bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ineffectiveness of lipid‐lowering therapy in primary care
Authors: Van Ganse E. , Souchet T. , Laforest L. , Moulin P. , Bertrand M. , Le Jeunne P. , Travier N. , Yin D. , Alemao E. , De Pouvourville G. 
Published: March 2005

BackgroundEvidence confirms the positive effects of lipid‐lowering agents on the risk of cardiovascular disease. Local guidelines in France (AFSSAPS) have defined therapeutic objectives for LDL‐cholesterol. These objectives vary with the number of cardiovascular risk factors in addition to dyslipidaemia. We determined the proportions of patients at therapeutic objective in different classes of cardiovascular risk to test the hypothesis that compliance with guidelines varies across the levels of risk. Comparison with international guidelines (ANDEM) was also performed.MethodsA group of 3173 dyslipidaemic patients treated with lipid‐lowering agents and managed by general practitioners was randomly selected from BKL‐Thales panel, a French computerized database. For each patient, history of coronary heart disease and the number of cardiovascular risk factors were documented. Compliance with guidelines was assessed from achievement of therapeutic objective.ResultsThe study population included 79% primary prevention patients (1.6, 25.5, 31.7 and 20.1%, with 1, 2, 3, and >3 risk factors, respectively) and 21.0% secondary prevention patients. Applying AFSSAPS guidelines, the proportions of primary prevention patients not at LDL‐cholesterol objectives varied across risk categories (P < 0.0001), from 3.9% for patients with one risk factor to 46.5% for patients with >3 risk factors, and therapeutic failure reached 39.9% in secondary prevention. Only 26% of patients who were at high cardiovascular risk (>3 risk factors or prior coronary heart disease) and not at therapeutic objective received high doses (>standard recommended doses) of lipid‐lowering agents in monotherapy. Applying ANDEM guidelines, 74% of secondary prevention patients were not at treatment goal.ConclusionCompliance with guidelines varied inversely with the level of cardiovascular risk. Besides, most patients not at therapeutic objective were not up‐titrated. The use of lipid‐lowering agents is inadequate, depriving many patients of an effective protection against cardiovascular diseases.
Self treatment with one of three self selected, ultramolecular homeopathic medicines for the prevention of upper respiratory tract infections in children. A double‐blind randomized placebo controlled trial
Authors: Steinsbekk Aslak , Bentzen Niels , Fønnebø Vinjar , Lewith George 
Published: March 2005

AimsHomeopathic medicines are frequently purchased over the counter (OTC). Respiratory complaints are the most frequent reason for such purchases. Children with upper respiratory tract infection (URTI) are frequent users of homeopathy. This study investigates the effect of self treatment with one of three self selected ultramolecular homeopathic medicines for the prevention of childhood URTI.MethodsA double‐blind randomized parallel group placebo controlled trial was carried out in 251 children below the age of 10 years, recruited by post from those previously diagnosed with URTI when attending a casualty department. The children were randomly assigned to receive either placebo or ultramolecular homeopathic medicines in C‐30 potency (diluted 10−60) administered twice weekly for 12 weeks. Parents chose the medicine based on simplified constitutional indications for the three medicines most frequently prescribed by Norwegian homeopaths for this group of patients. The main outcome measure relates to the prevention of new episodes of URTI measured with median total symptom score over 12 weeks.ResultsThere was no difference in the predefined primary outcome between the two groups (P = 0.733). Median URTI scores over 12 weeks in the homeopathic medicine group were 26.0 (95% confidence interval (CI) 16.3, 43.7) and for placebo 25.0 (95% CI 14.2, 38.4). There was no statistical difference between the two groups in median number of days with URTI symptoms or in the use of conventional medication/care.ConclusionsIn this study there was no effect over placebo for self treatment with one of three self selected, ultramolecular homeopathic medicines in preventing childhood URTI. This can be due to the lack of effect of the highly diluted homeopathic medicines or the process of selection and type of medicines.
Steady‐state pharmacokinetics and pharmacodynamics of CHF3381, a novel antineuropathic pain agent, in healthy subjects
Authors: Astruc Béatrice , Tarral Antoine , Dostert Philippe , Mariotti Fabrizia , Fabbri Laura , Imbimbo Bruno P. 
Published: March 2005

AimsTo evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of CHF3381, a dual NMDA and MAO‐A inhibitor, after multiple oral doses in healthy subjects.MethodsForty‐eight young males received CHF3381 at doses of 100 mg twice daily, 200 mg twice daily, 400 mg twice daily or placebo for 2 weeks according to a double‐blind, randomized, parallel group design. Plasma and urine concentrations of the parent drug and of two major metabolites (CHF3567 and 2‐aminoindane) were measured over time. MAO‐A activity in plasma was estimated by measuring plasma concentrations of 3,4‐dihydroxyphenylglycol. Sustained attention, memory and sedation were assessed throughout the study with standard psychometric tests.ResultsMost of the adverse events were mild in intensity, with dose regimens of 100 mg twice daily and 200 mg twice daily being indistinguishable from placebo. After 400 mg twice daily, the most frequent adverse events were mild dizziness, asthenia and insomnia. At steady‐state, 400 mg twice daily slightly increased supine heart rate (+ 9 ± 2 beats min−1) and diastolic blood pressure (+6 ± 2 mmHg) compared with placebo. There were no dose‐dependent or consistent effects of CHF3381 on attention, motor co‐ordination or memory, but 400 mg twice daily significantly decreased alertness compared with placebo. Plasma concentrations of CHF3381 peaked at around 3 h and were dose‐proportional. The elimination half‐life of CHF3381 was estimated to be 4–6 h. At steady‐state, significant CHF3381 plasma concentrations were detected at predose with a modest accumulation (1.3–1.5 times), showing that the drug given twice daily is active over the entire 24 h period. Plasma concentrations of CHF3567 and of 2‐aminoindane were also proportional to the dose of CHF3381. CHF3381 dose‐dependently inhibited MAO‐A activity with peak effects at steady‐state of 27 ± 4%, 46 ± 2% and 65 ± 5% after 100 mg twice daily, 200 mg twice daily and 400 mg twice daily, respectively. There were no significant effects of CHF3381 on attention (rapid visual information processing), motor co‐ordination (body sway) or memory (learning memory task) at any of the doses. At steady‐state, there was a significant decrease in alertness (Bond & Lader visual analogue scale) in the 400 mg twice daily group compared with placebo.ConclusionsA twice daily regimen of CHF3381 appears to be adequate from a pharmacokinetic and pharmacodynamic perspective. Plasma concentrations reached with 400 mg twice daily exceeded those observed in animals receiving pharmacologically active doses in chronic pain models.
Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein
Authors: Pinto A. G. , Horlander J. , Chalasani N. , Hamman M. , Asghar A. , Kolwankar D. , Hall S. D. 
Published: March 2005

AimsTo determine the effect of diltiazem on intestinal CYP3A activity and protein and mRNA expression in vivo in healthy subjects.MethodsIntestinal biopsies were obtained from ten healthy controls and from ten healthy subjects after receiving diltiazem 120 mg bid for 7 days. Intestinal CYP3A activity, CYP3A4 protein and mRNA concentrations were quantified in both groups. Intestinal CYP3A activity was determined by incubation of small bowel homogenate with midazolam (25 µM) and NADPH for 5 min and the rate of formation of 1’‐hydroxymidazolam was quantified.ResultsAll subjects in the treatment group had detectable diltiazem concentration in the serum. While there was no significant difference in CYP3A4 protein and mRNA expression between the control and treatment groups, the formation of 1’‐hydroxymidazolam (446 pmol min−1 mg−1 6 (control) vs. 170 (CI 112, 228) pmol min−1 mg−1 95% confidence interval (CI 269, 623) (diltiazem group)) was significantly reduced (P < 0.05).ConclusionDiltiazem decreased small bowel CYP3A activity by 62% as a result of irreversible inhibition with no corresponding change in intestinal CYP3A4 mRNA or protein concentrations.
New therapies for rheumatoid arthritis
Authors: Goldblatt F , Isenberg D A 
Published: March 2005

Summary
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which continues to cause significant morbidity in affected persons. In the past few years, a number of new exciting therapeutic options have become available. These reflect the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. A number of these therapies are outlined in the following review, including the various biological modifiers, in particular, anti-tumour necrosis factor-α agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centring on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. To evaluate this therapeutic option for RA, salient features from recent rituximab trials have been collated. Finally, a selection of other therapeutic alternatives, including anti-IL-6 receptor monoclonal antibody and tacrolimus, and newer anti-rheumatic therapies presently in development are summarized.
CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis
Authors: Möttönen M , Heikkinen J , Mustonen L , Isomäki P , Luukkainen R , Lassila O 
Published: March 2005

Summary
CD4+ CD25+ regulatory T (Treg) cells play a critical role in the maintenance of peripheral tolerance and the prevention of autoimmunity. In the present study, we have explored the characteristics of CD4+ CD25+ Treg cells in patients with rheumatoid arthritis (RA). The frequency and phenotype of CD4+ CD25+ T cells in paired samples of synovial fluid (SF) and peripheral blood (PB) from patients with RA and PB from normal controls were analysed. An increased frequency of CD4+ cells T cells expressing CD25 was detected in SF compared to PB from patients with RA. No significant difference was observed in the numbers of CD4+ CD25+ T cells in PB from patients and controls. SF CD4+ CD25+ T cells expressed high levels of CTLA-4 (both surface and intracellular), GITR and OX40, as well as Foxp3 transcripts. Functionally, SF CD4+ CD25+ T cells were impaired in their proliferative responses and could suppress the proliferation of their CD4+ CD25– counterparts. In conclusion, these data demonstrate that CD4+ CD25+ Treg cells, with the potential to regulate the function of effector T cells and antigen-presenting cells, accumulate in the synovium of patients with RA.
Constant IFNγ mRNA to protein ratios in cord and adult blood T cells suggests regulation of IFNγ expression in cord blood T cells occurs at the transcriptional level
Authors: Gupta A Kumar , Rusterholz C , Holzgreve W , Hahn S 
Published: March 2005

SummaryLow levels of IFNγ produced by umbilical cord blood (UCB) T lymphocytes upon activation may be due to the need for a high threshold of activation or to intrinsic blocking transcription/translation. We examined IFNγ mRNA accumulation and protein expression in pharmacologically stimulated human UCB and adult blood (AB) T cells. Our data indicate that both IFNγ mRNA accumulation and protein synthesis were significantly lower in stimulated UCB T cells than the AB T cells. Since the RNA dependent kinase PKR, an inhibitor of translation, can be activated by low levels of IFNγ mRNA, we measured its involvement. Treatment with 2-amino-purine, an inhibitor of PKR, did not enhance IFNγ protein expression in UCB T cells. Furthermore, our studies indicated that IFNγ promoter hypermethylation does not appear to regulate IFNγ expression either, as treatment with the demethylating agent, 5-aza-2′-deoxycytidine, did not lead to a significant increase in IFNγ mRNA accumulation in UCB T cells. What is readily evident from our studies is that the IFNγ mRNA to protein ratio was similar in UCB and AB T cells and it was not altered by any of the treatments used. These results therefore suggests that IFNγ expression in UCB T cells is suppressed at the transcriptional level by an unknown mechanism(s).
Lymphocyte subsets in term and significantly preterm UK infants in the first year of life analysed by single platform flow cytometry
Authors: Berrington J E , Barge D , Fenton A C , Cant A J , Spickett G P 
Published: March 2005

Summary
This observational study describes the ranges observed for lymphocyte subsets for significantly preterm infants (&lt;32 weeks) in the first year of life, measured by single platform flow cytometry and compared to identically determined subsets in term infants. After ethical approval 39 term and 28 preterm infants had lymphocyte subset analysis before and after their primary immunization series. Median values with 5th and 95th percentiles of absolute counts and percentages are presented for total lymphocytes, T cells, NK cells, B cells, cytotoxic T cells, helper T cells, dual positive T cells, activated T cells, activated T helper cells (including T regulatory cells), pan memory T cells, pan naïve T cells, memory helper T cells, naïve helper T cells and the T helper/suppressor ratio. The lymphocyte profile of the preterm infants differed from that of the term infants.
Increased expression of chemokines in patients with Wegener's granulomatosis − modulating effects of methylprednisolone in vitro
Authors: Torheim E A , Yndestad A , Bjerkeli V , Halvorsen B , Aukrust P , Frøland S S 
Published: March 2005

Summary
Chemokines, a group of cytokines that attracts and activates leucocyte subpopulations in inflamed tissue, have been associated with the pathogenesis of a number of inflammatory diseases, and some recent reports have suggested their involvement in Wegener's granulomatosis (WG). To elucidate further the possible role of chemokines in WG we examined serum levels of several CC- and CXC-chemokines in WG patients and assessed the ability of corticosteroids to modulate the expression of these mediators in vitro. Our main findings were: (i) WG patients (n = 14) had elevated serum levels of several inflammatory chemokines [i.e. regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8] compared to healthy controls (n = 9), as assessed by enzyme immunoassays (EIAs); (ii) by using EIAs and real-time reverse transcription-polymerase chain reaction (RT-PCR), we demonstrated the ability of methylprednisolone (MP) to down-regulate both the spontaneous and the staphylococcal enterotoxin B (SEB)-induced release of chemokines from peripheral blood mononuclear cells (PBMC) in vitro in both WG patients and controls, possibly involving both transcriptional and post-transcriptional mechanisms; and (iii) the ability of MP to attenuate chemokine secretion was less pronounced in WG patients than in controls, particularly with regard to inhibition of spontaneous release. Our findings suggest a role for chemokines in the pathogenesis of WG. The diminished MP-mediated suppression of chemokines in PBMC from WG patients suggests that more specific modulators of chemokine levels should be investigated in this disorder.
Transgenic over-expression of macrophage migration inhibitory factor renders mice markedly more susceptible to experimental colitis
Authors: Ohkawara T , Miyashita K , Nishihira J , Mitsuyama K , Takeda H , Kato M , Kondo N , Yamasaki Y , Sata M , Yoshiki T , Sugiyama T , Asaka M 
Published: March 2005

SummaryEnhanced production of macrophage migration inhibitory factor (MIF) is recognized in patients with inflammatory bowel disease (IBD) and mice with experimental colitis; however, the precise molecular function of MIF in colitis is not fully understood. To further investigate this matter, we examined the pathological features of MIF transgenic mice with dextran sulphate sodium (DSS)-induced colitis. We generated transgenic mice carrying a murine MIF cDNA driven by a cytomegalovirus enhancer and a β-actin/β-globin promoter. Mice were orally administered 1–4% DSS in drinking water for 7 days. Clinical disease activity, survival and histological features were evaluated. The level of myeloperoxidase (MPO) activity in the colon tissue was measured to assess neutrophil infiltration. The level of corticosterone in the serum was measured by enzyme linked-immunosorbent assay (ELISA). MIF mRNA and protein were markedly up-regulated in the colon and serum obtained from MIF transgenic mice. The severity of the colitis induced by 1% DSS treatment was markedly higher in MIF transgenic mice than in wild-type mice. We also found that MPO activity was significantly higher in MIF transgenic mice than wild-type mice in response to DSS stimulation. Interestingly, the corticosterone level remained unchanged in MIF transgenic mice. MIF enhances DSS-induced colitis, in part via neutrophil accumulation and inhibition of glucocorticoid bioactivity.
CpG oligodeoxynucleotides promote the host protective response against infection withCryptococcus neoformansthrough induction of interferon-gamma production by CD4+ T cells
Authors: Miyagi K , Kawakami K , Kinjo Y , Uezu K , Kinjo T , Nakamura K , Saito A 
Published: March 2005

SummaryIn the present study, we elucidated the effect of synthetic CpG-containing oligodeoxynucleotides (ODN) on pulmonary and disseminated infection caused by Cryptococcus neoformans. CDF-1 mice were inoculated intratracheally with a highly virulent strain of this pathogen, which resulted in massive bacterial growth in the lung, dissemination to the brain and death. Administration of CpG-ODN promoted the clearance of C. neoformans in the lungs, decreased their dissemination to brain and prolonged the survival of infected mice. These effects correlated well with the enhanced production of interleukin (IL)-12 and interferon (IFN)-γ and attenuated secretion of IL-4 in bronchoalveolar lavage fluids (BALF) and promoted development of Th1 cells, as indicated by the increased production of IFN-γ by paratracheal lymph node cells upon restimulation with cryptococcal antigens. The IFN-γ synthesis in BALF was inhibited by depletion of CD8+ and CD4+ T cells on days 7 and 14 after infection, respectively, but not by depletion of NK and γδ T cells. Consistent with these data, intracellular expression of IFN-γ was detected predominantly in CD8+ and CD4+ T cells in the lung on days 7 and 14, respectively. The protective effect of CpG-ODN, as shown by the prolonged survival, was completely and partially inhibited by depletion of CD4+ or CD8+ T cells, respectively, but not by depletion of other cells. Finally, TNF-α was markedly induced by CpG-ODN, and the protective effect of this agent was strongly inhibited by neutralizing anti-TNF-α MoAb. Our results indicate that CpG-ODN alters the Th1–Th2 cytokine balance and promotes host resistance against infection with C. neoformans.
Identification of a new HLA-A*0201-restricted CD8+ T cell epitope from hepatocellular carcinoma-associated antigen HCA587
Authors: Li B , Wang Y , Chen J , Wu H , Chen W 
Published: March 2005

AbstractFor the development of peptide-based cancer immunotherapies, we aimed to identify specific HLA-A*0201-restricted CTL epitopes in hepatocellular carcinoma (HCC) associated antigen HCA587, which has been identified as a member of the cancer/testis (CT) antigens highly expressed in HCC. We first combined the use of an HLA-A*0201/peptide binding algorithm and T2 binding assays with the induction of specific CD8+ T cell lines from normal donors by in vitro priming with high-affinity peptides, then IFN-γ release and cytotoxicity assays were employed to identify the specific HLA-A*0201 CD8+ T cell epitope using peptide-loaded T2 cells or the HCA587 protein+ HCC cell line HepG2. In the six candidate synthesized peptides, two peptides showed higher binding ability in T2 binding assays. No. 2 peptide, encompassing amino acid residues FLAKLNNTV (HCA587317−325), was able to activate a HCA587-specific CD8+ T-cell response in human lymphocyte cultures from two normal donors and two HCC patients, and these HCA587-specific CD8+ T cells recognized peptide-pulsed T2 cells as well as the HCA587 protein+ HCC cell line HepG2 in IFN-γ release and cytotoxicity assays. The results indicate that no. 2 peptide is a new HLA-A*0201-restricted CTL epitope capable of inducing HCA587-specific CTLs. Our data suggest that identification of this new HCA587/HLA-A*0201 peptide FLAKLNNTV may facilitate the design of peptide-based immunotherapies for the treatment of HCA587-bearing HCC patients.
Importance of stromal determinants in the generation of dendritic and natural killer cells in the human spleen
Authors: Briard D , Azzarone B , Brouty-Boyé D 
Published: March 2005

SummaryThe interaction between stroma and blood cells in the human spleen has received little attention, despite their well-defined roles during blood cell development in bone marrow. We have reported previously that human spleen-derived fibroblasts display a differentiated myofibroblast phenotype and constitutively express a biologically active form of membrane interleukin (IL)-15 that can drive co-cultured CD34+ blood cells to differentiate into activated natural killer (NK) cells. Here, we show that, in addition to NK cells, CD34/fibroblast co-cultures also yield myeloid CD1a+CD38+CD68+CD86+ HLA-DR+CD14–CD80– dendritic cells (DCs) after 3–4 weeks in culture. We found that DC development depended on endogenously secreted stromal macrophage colony-stimulating factor (M-CSF) and CD40/CD40L interaction rather than on fibroblast- and CD34-derived membrane IL-15. CD1a+ cells were necessary for co-produced NK cells to acquire lytic functions by a mechanism involving cell-to-cell contact and DC-derived IL-12. This study highlights the importance of spleen myofibroblasts in the in vitro generation of two distinct cell types (DC and NK cells) from the innate immune system and suggests that the human spleen is involved in the generation of NK cells from circulating progenitors.
New therapies for systemic lupus erythematosus
Authors: Goldblatt F , Isenberg D A 
Published: March 2005

SummaryIn the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.