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Biomedical subjects

P Jones

Publications and source records attributed to P Jones.

At least 91 records · Page 5Linked to original sources
PubMed2001

Enhanced dietary fat clearance in postobese women.

The objective of this study was to examine the postprandial response to an exogenous fat source in eight weight-stable postobese subjects (2;-3 years after gastric bypass) and eight matched control women, using a stable isotope, [13C]oleate. After a high fat breakfast meal (1,062 cal, 67% fat), [13C]oleate in triglyceride (TG)-rich lipoproteins (Sf >400 and Sf 20;-400) and nonesterified fatty acids (NEFA), and 13C in breath CO2, were monitored over 8 h. There were no differences in resting energy expenditure, thermic effect of food, carbohydrate/fat oxidation ratio, breath 13CO2 enrichment, or fecal fat content between postobese and control subjects. Postprandially, there was no difference in S(f) 20;-400 TG or NEFA, but postobese subjects had lower Sf >400 incremental area under the curve (AUC) (- 33%, P < 0.0025) and glucose [P < 0.01 by repeated measures analysis of variance (RM ANOVA)]. Postprandial 13C in Sf >400 TG returned to fasting levels 4 h earlier in postobese subjects and was lower than in control subjects at 4 and 6 h (P < 0.05 by RM ANOVA). The greatest difference was in the [13C]NEFA profiles. In control subjects [13C]NEFA increased markedly over 8 h; postobese subject [13C]NEFA remained close to fasting nonenriched values, and was strikingly lower than in control subjects (72% lower by AUC, P < 0.0001 by RM ANOVA). Finally, postobese subjects tended to have lower postprandial insulin (P < 0.01, 4 h), lower postprandial acylation-stimulating protein, and lower fasting leptin (-46%, P < 0.02). This study demonstrates clear metabolic differences in exogenous dietary fat partitioning in postobese women. These findings are compatible with an increased efficiency of dietary fat storage and suggest one possible mechanism for promotion of weight regain in postobese individuals.

Adult↗
PubMed2001

Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group.

OBJECTIVE: We previously reported that the new disease modifying antirheumatic drug leflunomide resulted in significant improvement in functional ability compared with placebo and sulfasalazine in a 6 month double blind, randomized, Phase III trial in rheumatoid arthritis (RA). The current study compared functional disability in cohorts of patients with RA from the initial study who volunteered to continue treatment with leflunomide or sulfasalazine. METHODS: The Health Assessment Questionnaire (HAQ) was used to assess functional ability in patients completing 6 months of therapy who chose to continue in double blinded 12 and 24 month extensions. Patients on active regimens continued taking leflunomide 20 mg/day or sulfasalazine 2 g/day; those taking placebo were switched at Month 6 to sulfasalazine. RESULTS: Leflunomide significantly improved patients' functional ability compared to placebo (p < or = 0.0001) and sulfasalazine (p < or = 0.01) at 6 months. These changes were seen as early as Month 1, and continued improvements were seen in 12 and 24 month cohorts. Mean HAQ scores were significantly improved with leflunomide compared with sulfasalazine at 24 months (-0.65 vs -0.36; p = 0.0149); corresponding changes in HAQ Disability Index (DI) were -0.73 vs -0.56 and were not statistically different. Leflunomide is safe and well tolerated and no unexpected adverse events were noted during the 2 year period; diarrhea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These longterm data confirm leflunomide improves functional ability as shown by reductions in HAQ scores. The benefit of leflunomide is reflected in other efficacy criteria, such as global assessments and the American College of Rheumatology response rates, all of which showed significantly more improvement with leflunomide than sulfasalazine at 24 months.

Adolescent↗
PubMed2000

Soluble urokinase receptor promotes cell adhesion and requires tyrosine-92 for activation of p56/59(hck).

The urokinase plasminogen activator receptor (uPAR) plays an important role in the migration of leukocytes. It occurs as a membrane-bound form that contains a glycosylphosphatidylinositol (GPI) anchor and also as a soluble form (suPAR) that lacks the GPI anchor. Recently, a sequence of amino acids, SRSRYLE, within the receptor has been found to become unmasked on uPA binding or chymotrypsin cleavage. Exposure of the epitope results in the activation of p56/p59(hck) kinase and chemotaxis of myelomonocytic cells. Using an epitope-tagged suPAR molecule, we found that both three-domain and two-domain suPAR promote the adhesion of differentiated THP-1 cells to fibronectin and vitronectin, indicating that suPAR can modify cell adhesion as well as cell migration. In addition, we found that the amino acid sequence RYLE, within the chemotactic peptide, is conserved across species and that alanine substitution of Tyr 92 decreased the ability of the peptide to activate p56/59(hck).

Amino Acid Sequence↗
PubMed2000

N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues.

The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported.

Administration, Oral↗
PubMed2000

Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy.

Although significant progress has been made in understanding immune reconstitution in peripheral blood following highly active antiretroviral therapy (HAART), less is known about immune changes in lymphoid tissue. Here, the expression of cytokine proteins (interferon gamma [IFN-gamma], interleukin [IL]-2, IL-4, IL-10, IL-1alpha, and IL-1beta) and surface antigens (CD4, CD8, CD1a, CD68) as well as cellular proviral HIV-1 DNA were determined in sequential tonsil biopsies before and at 4, 12, and 48 to 56 weeks posttherapy by quantitative in situ image analysis and fluorescent in situ 5;-nuclease assay (FISNA). Despite plasma virus suppression, a fraction of tonsil cells harbored pro-viral DNA for up to 1 year. A fourfold to eightfold increase in CD8+ T cells in tissue compared with seronegative controls and an increased frequency of CD1a+ dendritic cells prior to HAART reached control levels at week 56. The frequency of IFN-gamma expressing cells was 10-to 15-fold higher than controls before therapy and was comparable with findings in seronegative controls by week 56. Elevated baseline expression of IL-1alpha and IL-1beta was reduced by week 4 but IL-1alpha levels remained elevated in 1 of 3 patients at week 56. These findings suggest that with effective viral suppression the immune system in tissue may return to a more resting state.

Antiretroviral Therapy, Highly Active↗
PubMed2000

Determination of the substituent distribution in O-sulfonylbutyl-(1-->4)-glucans.

A method has been developed to determine the distribution of substituents in the glucose units of sulfonylbutylethers of cyclomaltoheptaose (beta-cyclodextrin). This method involves hydrolysis of the glucosidic linkages, permethylation, formation of sulfonylchlorides and subsequent transformation to the permethylated sulfonylfluoride derivatives. The latter were thermostable and could be analyzed by GLC and identified by EI and CIMS. For confirmation, the 2-, 3-, and 6-O-substituted standard compounds were independently synthesized and characterized by NMR and GLC-MS.

Alkanesulfonates↗
PubMed2000

Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters.

BACKGROUND: Human epidermis is renewed throughout life from stem cells in the basal layer of the epidermis. Signals from the surrounding keratinocytes influence the differentiation of the stem cells, but the nature of the signals is unknown. In many developing tissues, signalling mediated by the transmembrane protein Delta1 and its receptor Notch1 inhibits differentiation. Here, we investigated the role of Delta-Notch signalling in postnatal human epidermis. RESULTS: Notch1 expression was found in all living epidermal layers, but Delta1 expression was confined to the basal layer of the epidermis, with highest expression in those regions where stem cells reside. By overexpressing Delta1 or Delta(T), a truncated form of Delta1, in primary human keratinocytes and reconstituting epidermal sheets containing mixtures of Delta-overexpressing cells and wild-type cells, we found that cells expressing high levels of Delta1 or Delta(T) failed to respond to Delta signals from their neighbours. In contrast, wild-type keratinocytes that were in contact with neighbouring cells expressing Delta1 were stimulated to leave the stem-cell compartment and initiate terminal differentiation after a few rounds of division. Delta1 promoted keratinocyte cohesiveness, whereas Delta(T) did not. CONCLUSIONS: We propose that high Delta1 expression by epidermal stem cells has three effects: a protective effect on stem cells by blocking Notch signalling; enhanced cohesiveness of stem-cell clusters, which may discourage intermingling with neighbouring cells; and signalling to cells at the edges of the clusters to differentiate. Notch signalling in epidermal stem cells thus differs from other progenitor cell populations in promoting, rather than suppressing, differentiation.

Cell Differentiation↗
PubMed2000

The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin.

Although chloroquine-resistance (CQR) in Plasmodium falciparum is increasing and resistance to other blood schizonticidal anti-malarials has been reported, the molecular basis remains unclear. In this study fresh field isolates were obtained from The Gambia, an area of emerging CQR and tested for sensitivity to the anti-malarial drugs mefloquine, halofantrine, artemisinin, dihydroartemisinin, chloroquine and quinine. Sequence polymorphisms in the pfmdr1 gene and size polymorphisms in the cg2 gene were assessed using PCR-based systems. A strong association was observed between the presence of the tyr-86 allele of pfmdr1 and increased sensitivity to mefloquine and halofantrine, as well as the structurally unrelated drugs artemisinin and dihydroartemisinin. A weaker association was found between the presence of tyr-86 and increased resistance to chloroquine and quinine. The cg2 Dd2-like omega repeat size polymorphism was associated with increased resistance to chloroquine and increased sensitivity to mefloquine and halofantrine. An intragenic association was also found between a polymorphism in the polyasparagine linker region of pfmdr1 and the tyr-86 allele, which may be due to genetic hitchhiking, indicative of recent selection by chloroquine. Our data support a hypothesis where the pfmdr1 gene confers a true multidrug resistance phenotype which is lost by mutation.

ATP-Binding Cassette Transporters↗
PubMed2000

Regulation of urokinase receptor transcription by Ras- and Rho-family GTPases.

How cell adhesion is coordinated with extracellular proteolysis is a key question in understanding cell migration. Potentially, the small GTP-binding proteins that affect actin organisation and signal transduction may also regulate the expression of genes associated with extracellular proteolysis. We investigated the ability of Ras, Rac-1, Cdc42Hs, and RhoA to regulate transcription from the1.55-kb promoter region of the human urokinase plasminogen activator receptor (uPAR) gene. Constitutively active V12 H-Ras and Rho-A stimulated uPAR transcription while Cdc42Hs and Rac-1 did not. The use of Ras effector-loop mutants indicated that signalling via multiple Ras-effectors is necessary for the maximum activation of transcription.

3T3 Cells↗
PubMed2000

Determination of beryllium in a stream sediment by high-performance chelation ion chromatography.

High-performance chelation ion chromatography (HPCIC), involving a chelating silica substrate bonded with aminomethylphosphonic acid, has been developed as a novel technique for the quantitative determination of beryllium in complex matrices. An isocratic separation method, using an eluent containing 1 M KNO3, 0.5 M HNO3 and 0.08 M ascorbic acid, allowed the Be2+ to elute away from the sample matrix peak in under 6 min in a sample containing in excess of 800 mg l(-1) matrix metals. A detection limit of 35 microg l(-1) Be(II) was found using a post-column reaction involving Chrome Azurol S (CAS), 1 M hexamine and 10 mM EDTA buffered at pH 6. The standard addition curve gave excellent linearity (R2>0.999). The procedure was applied to the determination of trace beryllium in a certified sediment sample. The results obtained compared well with the certified value for beryllium.

Beryllium↗
PubMed2000

Selective omission of the donor cross-match before renal transplantation: efficacy, safety and effects on cold storage time.

BACKGROUND: A donor lymphocyte cross-match (XM) test performed before renal transplantation is considered mandatory but may delay the transplant and increase the cold storage time. With careful documentation of sensitizing events and with knowledge of previous antibody screening results, it is often possible to predict the XM result for a given donor HLA mismatch. In this study, a policy was adopted of omitting the pretransplant XM in patients in whom a negative result was predicted with absolute confidence. METHODS: Recipients were selected for cadaveric donor kidney transplantation using a computer algorithm based on HLA match, sensitization status, time on the waiting list and donor and recipient age. The immediate pretransplant cross-match test was omitted in non-sensitized recipients and in sensitized recipients where antibody specificities were precisely defined and not against donor HLA. RESULTS: From October 1997 to May 1999, 53 of 96 (55%) consecutive cadaveric kidney donor transplants were performed without a pretransplant XM. In all cases, a negative donor HLA-specific antibody XM was confirmed after transplantation. Omission of the pre-transplant XM was associated with a significant reduction in cold ischemic time (15.0 hr vs. 18.2 hr, P=0.01) and a reduced incidence of delayed graft function (13% vs. 33%, P=0.03). However, there was no difference in transplant outcome at 1 year. CONCLUSION: Rigorous attention to priming events together with careful antibody screening allows the pre-transplant XM test to be safely omitted in approximately half the patients awaiting renal transplantation. This policy allows a modest reduction in cold ischemia time, but it remains to be seen whether this is of clinical benefit.

Adult↗
PubMed2000

omega-3 fatty acids decrease endothelial adhesion of human colorectal carcinoma cells.

BACKGROUND: Diets rich in omega-3 fatty acids have been shown to decrease both the initiation and promotion of colon carcinogenesis although their effect on hepatic metastasis formation is less well understood. Since adhesion of human colorectal carcinoma (HCRC) cells to hepatic endothelial cells is an important step in the metastatic cascade, the effect of membrane omega-3 fatty acid alterations on endothelial cell adhesion was studied. MATERIALS AND METHODS: CX-1 cells, a moderately differentiated HCRC cell line known to produce hepatic metastases in an athymic mouse intrasplenic injection model, were used. Cells were grown in omega-3 fatty acid-enriched medium and membrane-free fatty acid modifications confirmed with gas chromatography. Both human umbilical vein and hepatic sinusoidal endothelial cells were used in the binding assays. Adhesion assays were performed in a standard fashion using (51)Cr-labeled cells to tumor necrosis factor (TNF)-stimulated endothelial cell monolayers. Immunohistochemical analysis was performed for sialyl-Lewis(x), the receptor involved in endothelial adhesion on the surface of control and fatty acid-modified cells. RESULTS: Gas chromatographic analysis confirmed membrane fatty acid modification of CX-1 cells by growth in docosahexanoic acid (omega-3) (4.761 nmol/10(6) cells vs 0.057 nmol/10(6) cells for controls). Binding of CX-1 to both human umbilical vein and hepatic sinusoidal endothelial cells decreased from 38.4 +/- 0.44 to 11.58 +/- 0.87% (P < 0.01). Immunocytochemical analysis showed a decrease in sialyl-Lewis(x) expression with omega-3 treatment. CONCLUSIONS: These data indicate that omega-3 fatty acids may also be protective against the formation of hepatic metastases. The mechanism for this may be decreased endothelial cell adhesion which in turn may be due to decreased expression of the endothelial receptor sialyl-Lewis(x).

Animals↗
PubMed2000

Childhood and adolescent predictors of schizophrenia in the Northern Finland 1966 birth cohort--a descriptive life-span model.

Subtle motor, emotional, cognitive and behavioral abnormalities are often present in apparently healthy children and adolescents who later develop schizophrenia. This suggests that some aspects of causation are established long before psychosis is manifest. We aim to develop a descriptive model of the factors contributing to the development of schizophrenia. Our main focus is on genetic factors, pregnancy and delivery complications, early development and scholastic performance. This is done by reviewing the Northern Finland 1966 Birth Cohort, its scientific activities (publications and work in progress) and selected literature.

Adolescent↗
PubMed2000

Glycosyltransferases in plant natural product synthesis: characterization of a supergene family.

Glycosyltransferases of plant secondary metabolism transfer nucleotide-diphosphate-activated sugars to low molecular weight substrates. Until recently, glycosyltransferases were thought to have only limited influence on the basic physiology of the plant. This view has changed. Glycosyltransferases might in fact have an important role in plant defense and stress tolerance. Recent results obtained with several recombinant enzymes indicate that many glycosyltransferases are regioselective or regiospecific rather than highly substrate specific. This might indicate how plants evolve novel secondary products, placing enzymes with broad substrate specificities downstream of the conserved, early, pivotal enzymes of plant secondary metabolism.

Amino Acid Motifs↗
PubMed2000

Isolation, characterization and expression of a GRA2 homologue from Neospora caninum.

A cDNA library derived from mRNA of tachyzoites of Neospora caninum (NC-Liverpool strain) was screened with antisera from a cow naturally infected with N. caninum. The DNA sequence of 1 recombinant isolated predicted a significant protein sequence homology of the gene product to the 28 kDa (GRA2) antigen of Toxoplasma gondii. Studies on the N. caninum gene coding for this antigen demonstrated the presence of a single intron flanked by 2 exons; the gene was also highly expressed in culture-derived tachyzoites. The antigen was expressed in Escherichia coli; when injected into mice it stimulated the production of antibodies which detected a 29 kDa antigen of N. caninum. Secondary structure predictions made for the N. caninum protein showed support for several amphipathic helices separated by loops and turns. The available evidence indicates maintenance of protein secondary structure, and not DNA or amino acid sequence, has occurred during the evolution of GRA2 proteins in N. caninum and T. gondii.

Amino Acid Sequence↗
PubMed2000

Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum.

Chloroquine-resistance in Plasmodium falciparum is associated with polymorphisms in a locus on or near the cg2 gene on chromosome 7, and in the pfmdr1 gene on chromosome 5. In this study we typed P. falciparum DNA from uncomplicated malaria cases in The Gambia in 1990, 1995 and 1996 for size polymorphism in the omega repeat of cg2, for sequence polymorphisms in pfmdr1 at codons 86 and 184, in dhfr at codon 108 and in the msp2 gene. Chloroquine sensitivity tests were conducted in vitro. A significant but incomplete association was found between the presence of the cg2 Dd2-like omega repeat size polymorphism and in vitro resistance, and between the tyr-86 allele of pfmdr1 and in vitro resistance. Furthermore there was strong linkage disequilibrium between the pfmdr1 asn-86 allele and the cg2 not Dd2-like omega repeat allele located on different chromosomes. In contrast, no linkage disequilibrium was found between these alleles and either the dhfr ser-108 allele or the msp2 IC sequence polymorphism. No significant linkage was measured between pfmdr1 asn-86 and phe-184 although these loci are separated only by 296 base pairs. Our results suggest that genetic elements linked to the cg2 and the pfmdr1 genes are important determinants of chloroquine resistance. It can be concluded that the observed linkage disequilibrium is maintained epistatically through selection by chloroquine.

ATP-Binding Cassette Transporters↗