bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of infliximab infusion reactions on long‐term outcomes in patients with Crohn’s disease
Authors: MOSS A. C. , FERNANDEZ‐BECKER N. , JO KIM K. , CURY D. , CHEIFETZ A. S. 
Published: October 2008

SummaryBackground  Little is known about long‐term outcomes in patients who experience infusion reactions while receiving infliximab.Aim  To investigate long‐term outcomes in patients who experience infusion reactions while receiving infliximab.Methods  Retrospective electronic chart review of long‐term clinical outcomes.Results  Clinical data on 287 patients who received infliximab infusions for Crohn’s disease were reviewed, of whom 51 developed at least one infusion reaction (18%). Ileo‐colonic disease (OR 2.2, 95% CI 1.1–4.4) and episodic infliximab (OR 2.4, 95% CI 1.2–4.7) were associated with a higher risk of infusion reactions in univariate analysis, but concomitant azathioprine/mercaptopurine therapy at the initiation of infliximab was associated with a reduced risk (OR 0.4, 95% CI 0.2–0.8). Only the effect of concomitant immunomodulators persisted on multivariate analysis. Patients who experienced infusion reactions were less likely to be in remission at 1 year (OR 0.6, 95% CI 0.3–1.2), 2 years (OR 0.4, 95% CI 0.2–0.8, P = 0.01), or 5 years (OR 0.4, 95% CI 0.1–1.3) and more likely to require surgery (OR 2.2, 95% CI 1.1–4.1, P = 0.01) than those who did not experience such reactions.Conclusions  Patients who experienced infusion reactions to infliximab had a high rate of discontinuation of therapy in this cohort. Concomitant immunomodulators and maintenance therapy reduced the risk of infusion reactions.
Review article: the utility of reagent strips in the diagnosis of infected ascites in cirrhotic patients
Authors: NGUYEN‐KHAC E. , CADRANEL J.‐F. , THEVENOT T. , NOUSBAUM J.‐B. 
Published: October 2008

Aliment Pharmacol Ther 28, 282–288SummaryBackground  Spontaneous bacterial peritonitis (SBP) can be diagnosed via leucocyte esterase reagent strips, although diagnostic performances vary.Aim  To perform critical review of literature on the use of reagent strips in SBP.Methods  Nineteen studies were analysed (Medline search), comparing reagent strips in cirrhotic ascites vs. cytobacteriological methods. Diagnostic grades (G) were: G0 = 0 leucocytes/mm3; G1 = 15; G2 = 70; G3 = 125; G4 = 500 for Multistix, G0 = 0; G1 = 25; G2 = 75; G3 = 500 for Nephur, Combur, UriScan, and G0 = 0; G1 = 25; G2 = 75; G3 = 250; G4 = 500 for Aution.Results  Medians per study were: 75 patients (range: 31–1041), 136 ascites (47–2123), 17 SBP (5–117). For Multistix (12 studies), the sensitivities fell within the ranges 64.7–100% (G ≥ 1), 45.7–83% (G ≥ 2) and 45.3–89% (G ≥ 3). For Nephur (n = 2), Combur (n = 6), UriScan (n = 1), sensitivities ranged 80.4–100% (G ≥ 1), 63–100% (G ≥ 2) and 67.7–97% (G ≥ 3). For Aution (n = 3), sensitivities ranged 93–96% (G ≥ 2) and 89% (G ≥ 3). Nephur, Combur, UriScan displayed higher sensitivities than Multistix. However, in larger studies, sensitivities dramatically fell at 45.3% for Multistix (G ≥ 3) if ascites polymorphonuclear count <1000/mm3 and 22.2% for bacterascites or 16.7–25% for asymptomatic patients.Conclusion  Use of reagent strips for the diagnosis of SBP cannot be recommended, in view of low sensitivity and a high risk of false negatives, especially in patients with SBP and low polymorphonuclear count.
Genetic variation in BoLA microsatellite loci in Portuguese cattle breeds
Authors: Bastos‐Silveira C. , Luís C. , Ginja C. , Gama L. T. , Oom M. M. 
Published: October 2008

SummaryMajor histocompatibility complex (MHC) typing based on microsatellites can be a valuable approach to understanding the selective processes occurring at linked or physically close MHC genes and can provide important information on variability and relationships of populations. Using microsatellites within or in close proximity with bovine lymphocyte antigen (BoLA) genes, we investigated the polymorphisms in the bovine MHC, known as the BoLA, in eight Portuguese cattle breeds. Additional data from non‐BoLA microsatellite loci were also used to compare the variability between these regions. Diversity was higher in BoLA than in non‐BoLA microsatellites, as could be observed by the number of alleles, allelic richness and observed heterozygosity. Brava de Lide, a breed selected for aggressiveness and nobility, presented the lowest values of observed heterozygosity and allelic richness in both markers. Results from neutrality tests showed few statistically significant differences between the observed Hardy–Weinberg homozygosity (F) and the expected homozygosity (FE), indicating the apparent neutrality of the BoLA microsatellites within the analysed breeds. Nevertheless, we detected a trend of lower values of observed homozygosity compared with the expected one. We also detected some differences in the levels of allelic variability among the four BoLA microsatellites. Our data showed a higher number of alleles at the BoLA‐DRB3 locus than at the BoLA‐DRBP1 locus. These differences could be related to their physical position in the chromosome and may reflect functional requirements for diversity.
The CADEUS study: burden of nonsteroidal anti‐inflammatory drug (NSAID) utilization for musculoskeletal disorders in blue collar workers
Authors: Rossignol Michel , Abouelfath Abdelilah , Lassalle Regis , Merlière Yvon , Droz Cécile , Bégaud Bernard , Depont Fanny , Moride Yola , Blin Patrick , Moore Nicholas , Fourrier‐Réglat Annie 
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • To our knowledge, no study has ever described the intensity of nonsteroidal anti‐inflammatory drug (NSAID) utilization in an employed population by occupation.• As the use of NSAIDs carries a well‐known risk of adverse effects, this risk adds to the burden of musculoskeletal disorders in employed populations.• Information on utilization of NSAIDs in this context will help to better characterize and prevent this risk. WHAT THIS STUDY ADDS • In spite of a previous history of dyspepsia, blue collar workers had the highest rate of chronic and continuous utilization of nonselective NSAIDs.• No clustering of cyclooxygenase‐2 selective NSAID utilization according to a previous history of dyspepsia was observed among blue collar workers.• The association between chronicity of NSAID utilization and occupation was independent of medical indication for the prescription and other lifestyle factors.AIMThe aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population.METHODSThis was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as ‘over four dispensations in one year with less than two months between any two’.RESULTSFactors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6–1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5–2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5–2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2–1.6). Blue collar workers also had a 20% higher prevalence of 5‐year history of dyspepsia. No difference was observed between sexes or in the use of COX‐2 selective inhibitors between occupations.CONCLUSIONFactors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication.
Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa
Authors: Ekhart Corine , Doodeman Valerie D. , Rodenhuis Sjoerd , Smits Paul H. M. , Beijnen Jos H. , Huitema Alwin D. R. 
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Thiotepa is metabolized by oxidative desulphuration by the cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 to tepa.• Furthermore, thiotepa and tepa are conjugated to glutathione, which is catalysed by glutathione S‐transferase (GST) isoenzymes A1‐1 and P1‐1.• Polymorphisms in these enzymes could influence exposure to thiotepa and tepa.• Little is known about the influence of polymorphisms in these enzymes on the pharmacokinetics of thiotepa and tepa. WHAT THIS STUDY ADDS • The presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics.• We show that probably only the GSTP1 C341T variant allele influences thiotepa exposure to a clinically relevant extent.AIMSThiotepa is widely used in high‐dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S‐transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa.METHODSWhite patients (n = 124) received a high‐dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC‐MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (nonmem).RESULTSThe polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C‐69T, G‐52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non‐inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients.CONCLUSIONSThis study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa.
Variability in the quality of overdose advice in Summary of Product Characteristics (SPC) documents: gut decontamination recommendations for CNS drugs
Authors: Wall Andrew J. B. , Bateman D. N. , Waring W. S. 
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The Summary of Product Characteristics (SPC) is a legal document that gives healthcare providers information concerning each specific drug, including advice on the management of overdose.• Clinical outcomes after drug overdose may be influenced by the appropriate use of gut decontamination procedures.• The extent to which poisoning management advice in the SPC agrees with Poisons Centres recommendations is uncertain. WHAT THIS STUDY ADDS • Significant discrepancies exist between poisoning management advice contained in SPC documents and TOXBASE recommendations.• SPC documents may include inappropriate recommendations for induced emesis and gastric lavage, or omission of oral activated charcoal as a potentially effective therapy.• The SPC document cannot be relied on as a primary reference source for advice concerning drug overdose.AIMSDeliberate self‐poisoning is a major cause of morbidity and mortality. The Summary of Product Characteristics (SPC) document is a legal requirement for all drugs, and Section 4.9 addresses the features of toxicity and clinical advice on management of overdose. The quality and appropriateness of this advice have received comparatively little attention.METHODSSection 4.9 of the SPC was examined for all drugs in the central nervous system (CNS) category of the British National Formulary. Advice concerning gut decontamination was examined with respect to specific interventions: induced vomiting, oral activated charcoal, gastric lavage, and other interventions. Data were compared with standard reference sources for clinical management advice in poisoning. These were graded ‘A’ if no important differences existed, ‘B’ if differences were noted but not thought clinically important, and ‘C’ if differences were thought to be clinically significant.RESULTSSPC documents were examined for 258 medications from 67 manufacturers. The overall agreement was ‘A’ in 23 (8.9%), ‘B’ in 28 (10.9%) and ‘C’ in 207 (80.2%). Discrepancies were due to inappropriate recommendation of induced emesis in 21.7% (95% confidence interval 17.1, 27.1), gastric lavage in 38.4% (32.7, 44.4), other gut decontamination in 5.8% (3.6, 9.4) and failure to recommend oral activated charcoal in 57.4% (51.1, 63.4).CONCLUSIONSGut decontamination advice in SPC documents with respect to CNS drugs was inadequate. Possible reasons for the observed discrepancies and ways of improving the consistency of advice are proposed.
Use of rituximab in diffuse large B‐cell lymphoma in the salvage setting
Authors: Gisselbrecht Christian 
Published: October 2008

SummaryThe addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy was a milestone in the development of front‐line therapy for diffuse large B‐cell lymphoma (DLBCL). R‐CHOP and equivalent rituximab‐containing anthracycline‐based regimens are now widely accepted as the standard of care in this setting. However, the optimal treatment for patients with DLBCL relapsing or progressing after front‐line therapy is not yet established. This review explores the role of rituximab in the treatment of DLBCL in the salvage setting, as monotherapy, in combination with chemotherapy or novel agents, and in the context of autologous stem cell transplantation (ASCT). Current evidence suggests that rituximab may improve outcomes in several ways: the higher response rates achieved with rituximab‐based induction in the salvage setting optimize the number of patients who are able to proceed to high‐dose therapy ‐ASCT; rituximab may improve outcomes following ASCT when used as post‐transplantation consolidation/maintenance therapy; and addition of rituximab to salvage regimens may improve outcomes for patients ineligible for transplantation. However, patients refractory to or relapsing after first‐line therapy (including rituximab‐based regimens) still have a poor prognosis. In conclusion, rituximab in salvage therapy for DLBCL is effective and well tolerated. Ongoing studies will further clarify the optimal use of rituximab in the salvage setting.
In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis
Authors: Hausmann M , Obermeier F , Paper D H , Balan K , Dunger N , Menzel K , Falk W , Schoelmerich J , Herfarth H , Rogler G 
Published: October 2008

Summary
Recently we demonstrated that in inflammatory bowel disease (IBD) macrophage-oxidative burst activity is increased and NADPH oxidase mRNA is induced. The herbal phenylethanoid acteoside isolated from Plantago lanceolata L. was shown to exhibit anti-oxidative potential. Using the dextran sulphate sodium (DSS)-induced colitis model, in this study we have assessed whether systemic application of acteoside affects colitis. Colitis was induced by DSS in Balb/c mice. Treatment with acteoside (120, 600 µg/mouse/day) was performed intraperitoneally. The colon lengths were determined. Colonic tissue was scored histologically (max. score 8) by a blinded investigator. T cells isolated from mesenteric lymph nodes (MLN) were stimulated with anti-CD3 antibody in the presence of interleukin (IL)-2 (final concentration 10 U/ml). After incubation for 24 h, IL-1β, IL-6, IL-12 tumour necrosis factor (TNF)-α and interferon (IFN)-γ levels in supernatants were analysed by the beadlyte® cytokine detection system. Histological scoring of colonic tissue revealed that application of acteoside was followed by a significantly improved histological score. In acute colitis the histological score was 3·2 with acteoside versus 5·2 with phosphate-buffered saline (PBS) (P &lt; 0·02). In chronic colitis both 120 µg (3·3 versus 5·2) or 600 µg acteoside (3·0 versus 5·2) significantly ameliorated colitis (both P &lt; 0·02). Stimulated MLN from mice with chronic DSS-induced colitis treated with acteoside showed a significant down-regulation of IFN-γ secretion (195 pg/ml with 600 µg acteoside versus 612 pg/ml with PBS, P &lt; 0·02). Inhibition of oxidative burst activity with acteoside reduced mucosal tissue damage in DSS colitis and could be a therapeutic alternative for IBD treatment. Further studies of this agent are warranted.
Role of the transgenic human thyrotropin receptor A-subunit in thyroiditis induced by A-subunit immunization and regulatory T cell depletion
Authors: Mizutori Y , Nagayama Y , Flower D , Misharin A , Aliesky H A , Rapoport B , McLachlan S M 
Published: October 2008

SummaryTransgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (Treg) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A–Z). In transgenic and WT mice, regardless of Treg depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After Treg depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4+ T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA–d). High affinity subsequences (inhibitory concentration of 50% &lt; 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.
Analysis of the interindividual conservation of T cell receptor α- and β-chain variable regions gene in the peripheral blood of patients with systemic lupus erythematosus
Authors: Luo W , Ma L , Wen Q , Wang N , Zhou M-Q , Wang X-N 
Published: October 2008

SummaryThe aim of this study was to find conserved motifs in specific T cell receptor (TCR) α- and β-chains, and to analyse the association between complementarity determining region 3 (CDR3) spectratype and systemic lupus erythematosus (SLE) activity. TCR α-and β-chain CDR3 spectratypes were analysed in 20 SLE patients. The CDR3 spectratypes of three patients were monitored over time, and the CDR3 regions of clonally expanded T cells were sequenced. CDR3 spectratype analysis showed prominent usage of TCR AV8, AV14, AV23, AV30, AV31, BV2, BV8, BV11, BV14, BV16, BV19 and BV24 families in SLE patients. The CDR3 spectratype showed dynamic change correlating with SLE activity. The sequence of the CDR3 region in clonally expanded T cells suggested a conserved GGX amino acid motif in both α- and β-chains. The Ja34 and Jb2s1 region genes were found in high frequency. Both TCR Vα and Vβ gene usage is highly restricted in SLE, suggesting that the TCRs recognize a limited number of antigenic epitopes. The conserved motifs and limited use of joining region genes may indicate the recognition of similar antigenic epitopes in multiple individuals.
Longitudinal analysis of immune function in the first 3 years of life in thymectomized neonates during cardiac surgery
Authors: Mancebo E , Clemente J , Sanchez J , Ruiz-Contreras J , De Pablos P , Cortezon S , Romo E , Paz-Artal E , Allende L M 
Published: October 2008

SummaryThe purpose of this study is to evaluate the effects of neonatal thymectomy in the functional capacity of the immune system. We selected a group of 23 subjects, who had undergone thymectomy in their first 30 days of life, during an intervention for congenital heart disease. Several parameters of the immune system were evaluated during their first 3 years of life. Lymphocyte populations and subpopulations (including naive, memory and effector subpopulations), T cell receptor (TCR) Vβ repertoire, response of T cells following in vitro stimulation by mitogen, quantification of immunoglobulins, TCR excision circles (TRECS) and interleukin (IL)-7 were measured. We found that neonatal thymectomy produces long-term diminution in total lymphocyte counts, especially in naive CD4+ and CD8+ T cells. Additionally, TRECS were decreased, and plasma IL-7 levels increased. A statistically significant negative correlation was found between absolute CD4+ T cells and IL-7 (r = −0·470, P = 0·02). The patients did not suffer more infectious events than healthy control children, but thymectomy in neonates resulted in a significant decrease in T lymphocyte levels and TRECS, consistent with cessation of thymopoiesis. This could produce a compromise in immune function later in life, especially if the patients suffer T cell depletion and need a reconstitution of immune function.
Influence of temperature on the spatial distribution of first spawning dates of the common frog (Rana temporaria) in the UK
Authors: CARROLL E. A. , SPARKS T. H. , COLLINSON N. , BEEBEE T. J. C. 
Published: October 2008

AbstractBetween 1998 and 2007, the UK Phenology Network collected nearly 70 000 records of the first spawn dates of the common frog Rana temporaria. Annual national mean dates varied by more than 2 weeks and were closely related to January–March temperatures. A 1 °C increase in Central England Temperature advanced national mean spawning by 5.1 days. The temporal pattern of spawning records varied between years; sometimes unimodal in form, sometimes multimodal, seemingly associated with steady or erratic rises in spring temperatures, respectively. Spatial patterns of frogspawn were similar in different years, the earliest records occurring in the southwest with records progressively later in the north and east. On average, 100 km of eastwards progression took 7.4 days and 100 km of northwards progression took 4.7 days. A composite map for the 1998–2007 period is constructed and compared with an earlier published map based on data 60 years previously. The similarity and dissimilarity of these two maps is discussed; the general progression pattern of frogspawn phenology is similar but an advance of a 10‐day contour category is apparent. We anticipate further advances of frog spawning dates in the future and an increase in the numbers of pre‐January 1 records of frog breeding.