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BACKGROUND: We previously reported that modified-release nicotinamide (NAMR) was superior to placebo in reducing serum phosphate concentrations over 12 weeks in a large cohort of haemodialysis patients with hyperphosphataemia. Here we report outcomes after 52 weeks of treatment. METHODS: NOPHOS was a phase 3, international, randomized, controlled, double-blind trial with a parallel group design. NAMR (250-1500 mg/day) was investigated in comparison to placebo as an add-on therapy to an individual therapy with approved phosphate binders. RESULTS: In the intention-to-treat population (NAMR: n = 539; placebo: n = 183), serum phosphate was significantly lower in the NAMR group compared with the placebo group at week 24 (5.40 ± 1.55 versus 5.79 ± 1.37 mg/dl, P < .001) with a mean difference of -0.39 mg/dl [95% confidence interval (CI) -0.66 to -0.13], but was comparable between the groups at week 52 [mean difference -0.08 (95% CI -0.36-0.20)]. In the completer population (n = 358), statistical significance in favour of NAMR was reached at weeks 24 and 52. The treatment effect was reduced in patients with high baseline serum intact parathyroid hormone (iPTH) compared with patients with low baseline serum iPTH. Compliant patients in the NAMR group had a more pronounced and sustained reduction in serum phosphate than non-compliant patients. NAMR treatment was associated with a significantly increased risk of thrombocytopenia, pruritus, anaemia, and diarrhoea. Herpes zoster occurred exclusively in patients randomized to NAMR. CONCLUSIONS: NAMR combined with phosphate binders significantly reduced serum phosphate over the first 24 weeks of treatment, but the treatment effect was not maintained up to week 52. Non-compliance may have contributed to reduced long-term efficacy. Several newly identified safety signals warrant further evaluation.
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Hiperfosfatemia , Humanos , Hiperfosfatemia/tratamiento farmacológico , Hiperfosfatemia/etiología , Niacinamida/efectos adversos , Diálisis Renal/efectos adversos , Hormona Paratiroidea , Fosfatos , Método Doble CiegoRESUMEN
OBJECTIVE: Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, which are mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets; however, â¼50% do not respond to this approach. Targeting of pathogenic T lymphocytes is emerging as an effective alternative/complementary therapeutic strategy, yet the factors that control T cell activation in joint disease are not well understood. Tenascin-C is an arthritogenic extracellular matrix glycoprotein that is not expressed in healthy synovium but is elevated in the rheumatoid joint, where high levels are produced by myeloid cells. Among these cells, tenascin-C expression is most highly induced in activated dendritic cells (DCs). The aim of this study was to examine the role of tenascin-C in this cell type. METHODS: We systematically compared the phenotype of DCs isolated from wild-type mice or mice with a targeted deletion of tenascin-C by assessing cell maturation, cytokine synthesis, and T cell polarization. RESULTS: Dendritic cells derived from tenascin-C-null mice exhibited no defects in maturation; induction of the class II major histocompatibility complex and the costimulatory molecules CD40 and CD86 was unimpaired. Dendritic cells that did not express tenascin-C, however, produced lower levels of inflammatory cytokines than did cells from wild-type mice and exhibited specific defects in Th17 cell polarization. Moreover, tenascin-C-null mice displayed ablated levels of interleukin-17 in the joint during experimental arthritis. CONCLUSION: These data demonstrate that tenascin-C is important in DC-mediated polarization of Th17 lymphocytes during inflammation and suggest a key role for this endogenous danger signal in driving adaptive immunity in erosive joint disease.
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Inmunidad Adaptativa , Artritis Experimental/inmunología , Células Dendríticas/metabolismo , Interleucina-17/biosíntesis , Tenascina/genética , Animales , Artritis Experimental/genética , Artritis Experimental/metabolismo , Polaridad Celular , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos , Ratones , Ratones Noqueados , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tenascina/metabolismoRESUMEN
Background: A modified-release dexamphetamine sulfate formulation (DEX-MR) is under development for the treatment of attention-deficit/hyperactivity disorder. Objective: We investigated the bioequivalence of once-daily DEX-MR to twice-daily immediate-release dexamphetamine sulfate (DEX-IR) after single and multiple dosing and between strengths, and effects of food and meal types. Method: Three randomized, open-label, crossover studies in healthy males were conducted. In the single-dose study, participants received DEX-MR 20 mg, DEX-MR 10 mg (20 mg dose), and twice-daily DEX-IR 10 mg under fasted conditions and after a high-fat, high-calorie breakfast. In the breakfast study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg after a normocaloric and a high-fat, high-calorie breakfast. In the multiple-dose study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg for seven days each. In the run-in period (five days), participants consumed a normocaloric breakfast; on profile days, participants consumed a normocaloric breakfast (day 6) or a high-fat, high-calorie breakfast (day 7). Results: Once-daily DEX-MR at a dose of 20 mg was bioequivalent to twice-daily DEX-IR 10 mg after single dosing under fasted and fed conditions and after multiple dosing under fed conditions. DEX-MR 10 mg and DEX-MR 20 mg were bioequivalent when administered as a single 20 mg dose. Food slightly reduced the rate and extent of absorption of DEX-MR and delayed the time to peak plasma concentration (tmax) by approximately two hours compared to the fasted state. Bioavailability of DEX-MR was comparable under different meal conditions (normocaloric vs. high-fat, high-calorie breakfast) both after single and multiple dosing. Conclusions: Bioequivalence of once-daily DEX-MR and twice-daily DEX-IR was established. 1×2 DEX-MR 10 mg was bioequivalent to 1×1 DEX-MR 20 mg. DEX-MR should be administered with/after a meal to achieve the targeted pharmacokinetic profile (delayed tmax). Bioavailability of DEX-MR is not affected by meal composition (i.e., fat and caloric content).
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As an inhibitor of cyclin-dependent kinases, p16(INK4A) is an important tumour suppressor and inducer of cellular senescence that is often inactivated during the development of cancer by promoter DNA methylation. Using newly established lymphoblastoid cell lines (LCLs) expressing a conditional EBNA3C from recombinant EBV, we demonstrate that EBNA3C inactivation initiates chromatin remodelling that resets the epigenetic status of p16(INK4A) to permit transcriptional activation: the polycomb-associated repressive H3K27me3 histone modification is substantially reduced, while the activation-related mark H3K4me3 is modestly increased. Activation of EBNA3C reverses the distribution of these epigenetic marks, represses p16(INK4A) transcription and allows proliferation. LCLs lacking EBNA3A express relatively high levels of p16(INK4A) and have a similar pattern of histone modifications on p16(INK4A) as produced by the inactivation of EBNA3C. Since binding to the co-repressor of transcription CtBP has been linked to the oncogenic activity of EBNA3A and EBNA3C, we established LCLs with recombinant viruses encoding EBNA3A- and/or EBNA3C-mutants that no longer bind CtBP. These novel LCLs have revealed that the chromatin remodelling and epigenetic repression of p16(INK4A) requires the interaction of both EBNA3A and EBNA3C with CtBP. The repression of p16(INK4A) by latent EBV will not only overcome senescence in infected B cells, but may also pave the way for p16(INK4A) DNA methylation during B cell lymphomagenesis.
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Oxidorreductasas de Alcohol/metabolismo , Antígenos Virales/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Infecciones por Virus de Epstein-Barr/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Oxidorreductasas de Alcohol/genética , Antígenos Virales/genética , Linfocitos B/metabolismo , Linfocitos B/patología , Western Blotting , Proliferación Celular , Ensamble y Desensamble de Cromatina , Inmunoprecipitación de Cromatina , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Metilación de ADN , Proteínas de Unión al ADN/genética , Infecciones por Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/genética , Citometría de Flujo , Regulación de la Expresión Génica , Herpesvirus Humano 4/genética , Humanos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Activación TranscripcionalRESUMEN
Our immune system is designed to protect us from danger. Upon pathogen invasion and tissue injury, activation of both innate and adaptive immunity enables us to combat infection and to repair tissue damage. Tenascin-C is a large, extracellular matrix glycoprotein that has a very tightly controlled pattern of expression. Little or no tenascin-C is expressed in most healthy adult tissues; however, it is rapidly and transiently induced at sites of tissue injury and infection. Persistent tenascin-C expression is associated with pathologies such as chronic, non-healing wounds, autoimmune diseases, cancer, and fibrotic diseases. We discuss the myriad roles that this multifunctional molecule plays during the immune response, with a focus on how tissue levels of tenascin-C are regulated and the consequences of misregulated tenascin-C expression in immune regulated disease pathogenesis.
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Regulación del Desarrollo de la Expresión Génica , Infecciones/inmunología , Tenascina/inmunología , Inmunidad Adaptativa , Animales , Regulación del Desarrollo de la Expresión Génica/inmunología , Humanos , Inmunidad Innata , Cicatrización de HeridasRESUMEN
BACKGROUND: Randomized controlled trials have shown that dexamphetamine sulfate (DEX) is efficacious in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents; however, data on the effectiveness and safety of DEX in routine practice are scarce. OBJECTIVE: This study investigated the long-term effectiveness and safety of Attentin® (immediate-release DEX) in children and adolescents with ADHD in routine practice. METHODS: ATTENTION was a multicenter, prospective, observational, non-interventional study that enrolled pediatric patients with ADHD (aged 6-17 years) with a clinically inadequate response to previous methylphenidate (MPH) treatment. Patients were assessed at baseline and two follow-up visits after approx. 6 and 12 months of DEX treatment. The primary endpoint was the investigator-rated ADHD rating scale IV (ADHD-RS-IV) total score change from baseline to the first follow-up visit. RESULTS: The study enrolled 140 patients (mean age: 11.2 years). Significant reductions in ADHD-RS-IV total scores were observed in the titration phase and were maintained up to the second follow-up visit. The mean ADHD-RS-IV total score change from baseline to the first follow-up visit was -11.9 (27.1 vs. 13.4, p < .001). Beneficial effects of DEX were observed on both ADHD-RS-IV subscales ('hyperactivity/impulsivity' and 'inattention') and in both children and adolescents. Clinical response, defined as a reduction in the ADHD-RS-IV total score of at least 30% at the first follow-up visit, was observed in 78.1% of patients. Patients reported an average onset of action of 36.2 minutes and an average duration of action of 6.5 hours after intake of the first dose of DEX in the morning. DEX was well tolerated. Small significant increases in mean systolic and diastolic blood pressure compared to baseline were observed. CONCLUSIONS: Attentin® is an effective and well-tolerated long-term treatment for pediatric ADHD patients with a clinically inadequate response to previous MPH treatment.
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AIM: To investigate the effect of Tenascin C (TNC) on the expression of pro-inflammatory cytokines and matrix metalloproteinases in human cardiac myofibroblasts (CMF). METHODS: CMF were isolated and cultured from patients undergoing coronary artery bypass grafting. Cultured cells were treated with either TNC (0.1 µmol/L, 24 h) or a recombinant protein corresponding to different domains of the TNC protein; fibrinogen-like globe (FBG) and fibronectin type III-like repeats (TNIII 5-7) (both 1 µmol/L, 24 h). The expression of the pro-inflammatory cytokines; interleukin (IL)-6, IL-1ß, TNFα and the matrix metalloproteinases; MMPs (MMP1, 2, 3, 9, 10, MT1-MMP) was assessed using real time RT-PCR and western blot analysis. RESULTS: TNC increased both IL-6 and MMP3 (P < 0.01) mRNA levels in cultured human CMF but had no significant effect on the other markers studied. The increase in IL-6 mRNA expression was mirrored by an increase in protein secretion as assessed by enzyme-linked immunosorbant assay (P < 0.01). Treating CMF with the recombinant protein FBG increased IL-6 mRNA and protein (P < 0.01) whereas the recombinant protein TNIII 5-7 had no effect. Neither FBG nor TNIII 5-7 had any significant effect on MMP3 expression. The expression of toll-like receptor 4 (TLR4) in human CMF was confirmed by real time RT-PCR, western blot and immunohistochemistry. Pre-incubation of cells with TLR4 neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mRNA and protein expression. CONCLUSION: TNC up-regulates IL-6 expression in human CMF, an effect mediated through the FBG domain of TNC and via the TLR4 receptor.