bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects
Authors: Jiang Xuemin , Williams Kenneth M. , Liauw Winston S. , Ammit Alaina J. , Roufogalis Basil D. , Duke Colin C. , Day Richard O. , McLachlan Andrew J. 
Published: March 2005

AimThe aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status.MethodsThis was an open label, three‐way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S‐7‐hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported.ResultsINR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S‐warfarin after warfarin alone, with ginkgo or ginger were 189 (167–210) ml h−1, 200 (173–227) ml h−1 and 201 (171–231) ml h−1, respectively. The respective apparent clearances of R‐warfarin were 127 (106–149) ml h−1, 126 (111–141) ml h−1 and 131 (106–156) ml h−1. The mean ratio (90% CI) of apparent clearance for S‐warfarin was 1.05 (0.98–1.21) and for R‐warfarin was 1.00 (0.93–1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC0−168 of INR was 0.93 (0.81–1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S‐warfarin was 1.05 (0.97–1.13) and for R‐warfarin was 1.02 (0.95–1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC0−168 of INR was 1.01 (0.93–1.15) when coadministered with ginger. The mean ratio (90% CI) for S‐7‐hydroxywarfarin urinary excretion rate was 1.07 (0.85–1.32) for ginkgo treatment, and 1.00 (0.81–1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S‐warfarin or R‐warfarin.ConclusionsGinkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.
Reproducibility of forearm vasodilator response to intra‐arterial infusion of calcitonin gene‐related peptide assessed by venous occlusion plethysmography
Authors: Vanmolkot Floris H. M. , De Hoon Jan N. J. M. 
Published: March 2005

AimsTo assess the reproducibility of the forearm blood flow (FBF) response to intra‐arterial infusion of calcitonin‐gene related peptide (CGRP), measured by venous occlusion plethysmography. In addition, to compare different ways of expressing the FBF response and perform sample size calculations.MethodsOn two separate visits, CGRP (10 ng min−1 dl−1 forearm) was infused for 45 min into the brachial artery of six healthy subjects. Reproducibility was assessed by calculating mean difference, repeatability coefficient, within‐subject coefficient of variation (WCV) and intraclass correlation coefficient.ResultsCGRP increased FBF from 2.8 ± 0.4 and 3.2 ± 0.7 (at baseline) to 15.4 ± 1.4 and 15.2 ± 1.5 ml min−1 dl−1 forearm (at 45 min) on visits 1 and 2, respectively (P < 0.0001 for both visits). Mean difference in FBF at 45 min between both visits was 0.3 ml min−1 dl−1 forearm (repeatability coefficient: 4.1 ml min−1 dl−1 forearm). This FBF response appeared to be more reproducible when expressed as absolute FBF in the infused arm (WCV 11%) compared with absolute FBF‐ratio between both arms (WCV 37%), percentage change from baseline in FBF in the infused arm (WCV 29%) and percentage change from baseline in FBF‐ratio (WCV 40%). When expressed as absolute FBF, a sample size of five (95% confidence interval: 2–12) subjects gives 90% power at a type I error probability of 0.05 to detect a 25% shift in FBF response.ConclusionsIntra‐arterial infusion of CGRP results in a forearm vasodilator response which is reproducible between days. This response is most reproducible when expressed as absolute FBF. The presented methodology provides a suitable pharmacodynamic model to assess the in vivo activity of CGRP‐receptor antagonists in a small number of subjects.
Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV‐1‐infected patients
Authors: Van Heeswijk R. P. G. , Bourbeau M. , Seguin I. , Giguere P. , Garber G. E. , Cameron D. W. 
Published: March 2005

AimsTo compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening.MethodsThis was a randomized, two‐way, cross‐over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC‐MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis.ResultsFourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (Cmax) and concentration at the end of the dosing interval (C24 h) after am and pm dosing was, respectively, 143 (116–214) mg l−1 h, 12.8 (10.3–17.2) mg l−1, 1.34 (0.58–3.25) mg l−1, and 171 (120–232) mg l−1 h, 12.9 (8.22–16.3) mg l−1, 1.15 (0.59–1.98) mg l−1. The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), Cmax, and C24 h was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir Cmax after am and pm dosing was 1.05 and 0.90 mg l−1, respectively. The GMR (95% CI) of the RTV AUC(0,24 h), Cmax, and C24 h was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once‐daily regimen was generally well tolerated.ConclusionsNo differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.
The role of interleukin-16 in murine contact hypersensitivity
Authors: Masuda K , Katoh N , Soga F , Kishimoto S 
Published: March 2005

SummaryContact hypersensitivity (CHS) is a T-cell-mediated skin inflammatory response. It is controversial whether CD4+ T cells play an enhancing or regulatory role in the pathogenesis of CHS. Because interleukin (IL)-16 is a chemoattractant cytokine for CD4-expressing cells, we investigated the involvement of IL-16 in the CHS reaction. IL-16 production was induced in the epidermis and dermis during the elicitation phase of the CHS response with trinitrochlorobenzene. In the sensitization phase, the single application of haptens such as trinitrochlorobenzene and oxazolone also induced IL-16, whereas primary irritants or vehicle control did not. IL-16 was produced mainly by CD11c-negative cells in the epidermis during the elicitation phase. Furthermore, treatment of sensitized mice with anti-IL-16 neutralizing MoAb enhanced the ear swelling and reduced the number of infiltrating CD4+ T cells. These data indicate that IL-16 plays a role in CHS, whereby IL-16 induces CD4+ T cells and these CD4+ T cells subsequently exhibit down-regulating properties.
The effects of renal transplantation on circulating dendritic cells
Authors: Hesselink D A , Vaessen L M B , Hop W C J , Schoordijk W , IJzermans J N M , Baan C C , Weimar W 
Published: March 2005

SummaryThe effects of immunosuppressive agents on T cell function have been well characterized but virtually nothing is known about the effects of renal transplantation on human dendritic cells (DCs). With the use of flow cytometry, we studied the kinetics of myeloid and plasmacytoid DCs in peripheral blood of 24 kidney allograft recipients before and after transplantation, and in 23 donors before and after kidney donation. All patients were treated with tacrolimus, mycophenolate mofetil and prednisone. Surgery resulted in a strong decline in the number of myeloid and plasmacytoid DCs, both in kidney donors and in their recipients. However, in donors this effect was transient, as the numbers of both DC subsets had normalized completely by the third postoperative month. In contrast, the recovery of myeloid DC counts in kidney transplant recipients was only incomplete at the end of the 3-month follow-up, despite tapering of immunosuppression. The seven patients who required additional immunosuppressive treatment because of acute rejection experienced an even more marked decrease in DC counts in the early postoperative period compared with patients who remained rejection-free. Surgical procedures markedly affect the numbers of circulating myeloid and plasmacytoid DCs. Immunosuppressive drugs have important additional in vivo effects on this cell type and impair the reconstitution of the myeloid DC subset in peripheral blood after renal transplantation.
Persistently high IgA serum levels are a marker of immunological or virological failure of combined antiretroviral therapy in children with perinatal HIV-1 infection
Authors:   The Italian Register for HIV Infection in Children, Chiappini Elena , Galli Luisa , Tovo Pier-Angelo , Gabiano Clara , De Martino Maurizio 
Published: March 2005

SummaryNon-expensive and low-complexity surrogate markers for monitoring the response to combined antiretroviral therapy (combined-ART) are needed in poor-resource settings where routine assessment of CD4+ T-lymphocyte count and viral load can not be afforded. We longitudinally evaluated Ig serum levels in 234 HIV-1 infected children receiving combined-ART with ≥ 3 drugs. Since Ig levels physiologically vary with age, differences at different age periods were evaluated as differences in z-scores calculated using the mean and standard deviation of the normal population for each age period. Data from 17 (7·3%) children with immunological failure and from 54 (23·1%) children with virological failure of combined-ART were compared with data from not-failed children. At baseline children with immunological failure showed higher IgM z-scores (P = 0·042) than children without. After 3–12 months of therapy immunologically failed children displayed higher viral loads (P &lt; 0·0001) and IgA (P = 0·043) z-scores than not-failed children. Similarly, at the same follow-up time, children with virological failure showed lower CD4+ T-lymphocyte percentages (P = 0·005) and higher IgA z-scores (P &lt; 0·0001) than not-failed children. No difference in IgG or IgM z-scores was evidenced between failed and not-failed children after 3–12 months of therapy. In conclusion, IgA serum level is a cheap and low-complexity marker of immunological or virological failure of combined-ART which might be adopted in poor-resource settings.
Pneumolysin-mediated activation of NFκB in human neutrophils is antagonized by docosahexaenoic acid
Authors: Fickl H , Cockeran R , Steel H C , Feldman C , Cowan G , Mitchell T J , Anderson R 
Published: March 2005

SummaryThis study was designed to investigate the relationship between influx of extracellular Ca2+, activation of NFκB and synthesis of interleukin-8 (IL-8) following exposure of human neutrophils to subcytolytic concentrations (8·37 and 41·75 ng/ml) of the pneumococcal toxin, pneumolysin, as well as the potential of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid, to antagonize these events. Activation and translocation of NFκB were measured using a radiometric electrophoretic mobility shift assay, while influx of extracellular Ca2+ and synthesis of IL-8 were determined using a radioassay and an ELISA procedure, respectively. Exposure of neutrophils to pneumolysin was accompanied by influx of Ca2+, activation of NFκB, and synthesis of IL-8, all of which were eliminated by inclusion of the Ca2+-chelating agent, EGTA (10 m m), in the cell-suspending medium, as well as by pretreatment of the cells with docosahexaenoic acid (5 and 10 µg/ml). The antagonistic effects of docosahexaenoic acid on these pro-inflammatory interactions of pneumolysin with neutrophils were not attributable to inactivation of the toxin, and required the continuous presence of the fatty acid. These observations demonstrate that activation of NFκB and synthesis of IL-8, following exposure of neutrophils to pneumolysin are dependent on toxin-mediated influx of Ca2+ and that these potentially harmful activities of the toxin are antagonized by docosahexaenoic acid.
CARD15 polymorphisms are associated with anti-Saccharomyces cerevisiae antibodies in caucasian Crohn's disease patients
Authors: Cruyssen B Vander , Peeters H , Hoffman I E A , Laukens D , Coucke P , Marichal D , Cuvelier C , Remaut E , Veys E M , Mielants H , De Vos M , De Keyser F 
Published: March 2005

Summary
Carriage of CARD15 gene polymorphisms and the serological marker anti-Saccharomyces cerevisiae antibodies (ASCA) are two markers for Crohn's disease (CD). Similar phenotypes have been associated with both markers. In the present study we analysed whether both markers were associated with each other and, if so, whether this association could be explained by a direct link or by an indirect association with those phenotypes. Therefore, we included 156 consecutive Caucasian CD patients and assessed the prevalence of the three common single nucleotide polymorphisms in the CARD15 gene. Serum samples were analysed for IgA and IgG ASCA by ELISA. CD patients with CARD15 polymorphisms were more frequently ASCA positive (OR 2·7 (1.4–5.2); P = 0·002) and had higher titres for ASCA IgA (P = 0·005) and ASCA IgG (P &lt; 0·001) compared to patients carrying the wild type polymorphisms. Multivariate analysis demonstrated that this association was independent from ileal disease, penetrating disease and stricturing disease, the need for resective bowel surgery, familial cases, smoking habits and early age at onset. Homozygotes or compound heterozygotes for CARD15 polymorphisms had significantly more frequent ASCA positivity compared to single heterozygotes (OR 9·1 (1.1–74.2), Pc (corrected P-value) = 0·030). These data indicate that there is a significant association between the carriage of CARD15 polymorphisms and ASCA, independent of the described phenotypes. Moreover, ASCA positivity is more frequent in CD patients carrying 2 CARD15 polymorphisms compared to single heterozygotes.
Alpha tropomyosin as a self-antigen in patients with Behçet's disease
Authors: Mahesh S P , Li Zhuqing , Buggage R , Mor F , Cohen I R , Chew E Y , Nussenblatt R B 
Published: March 2005

SummaryWe report for the first time a significant increased lymphoproliferative response to alpha tropomyosin as well as observing autoantibodies to tropomyosin observed in Behçet's disease (BD) patients with posterior uveitis. Peripheral blood mononuclear cells (PBMCs) from 18 BD patients with posterior uveitis, 18 patients with other forms of noninfectious uveitis, 9 patients with retinal damage due to photocoagulation as well as 18 healthy donors were evaluated for antigen-specific lymphoproliferative responses to alpha tropomyosin and its derivative peptides. The proliferative responses of PBMCs to these antigens were studied using 3H thymidine incorporation assay. Serum samples were also screened by ELISA for autoantibodies against tropomyosin. Six of the 18 (33%) BD patients with posterior uveitis showed increased proliferative response to alpha tropomyosin or its derivative peptides, while none of the healthy, disease controls were positive. The mean lymphoproliferative responses to tropomyosin were significantly higher (P &lt; 0·02) in the BD patients compared to healthy or disease controls. Higher titres of anti-tropomyosin antibodies were also seen in four of the 18 BD patients but none in the healthy or disease control groups (P &lt; 0·002). The occurrence of these abnormalities supports a possible role for alpha tropomyosin as a self-antigen in a subset of patients with Behçet's disease.
Effect of specific antigen stimulation on intraepithelial lymphocyte migration to small intestinal mucosa
Authors: Komoto S , Miura S , Koseki S , Goto M , Hachimura S , Fujimori H , Hokari R , Hara Y , Ogino T , Watanabe C , Nagata H , Kaminogawa S , Hibi T , Ishii H 
Published: March 2005

SummaryMigration of intraepithelial lymphocytes (IELs) into intestinal epithelium is not yet well understood. We established an IEL-cell line from ovalbumin (OVA) 23–3 transgenic (Tg) mice and investigated the effect of antigen stimulation on the dynamic process of IEL migration into small intestinal mucosa. The cell line was a T cell receptor (TCR) αβ+ CD4+ CD8– phenotype, expressing αEβ7 integrin in 90% of cells. Under intravital microscopy, the lined IELs adhered selectively to the microvessels of the intestinal villus tip of the Tg mice. The accumulation of IELs was significantly inhibited by an antibody against β7-integrin and MAdCAM-1. When IELs were stimulated with OVA, the accumulation was attenuated compared to that of resting cells, with decreased expression of αEβ7 integrin. In Tg mice fed with OVA, the number of IELs which migrated in the villus mucosa was significantly smaller than in the non-fed controls. The preferential migratory capacity of IELs to villus mucosa may be altered by specific antigen stimulations.
Age-associated deficiency in activation-induced up-regulation of telomerase activity in CD4+ T cells
Authors: Marinova E , Han S , Zheng B 
Published: March 2005

SummaryFor lymphocytes, the ability to undergo clonal expansion is crucial for effective immune function. Telomerase activity compensates for telomere erosion during cell division and contributes to the capability of lymphocytes to maintain cellular proliferation. In addition, telomerase activity may have a fundamental role in cell growth and survival. To determine whether age-related immune dysfunction is associated with an abnormality in telomerase activity, we investigated telomerase activity in T cell populations from young adult and aged mice. Our data show that the ability of T cells from aged mice to up-regulate telomerase activity after activation was significantly diminished. This age-related deficiency in telomerase induction is restricted to CD4+ T cells, as CD8+ T cells retain the capability to up-regulate telomerase activity. These findings reinforce the notion that age-related immune dysfunction results mainly from impairment of helper T cells, and may have important implications for designing novel means to improve immune responses in aged individuals by enhancing CD8+ T cell functions, which are crucial in both viral and tumour immunity.
Circulating YKL-40 levels during human endotoxaemia
Authors: Johansen J S , Krabbe K S , Møller K , Pedersen B K 
Published: March 2005

Summary
YKL-40 is secreted by macrophages and neutrophils and patients with bacterial infections have elevated circulating YKL-40. The aim was to evaluate changes in plasma YKL-40 (determined by enzyme-linked immunosorbent assay (ELISA) at 0, 2, 4, 8, 24 and 32 h) in eight healthy volunteers after injection with Esherichia coli endotoxin or saline. Plasma YKL-40 increased after endotoxin injection from 31 µg/l (range 19–39 µg/l) to a maximum of 159 µg/l (61–552 µg/l, P &lt; 0·01) at 24 h. The finding that plasma YKL-40 increased after endotoxin injection compared with saline (P &lt; 0·001) suggests that YKL-40 has a functional role in infections.
A transgenic mouse model for studying the clearance of blood-borne pathogens via human complement receptor 1 (CR1)
Authors: Repik A , Pincus S E , Ghiran I , Nicholson-Weller A , Asher D R , Cerny A M , Casey L S , Jones S M , Jones S N , Mohamed N , Klickstein L B , Spitalny G , Finberg R W 
Published: March 2005

SummaryComplement receptor 1 (CR1) on the surface of human erythrocytes facilitates intravascular clearance of complement-opsonized pathogens. The need for complement activation can be circumvented by directly coupling the organism to CR1 using a bispecific monoclonal antibody heteropolymer (HP). Lack of a functional homologue to CR1 on mouse erythrocytes has made it difficult to study HP-dependent clearance of pathogens in small animals. We have developed a transgenic mouse that expresses human CR1 on erythrocytes. CR1 antigen is of appropriate size and in a clustered distribution as confirmed by immunoblotting and fluorescence microscopy, respectively. HP that immobilized bacteriophage ΦX174 prototype pathogen to erythrocyte CR1 of the transgenic mice increased the rate of clearance of the virus compared with HP that bound bacteriophage, but not CR1. This transgenic mouse model will allow evaluation of different HPs for their in vivo efficacy and potential as human therapeutics.
Hepatitis B surface antigen presentation and HLA-DRB1*– lessons from twins and peptide binding studies
Authors: Kruger A , Adams P , Hammer J , Böcher W O , Schneider P M , Rittner C , Hoehler T 
Published: March 2005

SummaryThe aim of this study was to investigate the underlying mechanisms of the genetic association between certain HLA-DRB1* alleles and the immune response to HBsAg vaccination. Therefore, HBsAg peptide binding to HLA-DR molecules was measured in vitro by peptide binding ELISAs. Additionally, HBsAg-specific T cell reaction and cytokine profile of immune response were analysed ex vivo in ELISPOT assays and DR-restriction of T-cell proliferative responses was investigated with HBsAg specific T cell clones. In addition, we compared HBsAg specific T cell responses of 24 monozygotic and 3 dizygotic twin pairs after HBsAg vaccination. Our results showed that the peptide binding assays did not reflect antigen presentation in vivo. DR alleles associated with vaccination failure like DRB1*0301 and 0701 efficiently presented HBsAg peptides. In 11 of 24 investigated monozygotic twin pairs we observed pronounced differences in the recognition of HBsAg peptides. This study indicates that HLA–DR associations with HBsAg vaccination response are not caused by differences in peptide binding or by a shift in the Th1/Th2 profile. Our findings strongly argue for differences in the T cell recognition of peptide/MHC complexes as the critical event in T cell responsiveness to HBsAg.