine liver. Target analytes were extracted from liver homogenate using C8 solid phase cartridges, chromatographed under basic pH conditions in order to promote the formation of analyte anions, and detected by ion-trap mass spectrometry (MS) in negative ion mode using an atmospheric pressure chemical ionization interface (APCI). The method provided detection capabilities (CC beta, where beta = 0.05) for eprinomectin, abamectin, doramectin, moxidectin and ivermectin of 3.1, 3.2, 2.2, 4.0 and 3.2 ng g-1 liver respectively, well below their respective maximum residue limits (MRLs). The critical concentrations for MRL compliance (CC alpha, where alpha = 0.01) were 840, 28, 130, 130 and 130 ng g-1 respectively. Analysis of liver fortified at the appropriate MRLs gave recoveries (% +/- RSD) of 70.9 +/- 11.6 (n = 14), 69.1 +/- 3.9 (n = 13), 65.9 +/- 6.4 (n = 19), 69.7 +/- 9.3 (n = 19) and 73.2 +/- 10.5 (n = 19), respectively, for each analyte. Calibration curves fitted a second order polynomial function (R2 > or = 0.9978) over a wide range of concentrations (0 to 10,000 ng ml-1). The detection of two daughter-ions for each analyte allowed for quantitation and the confirmation of identity. The method is suitable for application in European Union statutory veterinary drug residue surveillance programmes, since it fulfills appropriate analytical criteria, and has the particular advantage of enabling high throughput multi-residue quantitation and confirmation of the target analytes.

Animals↗
PubMed2001

Development and optimisation of an improved derivatisation procedure for the determination of avermectins and milbemycins in bovine liver.

A robust procedure has been developed to overcome the instability problems experienced with the fluorescent derivative of eprinomectin. The procedure involves addition of acetic acid, together with the typical reagents methylimidazole and trifluoroacetic anhydride, to produce a fluorescent molecule that can be determined by high performance liquid chromatography (HPLC) with fluorescence detection. Derivatisation is completed in 30 min at 65 degrees C. This derivatisation procedure was shown to be suitable, also, for the related compounds, moxidectin, abamectin, doramectin and ivermectin. A multi-residue method for these compounds in bovine liver has been developed using the derivatisation procedure. Samples are extracted with acetonitrile; followed by clean-up on deactivated alumina and C18 solid phase extraction (SPE) cartridges. The method was validated using bovine liver fortified at levels of 4 and 20 micrograms kg-1 with the drugs. The mean recovery ranged between 73 and 97%. The intra- and inter-assay variations showed relative standard deviations typically of < 6% and < 14%, respectively. The limit of quantitation of the method is 2 micrograms kg-1 (ppb).

Animals↗
PubMed2001

The potential for CYP2D6 inhibition screening using a novel scintillation proximity assay-based approach.

High throughput inhibition screens for human cytochrome P450s (CYPs) are being used in preclinical drug metabolism to support drug discovery programs. The versatility of scintillation proximity assay (SPA) technology has enabled the development of a homogeneous high throughput assay for cytochrome P450 2D6 (CYP2D6) inhibition screen using [O-methyl-(14)C]dextromethorphan as substrate. The basis of the assay was the trapping of the O-demethylation product, [(14)C]HCHO, on SPA beads. Enzyme kinetics parameters V(max) and apparent K(m), determined using pooled human liver microsomes and microsomes from baculovirus cells coexpressing human CYP2D6 and NADPH-cytochrome P450 reductase, were 245 pmol [(14)C]HCHO/min/mg protein and 11 microM, and 27 pmol [(14)C]HCHO/min/pmol and 1.6 microM, respectively. In incubations containing either pooled microsomes or recombinant CYP2D6, [(14)C]dextromethorphan O-demethylase activity was inhibited in the presence of quinidine (IC(50) = 1.0 microM and 20 nM, respectively). By comparison, inhibitors selective for other CYP isoforms were relatively weak (IC(50) > 25 microM). In agreement, a selective CYP2D6 inhibitory monoclonal antibody caused greater than 90% inhibition of [(14)C]dextromethorphan O-demethylase activity in human liver microsomes, whereas CYP2C9/19- and CYP3A4/5-selective antibodies elicited a minimal inhibitory effect. SPA-based [(14)C]dextromethorphan O-demethylase activity was also shown to correlate (r(2) = 0.6) with dextromethorphan O-demethylase measured by high-performance liquid chromatography in a bank of human liver microsomes (N = 15 different organ donors). In a series of known CYP2D6 inhibitors/substrates, the SPA-based assay resolved potent inhibitors (IC(50) < 2 microM) from weak inhibitors (IC(50) >or= 20 microM). It is concluded that the SPA-based assay described herein is suitable for CYP2D6 inhibition screening using either native human liver microsomes or cDNA-expressed CYP2D6.

Antibodies, Monoclonal↗
PubMed1999

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.

Antineoplastic Agents↗
PubMed1994

Melanin as an adsorbent for drug residues.

The binding of seven veterinary drugs (clenbuterol, chlorpromazine, diethylstilbestrol, 19-nortestosterone, salbutamol, salicylic acid and trenbolone) to melanin from Sepia officinalis was investigated. Basic and hydrophobic drugs were the most strongly bound. Desorption by ethanol was complete for neutral drugs but only partial for the basic drugs, which suggests that binding of the latter involves an ionic component. A method of synthesizing melanin in an immobilized form (melanin-PS) on the surface of porous silica was developed. When the drug binding properties of melanin-PS were investigated, its capacity to bind the basic drug clenbuterol was found to be higher (5.9 nmol mg-1) than that for the neutral hydrophobic drug 19-nortestosterone (0.56 nmol mg-1); for both drugs the attainment of binding equilibrium with melanin-PS was relatively rapid (< 5 min). By virtue of its binding kinetics, high capacity and mechanical robustness, melanin-PS offers potential for use in chromatography or solid-phase extraction and may additionally enable modelling of drug-melanin interactions.

Adsorption↗
PubMed1993

Cognitive therapy for depression with individuals with intellectual disabilities.

The increase in research into psychopathology in people with intellectual disability has recently spread to include depression. Several reports have appeared on the assessment of depression in the client group and there is a pressing need for research into treatment of depression in people with intellectual disability. The present paper reviews cognitive behaviour therapy for depression and reports on its adaptation for people with intellectual disability. Two case studies of individuals with mild intellectual disability illustrate the clinical applications. All the elements of cognitive behaviour therapy for depression were maintained and simplified. Both subjects were able to monitor their feelings of depression and subject 2 monitored the frequency of suicidal thoughts. Improvements were seen in both cases on the Zung Depression Inventory and daily monitoring of depressive feelings.

Adult↗