Antioestrogens Enhance Tumour Necrosis Factor Receptor 2 (TNF-R2) Expression and TNF-R2-Mediated Proliferation in Activated T Cells

In the present study we demonstrate that the non-steroidal antioestrogens toremifene and tamoxifen inhibit mitogen-induced proliferation and up-regulation of tumour necrosis factor (TNF) receptor family molecules on peripheral blood T cells. In activated T cells, however, toremifene and tamoxifen increase the surface expression of tumour necrosis factor receptor 2 (TNF-R2). This up-regulation is functionally important as TNF-R2-mediated proliferation is significantly enhanced in antioestrogen-treated activated T cells. The regulation of TNF-R2 expression in activated T cells seems to involve the c-Jun amino terminal kinase (JNK) pathway, as activation of JNK with anisomycin down-regulates TNF-R2. In activated T cells toremifene clearly inhibits phorbol 12-myristate 13-acetate (PMA)-induced JNK activity, suggesting that the JNK pathway may also be involved in the up-regulation of TNF-R2 expression by antioestrogens. Taken together, the enhancement of TNF-R2 expression and TNF-R2-mediated proliferation in activated T cells represents a novel feature for the effects of antioestrogens. The inhibitory effects of toremifene on the JNK pathway demonstrates that antioestrogens can influence not only cell growth, but also a variety of other cellular responses by inhibiting protein kinase C (PKC).     

Immunoglobulin diversification in embryonic chicken bursae and in individual bursal follicles

Previous studies have shown that the same immunoglobulin (Ig) V lambda gene (V lambda 1) is rearranged in all chicken B cells, and that extensive sequence diversification of this gene occurs during B cell development in the bursa of Fabricius. We used two-dimensional gel electrophoresis to compare the heterogeneity of Ig lambda light chains produced by B cells at different stages of bursal development. Somatically diversified light chains were observed in Ig molecules produced by bursal cells as early as 15 days of embryonic incubation. The two principal species of light chain observed probably represent glycosylated and nonglycosylated forms of lambda chain encoded by alleles of a single lambda gene. Extensive diversification was observed during late embryogenesis. We also studied lambda light chain diversity in cyclophosphamide-treated birds repopulated with normal bursal cells. In these birds, individual bursal follicles are repopulated by single B cell precursors. Follicular cells derived from single B cell precursors were able to produce a spectrum of light chains almost as diverse as that of the total bursal cell population. We used two monoclonal anti-idiotype antibodies to study idiotype expression in individual normal or reconstituted follicles. About 30% of follicles contained 0.1% to 5% of lymphocytes which reacted with one or both of the antibodies. The results indicate that within individual bursal follicles bursa stem cells undergo Ig hyperdiversification.     

Maternal Vitamin C and Iron Intake during Pregnancy and the Risk of Islet Autoimmunity and Type 1 Diabetes in Children: A Birth Cohort Study

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring’s risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997–2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.     

A sudden increase in plasma epinephrine levels transiently enhances platelet deposition on severely damaged arterial wall--studies in a porcine model

Epidemiologic evidence has shown that sympathoadrenal activation plays a triggering role in the onset of acute coronary syndromes. However, its mechanism is not yet clearly understood. The aim of this study was to assess the effect of a sudden increase in epinephrine on platelet deposition on severely damaged vessel wall at shear rate conditions modelling stenotic vessels in the porcine model. The selected epinephrine concentrations (0.5 micromol/l-1 mmol/l) alone or in combination with collagen or ADP did not affect platelet aggregation in vitro either in whole blood or in PRP, although porcine platelets express alpha2-adrenergic receptors as assessed by PCR. In vitro and ex vivo perfusion experiments were performed using the Badimon chamber at high shear rate conditions (1690 s(-1)). In vitro, epinephrine (130 nmol/l) increased platelet deposition on severely damaged vessel wall (exposing tunica media; approximately 1.6-fold, p <0.05) or immobilized collagen (2.2-fold, p <0.01). Ex vivo perfusion experiments were performed from animals that received intravenous epinephrine infusion for one hour at a low (0.3 microg/kg/min; approximately 17 nmol/l in plasma, at 20 min of the infusion) and a high dose (1.0 microg/kg/min; approximately 106 nmol/l in plasma, at 20 min of the infusion). Only the low dose temporarily increased platelet deposition on severely damaged vessel wall during the first 30 min of infusion [2.4-fold (p <0.05) and 4.2-fold (p <0.01) at 10 and 30 min of the infusion respectively] declining afterwards. Thus, in flow conditions typical of atherosclerotic arteries, a sudden physiological release of epinephrine can temporarily enhance platelet deposition on severely damaged vessel wall while an extensive exposure leads to refractoriness.     

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes,risk factors and genotypes

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10^-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.     

Surface Integrity of Dimethacrylate Composite Resins with Low Shrinkage Comonomers

The goal of current research was to investigate the influence of adding low shrinkage “Phene” like comonomers hexaethylene glycol bis(carbamate-isoproply-α-methylstyrene) (HE-Phene) and triethylene glycol bis(carbamate-isoproply-α-methylstyrene) (TE-Phene) on the surface and color characteristics of composite resin. A range of weight fractions (0, 10, 20, 30, 40 wt.%) of HE/TE-Phene monomers were mixed with bisphenol A glycidyl methacrylate (GMA)/triethylene glycol dimethacrylate (TEGDMA) monomer. Experimental composite resins were made by mixing 71 wt.% of silica fillers to 29 wt.% of the resin matrix. A Vickers indenter and glossmeter were used for testing surface hardness (SH) and gloss (SG) at 60°. A chewing-simulator was used to evaluate the surface wear after 15,000 cycles. Color change (∆E) and translucency parameter (TP) were measured using a spectrophotometer. Data showed that HE/TE-Phene monomer had no negative impact (p > 0.05) on surface gloss, wear, color change and translucency of experimental composite resins. Surface hardness was in a reducing direction with the increas in HE/TE-Phene weight fraction (p < 0.05). The study results suggested that incorporating HE/TE-Phene monomers up to 30 wt.% with Bis-GMA/TEGDMA resin did not negatively influence the surface integrity of composite resins except for SH.