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Biomedical subjects

N Lambert

Publications and source records attributed to N Lambert.

At least 19 recordsLinked to original sources
PubMed2003

Low-income consumers' attitudes and behaviour towards access, availability and motivation to eat fruit and vegetables.

OBJECTIVE: To determine low-income consumers' attitudes and behaviour towards fruit and vegetables, in particular issues of access to, affordability of and motivation to eat fruit and vegetables. DESIGN AND SETTING: Questionnaire survey mailed to homes owned by a large UK housing association. PARTICIPANTS: Participants were 680 low-income men and women, aged 17-100 years. RESULTS: Age, employment, gender, smoking and marital status all affected attitudes towards access, affordability and motivation to eat fruit and vegetables. Few (7%) participants experienced difficulty in visiting a supermarket at least once a week, despite nearly half having no access to a car for shopping. Fruit and vegetables were affordable to this low-income group in the amounts they habitually bought; purchasing additional fruits and vegetables was seen as prohibitively expensive. Less than 5% felt they had a problem with eating healthily and yet only 18% claimed to eat the recommended 5 or more portions of fruit and vegetables every day. CONCLUSIONS: Supported by research, current UK Government policy is driven by the belief that low-income groups have difficulties in access to and affordability of fruit and vegetables. Findings from this particular group suggest that, of the three potential barriers, access and affordability were only a small part of the 'problem' surrounding low fruit and vegetable consumption. Thus, other possible determinants of greater consequence need to be identified. We suggest focusing attention on motivation to eat fruit and vegetables, since no dietary improvement can be achieved if people do not recognise there is a problem.

Adolescent↗
PubMed2002

Perceptions of HAART among gay men who declined a treatment offer: preliminary results from an interview-based study.

As part of a prospective study of treatment decision making among people with HIV infection, we explored perceptions of HAART in a cohort who declined a treatment offer. This was a qualitative study in which 26 gay men were interviewed in relation to their views about HAART soon after treatment was recommended by their HIV physician. Fifteen themes were associated with the decision to decline HAART. These were grouped under three broad categories: doubts about personal necessity for HAART, concerns about potential adverse effects of taking HAART and satisfaction with the amount of personal control over the decision. These findings provide new insights into the type of beliefs that might inform people's evaluation of their perceived need for HAART and their concerns about HAART. Initiatives to support informed decisions should take account of these perceptions.

Adult↗
PubMed2001

In vitro metabolism and drug interaction potential of a new highly potent anti-cytomegalovirus molecule, CMV423 (2-chloro 3-pyridine 3-yl 5,6,7,8-tetrahydroindolizine I-carboxamide).

AIMS: To identify the enzymes involved in the metabolism of CMV423, a new anticytomegalovirus molecule, to evaluate its in vitro clearance and to investigate its potential involvement in drug/drug interactions that might occur in the clinic. METHODS: The enzymes involved in and the kinetics of CMV423 biotransformation were determined using pools of human liver subcellular fractions and heterologously expressed human cytochromes P450 (CYP) and FMO. The effect of CMV423 on CYP probe activities as well as on indinavir and AZT metabolism was determined, and 26 drugs were tested for their potential to inhibit or activate CMV423 metabolism. RESULTS: CMV423 was oxidized by CYP and not by FMO or cytosolic enzymes. The Km values for 8-hydroxylation to rac-RPR 127025, an active metabolite, and subsequent ketone formation by human liver microsomes were 44 +/- 13 microM and 47 +/- 11 microM, respectively, with corresponding Vmax/Km ratios of 14 and 4 microl min(-1) nmol(-1) P450. Inhibition with selective CYP inhibitors indicated that CYP1A2 was the main isoform involved, with some participation from CYP3A. Expressed human CYP1A1, 1A2, 2C9, 3A4 and 2C8 catalysed rac-RPR 127025 formation with Km values of < 10 microM, 50 +/- 21 microM, 55 +/- 19 microM, circa 282 +/- 61 microM and circa 1450 microM, respectively. CYP1B1, 2A6, 2B6, 2C19, 2D6, 2E1 or 3A5 did not catalyse the reaction to any detectable extent. CYP1A1 and 3A4 also catalysed ketone formation from rac-RPR 127025. In human liver microsomes, CMV423 at 1 and 10 microM inhibited CYP1A2 activity up to 31% and 63%, respectively, CYP3A4 activity up to 40% (10 microM) and CYP2C9 activity by 35% (1 and 10 microM). No effect was observed on CYP2A6, 2D6 and 2E1 activities. CMV423 had no effect on indinavir and AZT metabolism. Amongst 26 drugs tested, none inhibited CMV423 metabolism in vitro at therapeutic concentrations. CONCLUSIONS: CMV423 is mainly metabolized by CYP1A2 and 3A4. Its metabolism should not be saturable at the targeted therapeutic concentrations range (Cmax < 1 microM). CMV423 will probably affect CYP1A2 and 1A1 activities in vivo to some extent, but no other drug-drug interactions are expected.

Adolescent↗
PubMed2001

Understanding patients' preferences for treatment: the need for innovative methodologies.

Treatment selection is now much more consumer driven than in the past. However, there is a need to develop investigative methodological approaches that are sensitive to differences in patient preferences if full account is to be taken of what the patient sees as the best option in terms of different possible treatments available for a particular condition. Previous attitude research has been criticised because it does not provide insight into reasons why people hold different preferences or beliefs. A methodology is described which allows people to describe their concerns and values associated with different treatment options in their own words. This is the repertory grid method of eliciting personal constructs used in conjunction with generalised Procrustes analysis (GPA). An example of the use of this methodology is provided, drawn from research directed towards understanding people's beliefs about genetic technologies. A possible application of the method to understanding treatment preferences related to type 2 diabetes is also discussed. It is concluded that the use of innovative methodologies is essential if our understanding of patient preferences regarding treatment options is to have a significant impact on patient quality of life.

Adult↗
PubMed2000

Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B.

Expression of major histocompatibility complex (MHC) class II genes is controlled at the transcriptional level by at least four trans-acting genes, CIITA, RFXANK, RFX5, and RFXAP. Defects in these regulatory genes result in the absence of MHC class II molecule expression and, thereby, cause a combined immunodeficiency. MHC class II deficiency is inherited as an autosomal recessive trait. Since the first description of the disease, about 70 patients from 50 families have been reported. Forty-three of these families have been classified into four complementation groups: A, B, C, and D. In the largest group, B, the majority of patients are of North African origin. In two of these patients, the same mutation in the RFXANK gene (752delG-25) was identified. We performed a mutation analysis in 20 additional patients belonging to complementation group B and detected the 752delG-25 mutation in 17. All of these patients are of North African origin. A founder effect for this mutation was documented, since all tested patients, except one, display a common haplotype spanning the RFXANK locus.

Africa, Northern↗
PubMed1999

Purification of cytosolic beta-glucosidase from pig liver and its reactivity towards flavonoid glycosides.

Flavonoid glycosides are common dietary components which may have health-promoting activities. The metabolism of these compounds is thought to influence their bioactivity and uptake from the small intestine. It has been suggested that the enzyme cytosolic beta-glucosidase could deglycosylate certain flavonoid glycosides. To test this hypothesis, the enzyme was purified to homogeneity from pig liver for the first time. It was found to have a molecular weight (55 kDa) and specific activity (with p-nitrophenol glucoside) consistent with other mammalian cytosolic beta-glucosidases. The pure enzyme was indeed found to deglycosylate various flavonoid glycosides. Genistein 7-glucoside, daidzein 7-glucoside, apigenin 7-glucoside and naringenin 7-glucoside all acted as substrates, but we were unable to detect activity with naringenin 7-rhamnoglucoside. Quercetin 4'-glucoside was a substrate, but neither quercetin 3, 4'-diglucoside, quercetin 3-glucoside nor quercetin 3-rhamnoglucoside were deglycosylated. Estimates of K(m) ranged from 25 to 90 microM while those for V(max) were about 10% of that found with the standard artificial substrate p-nitrophenol glucoside. The non-substrate quercetin 3-glucoside was found to partially inhibit deglycosylation of quercetin 4'-glucoside, but it had no effect upon activity with p-nitrophenol glucoside. This study confirms that mammalian cytosolic beta-glucosidase can deglycosylate some, but not all, common dietary flavonoid glycosides. This enzyme may, therefore, be important in the metabolism of these compounds.

Animals↗
PubMed1999

Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma.

Fetal CD34(+) CD38(+) cells have recently been found to persist in maternal peripheral blood for many years after pregnancy. CD34(+) CD38(+) cells are progenitor cells that can differentiate into mature immune-competent cells. We asked whether long-term fetal microchimerism occurs in T lymphocyte, B lymphocyte, monocyte, and natural-killer cell populations of previously pregnant women. We targeted women with sons and used polymerase chain reaction for a Y-chromosome-specific sequence to test DNA extracted from peripheral blood mononuclear cells (PBMC) and from CD3, CD19, CD14, and CD56/16 sorted subsets. We also asked whether persistent microchimerism might contribute to subsequent autoimmune disease in the mother and included women with the autoimmune disease scleroderma. Scleroderma has a peak incidence in women after childbearing years and has clinical similarities to chronic graft-versus-host disease that occurs after allogeneic hematopoietic stem-cell transplantation, known to involve chimerism. Sixty-eight parous women were studied for male DNA in PBMC and 20 for PBMC subsets. Microchimerism was found in PBMC from 33% (16 of 48) of healthy women and 60% (12 of 20) women with scleroderma, P =.046. Microchimerism was found in some women in CD3, CD19, CD14, and CD56/16 subsets including up to 38 years after pregnancy. Microchimerism in PBMC subsets was not appreciably more frequent in scleroderma patients than in healthy controls. Overall, microchimerism was found in CD3, CD19, and CD14 subsets in approximately one third of women and in CD56/16 in one half of women. HLA typing of mothers and sons indicated that HLA compatibility was not a requirement for persistent microchimerism in PBMC subsets. Fetal microchimerism in the face of HLA disparity implies that specific maternal immunoregulatory pathways exist that permit persistence but prevent effector function of these cells in normal women. Although microchimerism in PBMC was more frequent in women with scleroderma than healthy controls additional studies will be necessary to determine whether microchimerism plays a role in the pathogenesis of this or other autoimmune diseases.

Adult↗
PubMed1999

Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder (incidence around 1 in 106 births), characterised by a complex immunologic defects, reduced pigmentation, and presence of giant granules in many different cell types. It most likely results from defective organellar trafficking or protein sorting. The causative gene (LYST) has recently been identified and shown to be homologous to the beige locus in the mouse. CHS has always been reported associated with premature-termination-codon mutations in both alleles of LYST. We report a unique patient with CHS, who was homozygous for a stop codon in the LYST gene on chromosome 1 and who had a normal 46,XY karyotype. The mother was found to be a carrier of the mutation, whereas the father had two normal LYST alleles. Non-paternity was excluded by the analysis of microsatellite markers from different chromosomes. The results of 13 informative microsatellite markers spanning the entire chromosome 1 revealed that the proband had a maternal isodisomy of chromosome 1 encompassing the LYST mutation. The proband's clinical presentation also confirms the absence of imprinted genes on chromosome 1.

Alleles↗
PubMed1998

Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis: evidence of increased interleukin-4 and interleukin-10 gene expression demonstrated in vitro by competitive reverse transcriptase-polymerase chain reaction.

OBJECTIVE: To look for in vitro modulation of the main immunoregulatory and antiinflammatory cytokines by methotrexate (MTX) during the course of rheumatoid arthritis (RA). METHODS: We quantified interleukin-2 (IL-2), IL-4, IL-10, and interferon-gamma (IFNgamma) gene expression by peripheral blood mononuclear cells ex vivo under basal conditions and in vitro after stimulation with phytohemagglutinin (PHA) or PHA plus MTX, by competitive reverse transcriptase-polymerase chain reaction (RT-PCR), in 12 patients with untreated active RA (group 1), 10 patients with MTX-treated disease in partial remission (group 2), and 11 healthy control subjects. Simultaneously, under the same experimental conditions, we quantified cytokine production by specific enzyme-linked immunosorbent assays (ELISAs). RESULTS: Under basal conditions, we found no differences in IL-2, IL-10, and IFNgamma gene expression in the 3 groups, while IL-4 gene expression was significantly decreased in RA patient group 1 compared with the control group. In vitro, under the action of MTX, IL-10 gene expression was significantly increased in the 3 groups, IL-4 gene expression was significantly increased in RA group 1 and in the control group, and IL-2 and IFNgamma gene expression was significantly decreased in RA group 1. Cytokine gene expression assessed by RT-PCR and cytokine production assessed by specific ELISAs were highly correlated. CONCLUSION: In vitro modulation of the cytokine network by MTX, increasing Th2 cytokines and decreasing Th1 cytokines, could explain its antiinflammatory and immunoregulatory actions in vivo during the treatment of RA.

Adult↗
PubMed1998

Substance P enhances cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression on cultured rheumatoid fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the synovial membrane of multiple joints. This inflammatory microenvironment allows fibroblast-like synoviocytes (FLS) to express or enhance several adhesion or costimulatory molecules. This phenotypic shift, under proinflammatory cytokines, seems to be related to functional consequences for antigen presentation to T cells. The sensory neuropeptide substance P (SP), present at high levels, is able to act on FLS proliferation and enzyme secretion. These data led us to investigate whether SP could also provoke a phenotypic change of FLS. Using flow cytometry and a three-step cellular ELISA method, we determined whether SP has an influence on the expression of MHC class II, intercellular adhesion molecule-1 (ICAM-1), VCAM-1, LFA-3, CD40, B7.1 or B7.2 molecules on RA FLS incubated with interferon-gamma (IFN-gamma) or IL-1beta or tumour necrosis factor-alpha (TNF-alpha) with or without SP. Our results indicate that SP potentiates the effect of proinflammatory cytokines on the expression of VCAM-1 on RA FLS. We verified the presence of specific SP (NK1) receptor mRNA. Using reverse transcription-polymerase chain reaction, we showed that RA FLS of patients express NK1 receptor mRNA. These results suggest that SP increase of cytokine-induced VCAM-1 expression acts via this specific SP receptor. Thus, during chronic inflammation RA FLS are at the interface between the immune and the nervous systems.

Arthritis, Rheumatoid↗
PubMed1998

Antioxidant effects of propofol in human hepatic microsomes: concentration effects and clinical relevance.

Propofol is known to possess antioxidant properties. There is controversy regarding the mechanisms by which the drug produces its antioxidant effects and the significance of these effects in relation to plasma concentrations of propofol in clinical practice. We studied the effects of increasing concentrations of Intralipid, propofol, butylated hydroxytoluene (BHT) and a vitamin E analogue (Trolox C) in 0.9% saline on non-enzymic and enzymic lipid peroxidation in human hepatic microsomes, and on concentrations of antioxidant enzymes in a Hep G2 cell line. Propofol showed significant inhibition of lipid peroxidation, but was less potent than BHT or Trolox C. IC50 values for non-enzymic and enzymic lipid peroxidation were mean 9.47 (SD 0.86) and 7.39 (0.84) mumol litre-1 for propofol, 1.30 (0.57) and 0.32 (0.02) mumol litre-1 for BHT and 2.34 (0.68) and 0.35 (0.04) mumol litre-1 for Trolox C, respectively. The antioxidant activities of propofol were substantially retained in the presence of up to 30 g litre-1 of human serum albumin. Propofol at concentrations of up to 100 mumol litre-1 had no significant effect on the activities of antioxidant enzymes. Clinically relevant concentrations of propofol produced significant inhibition of both enzymic and non-enzymic lipid peroxidation in hepatic microsomal preparations, possibly as a result of accumulation in lipophilic environments. Measurement of antioxidant effects of drugs in aqueous media may have little relevance to their effects in protecting against lipid peroxidation in biological systems.

Anesthetics, Intravenous↗
PubMed1998

T cell receptor gene in synovial tissues of rheumatoid arthritis.

Rheumatoid arthritis is a chronic and destructive autoimmune joint disease characterized by inflammation of synovial tissue of unknown aetiology. Studies on TCR genes expressed by infiltrating T cells in synovial tissues have attempted to identify mechanism and specificity of the recruitment. T cell infiltrate in rheumatoid arthritis appears to be an association of a polyclonal non specific infiltrate with dominant clones or clonotypes. T cell repertoire in synovial tissue is biased compared to peripheral blood but no TCR V gene can be identified as commonly over-used. Comparison of motifs found in the CDR3 region of dominant clones from different studies has currently failed to identified a commonly motif. The fact that a number of dominant clones or clonotypes is present in different joints and at different times of the disease suggests a selective expansion of T lymphocytes in rheumatoid arthritis synovial membrane. Further investigations are needed to characterize the specificity of these dominant clonotypes.

Animals↗
PubMed1996

Persistence of dominant T cell clones in synovial tissues during rheumatoid arthritis.

In a previous study, we showed that the T cell repertoire is biased in the synovial membrane (SM) compared with peripheral blood during rheumatoid arthritis (RA). The same bias was observed in different joints from the same patient and seems to be the same over time. To discover whether this bias was due to expansion of a clonal subset resulting from activation by conventional Ag(s) or to polygonal stimulation by superantigen(s), we sequenced more than 650 TCRBV-D-J junctional regions from freshly isolated SM and peripheral blood of two DR4-RA patients. From each patient, two SM were obtained on the same day, and a third was obtained later. Several dominant clones were found in SM but not in peripheral blood. Some of them were found only at the first time point in anatomically different SM, the majority persisted over time, and others were detected only at the second time point. Analysis of the complementarity-determining region 3 (CDR3) showed a bias in TCRBD and amino acid usage. Valine, encoded by randomly inserted N nucleotides, was used by 45% of dominant clones compared with 18% in the control population (p less than 0.001). In addition, GXXG and TSG motifs were frequently observed in the CDR3 of these dominant clones. These data indicate a dynamic TCR selection process during the perpetuation phase of RA. The dynamic changes of dominant clones also suggest a determinant spreading mechanism during RA.

Amino Acid Sequence↗
PubMed1996

Isolated X-linked thrombocytopenia in two unrelated families is associated with point mutations in the Wiskott-Aldrich syndrome protein gene.

The Wiskott-Aldrich syndrome (WAS) is characterized by defective platelet and lymphocyte function associated with eczema and increased susceptibility to malignancies. It is caused by mutations of the WAS protein-encoding gene (WASP). X-lined thrombocytopenia, defined by low platelet counts and volume, may be an allelic variant of WAS. In patients with XLT from two unrelated families, WASP gene defects were identified by single-strand conformational polymorphism and by sequencing. Point mutations in exon 2 of the WASP gene were found in the patients from both families in which XLT segregated. Several obligate heterozygote female members of these families display a random pattern of X inactivation in their peripheral blood leukocytes. This study shows that XLT may be caused by mutations of the WASP, thus representing an allelic variant of WAS.

Adult↗
PubMed1996

Human cytochrome P450's are pro-oxidants in iron/ascorbate-initiated microsomal lipid peroxidation.

We have examined the effect of human cytochrome P450's (1A1,1A2,3A4,2A6,2B6,2D6,2E1) on ascorbate/iron-induced lipid peroxidation. Using microsomes prepared from human lymphoblastic cells enriched in recombinant cytochrome P450 isoenzymes, we have shown that the degree of peroxidation is a function of the amount of P450 present rather than the presence of any specific isoenzyme. Incorporated P450 increased the amount of peroxidation products by up to 2.1-fold compared to the control microsomes with no P450. It is therefore concluded that cytochrome P450's play a significant role in ascorbate/iron peroxidation.

Ascorbic Acid↗
PubMed1996

Are whole extracts and purified glucosinolates from cruciferous vegetables antioxidants?

Fruits and vegetables contain several classes of compounds that can potentially contribute to antioxidant activity, including vitamins, simple and complex phenolics, sulphur-containing compounds and glucosinolates. The glucosinolates are found in high concentration in many cruciferous vegetables, and it is well established that their breakdown products induce endogenous antioxidant defences such as quinone reductase and glutathione S-transferase in cells and in vivo. Despite the anticarcinogenic effect of these compounds in animal models, the direct antioxidant properties of this class of compounds have not been systematically studied. We therefore examined the free radical-scavenging properties of representative extracts and of purified glucosinolates from cruciferous vegetables, by measuring their effect on ascorbate- or NADPH/iron-induced peroxidation of human liver microsomes, ascorbate/iron-induced peroxidation on phospholipid liposomes, iron chelation and hydroxyl radical scavenging using the deoxyribose assay, total antioxidant potential using ABTS (2,2'-azinobis(3-ethyl-benzothiazoline-6-sulphonate)) and the bleomycin assay. Most of the extracts from cruciferous vegetables exhibited some antioxidant properties, although extracts from cooked Brussels sprouts increased the rate of microsomal lipid peroxidation. The effects in these assays were dependent upon processing and species of crucifer, and the glucosinolate content appeared to play a minor role in these effects, since purified glucosinolates exhibited only weak antioxidant properties. The total antioxidant activities of extracts from cooked and autolysed Brussels sprouts were identical within experimental error. This is probably due to the content of phenolics which is unaltered by autolysis, despite the differences between these samples in other assays especially NADPH-iron-induced lipid peroxidation of human liver microsomes. The results demonstrate that glucosinolates are unlikely to account for the direct antioxidant effects of extracts from cruciferous vegetables.

Antioxidants↗