Association of PTPN22 single nucleotide polymorphism with rheumatoid arthritis but not with allergic asthma

PTPN22 gene encodes a lymphoid tyrosine phosphatase (LYP), an important negative regulator of T-cell responses. The 1858C>T (Arg620Trp) single nucleotide polymorphism (rs2476601) was found associated with autoimmune diseases, including rheumatoid arthritis (RA). Allergic diseases are similar to autoimmune diseases, by an exaggerated immune response to an antigen (allergen in this case) normally not invoking such response in healthy individuals. We investigated whether polymorphism 1858C>T in PTPN22 gene is associated with susceptibility to allergic asthma and RA in a Polish population. PTPN22 was genotyped in 173 patients with RA, in 198 patients with allergic asthma, and in 543 controls using PCR-RFLP. The patients with RA differed from healthy controls in frequencies of PTPN22 1858C>T alleles (P=0.0004; odds ratio (OR), 1.8; 95% CI, 1.33-2.55) and genotypes (P=0.0009). Strong associations of 1858T allele with RA limited to joints (0.21 vs 0.12, P=0.0002; OR, 2.1; 95% CI, 1.44-3.00), with erosive disease (0.20 vs 0.12, P=0.0003; OR, 1.92; 95% CI, 1.34-2.71), with a lack of rheumatoid factor (RF; 0.23 vs 0.12, P=0.0008; OR, 2.29; 95% CI, 1.44-3.63), and weak association with the presence of RF (0.17 vs 0.12, P=0.02; OR, 1.6; 95% CI, 1.10-2.40) in comparison with healthy controls were observed. Very strong association of 1858T allele (P<0.0001; OR, 2.72; 95% CI, 1.9-3.9) and T phenotype (P<0001; OR, 3.2; 95% CI, 2.1-4.9) with antibodies to cyclic citrullinated peptide (CCP) was found. When patients with allergic asthma were typed for PTPN22 1858C>T polymorphism, no difference with control was found. Subdivision of patients into those with mild, moderate, or severe asthma did not reveal any associations. In conclusion, we confirmed associations between several clinical manifestations of RA and PTPN22 1858T allele. However, no association with 1858C>T polymorphism was found for susceptibility to allergic asthma or for severity of the disease.     

NMDA receptor antagonist-enhanced high frequency oscillations: Are they generated broadly or regionally specific?

Systemic administration of NMDA receptor antagonists, used to model schizophrenia, increase the power of high-frequency oscillations (130–180 Hz, HFO) in a variety of neuroanatomical and functionally distinct brain regions. However, it is unclear whether HFO are independently and locally generated or instead spread from a distant source. To address this issue, we used local infusion of tetrodotoxin (TTX) to distinct brain areas to determine how accurately HFO recorded after injection of NMDAR antagonists reflect the activity actually generated at the electrode tip. Changes in power were evaluated in local field potentials (LFPs) recorded from the nucleus accumbens (NAc), prefrontal cortex and caudate and in electrocorticograms (ECoGs) from visual and frontal areas. HFO recorded in frontal and visual cortices (ECoGs) or in the prefrontal cortex, caudate (LFPs) co-varied in power and frequency with observed changes in the NAc. TTX infusion to the NAc immediately and profoundly reduced the power of accumbal HFO which correlated with changes in HFO recorded in distant cortical sites. In contrast, TTX infusion to the prefrontal cortex did not change HFO power recorded locally, although gamma power was reduced. A very similar result was found after TTX infusion to the caudate. These findings raise the possibility that the NAc is an important neural generator. Our data also support existing studies challenging the idea that high frequencies recorded in LFPs are necessarily generated at the recording site.     

Electrical and Structural Properties of Li1.3Al0.3Ti1.7(PO4)3—Based Ceramics Prepared with the Addition of Li4SiO4

The currently studied materials considered as potential candidates to be solid electrolytes for Li-ion batteries usually suffer from low total ionic conductivity. One of them, the NASICON-type ceramic of the chemical formula Li_1.3Al_0.3Ti_1.7(PO₄)₃, seems to be an appropriate material for the modification of its electrical properties due to its high bulk ionic conductivity of the order of 10⁻³ S∙cm⁻¹. For this purpose, we propose an approach concerning modifying the grain boundary composition towards the higher conducting one. To achieve this goal, Li₄SiO₄ was selected and added to the LATP base matrix to support Li⁺ diffusion between the grains. The properties of the Li_1.3Al_0.3Ti_1.7(PO₄)₃−xLi₄SiO₄ (0.02 ≤ x ≤ 0.1) system were studied by means of high-temperature X-ray diffractometry (HTXRD); ⁶Li, ²⁷Al, ²⁹Si, and ³¹P magic angle spinning nuclear magnetic resonance spectroscopy (MAS NMR); thermogravimetry (TG); scanning electron microscopy (SEM); and impedance spectroscopy (IS) techniques. Referring to the experimental results, the Li₄SiO₄ additive material leads to the improvement of the electrical properties and the value of the total ionic conductivity exceeds 10⁻⁴ S∙cm⁻¹ in most studied cases. The factors affecting the enhancement of the total ionic conductivity are discussed. The highest value of σ_tot = 1.4 × 10⁻⁴ S∙cm⁻¹ has been obtained for LATP–0.1LSO material sintered at 1000 °C for 6 h.     

Distribution of LILRA3 (ILT6/LIR4) deletion in psoriatic patients and healthy controls

The leukocyte immunoglobulinlike receptor (LILRA3; ILT6) gene is localized on human chromosome 19 in the region 19q13.4, in the leukocyte receptor complex that encodes leukocyte receptors LILR (ILT/LIR), killer cell immunoglobulinlike receptors (KIR), LAIR, Fc IgA receptor, and others. The biologic role of the LILRA3 molecule and the nature of its ligand are not known. Comparison of LILRA3 gene sequence with those of other LILRs suggests LILRA3 is a soluble molecule. If LILRA3 binds human leukocyte antigen (HLA) class I molecules like other LILRs whose ligands are known, then it might block recognition of HLA by these receptors, influencing immune response and susceptibility to HLA class I associated disease. A deletion of LILRA3 gene was found in a minority of British population. We typed 108 healthy individuals from the Low Silesia region and 103 patients diagnosed with psoriasis vulgaris (a disease associated with HLA class I antigen, HLA-Cw6) for LILRA3 to examine whether LILRA3 deletion was distributed differently in patients affected with the disease. No differences in frequencies of the LILRA3 deletion were found between controls and patients or between HLA-Cw6(+) and HLA-Cw6(-) controls or patients, suggesting that LILRA3 has no role in psoriasis.     

New bradykinin analogues modified in the C-terminal part with sterically restricted 1-aminocyclohexane-1-carboxylic acid

In the present work, a sterically constrained noncoded amino acid, 1-aminocyclohexane-1-carboxylic acid (Acc), was substituted in position 8 of the peptide chain of bradykinin (BK) and position 6, 7, or 8 of its B2 receptor antagonist [D-Arg0,Hyp3,Thi,(5,8)D-Phe7]BK, previously synthesized by Stewart's group, to reduce the flexibility of the peptides, thus forcing the peptide backbone and side chains to adopt specific orientations. Knowing that acylation of the N-terminus of several known B2 blockers with a variety of bulky groups has consistently improved their antagonistic potency in the rat blood pressure assay, the Acc substituted analogues were also synthesized in the N-acylated form with 1-adamantaneacetic acid (Aaa). The activity of eight new analogues was assayed in isolated rat uterus and in rat blood pressure tests. The results clearly demonstrated the importance of the position in the peptide chain into which the sterically restricted Acc residue was inserted. Meanwhile, Acc at positions 6 and 7 led to reduction of antagonistic qualities or even restored the agonism, respectively. Acc at position 8 enhanced antagonistic qualities in both tests. The Acc at position 8 of BK strongly reduced the agonistic potency. In most cases acylation of the N-terminus led either to enhancement of antagonistic potencies or to further decrease of agonistic potency. Our findings offer new possibilities for designing new potent and selective B2 blockers.     

The influence of smoking on plasma homocysteine and cysteine levels in passive and active smokers.

Total plasma homocysteine (tHcy) and cysteine (tCys) levels are associated with cardiovascular diseases. One of the determinants that influence their levels is cigarette smoking. The aim of this study was to determine the relationship between plasma levels of both amino acids and urinary cotinine concentration as a reliable biomarker of tobacco smoke exposure. One hundred and seventeen volunteers (61 women and 56 men) aged 19-60 years (mean 40.3 +/- 11.0) were included in the study. The study subjects were qualified into non-smokers, passive smokers and active smokers based upon the urinary cotinine concentration. In each particular group, plasma tHcy and tCys levels were measured and evaluated in the whole population and separately in women and men. Statistically insignificant differences in plasma tHcy and tCys levels in the whole group of passive smokers in comparison with non-smokers were observed (11.47 vs. 10.94 micromol/l, p=0.414, and 253.0 vs. 266.9 micromol/l, p=0.163, respectively). However, statistically significant differences in plasma tHcy levels (13.29 vs. 10.94 micromol/l, p=0.011) and in plasma tCys levels (218.2 vs. 266.9 micromol/l, p<0.001) were found in the whole group of active smokers compared with non-smokers. The Pearson's coefficient (r) for the correlation between plasma tHcy level and urinary cotinine concentration was r=0.630 (p<0.001) in the whole group of active smokers and r=0.480 (p=0.003) in the whole group of passive smokers. The correlation between plasma tCys level and urinary cotinine concentration in both study groups was insignificant. Similar results were obtained when calculated separately for men and women. The results suggest that cigarette smoking is a strong determinant of plasma tHcy level, but it is not a determinant of plasma tCys level.     

The association of ERAP1 and ERAP2 single nucleotide polymorphisms and their haplotypes with psoriasis vulgaris is dependent on the presence or absence of the HLA-C*06:02 allele and age at disease onset

The aim of this case-control study was to elucidate the role of some single nucleotide polymorphisms (SNPs) in the ERAP1 (rs27524, rs27044, rs30187, rs2287987 and rs26653) and ERAP2 (rs2248374) genes in predicting the risk for psoriasis vulgaris in the Polish population. ERAP1, ERAP2 and HLA-C*06:02 typing was done using the TaqMan SNP genotyping assays. We confirmed a strong association of the HLA-C*06:02 allele with early-onset psoriasis. In ERAP1, rs30187T increased the risk of psoriasis in HLA-C*06:02-positive patients, most strongly in late onset psoriasis, whereas it was protective when the HLA-C*06:02 allele was absent. We also found a protective effect of the ERAP2 rs2248374A allele and rs2248374AA genotype only in HLA-C*06:02 carriers, especially in the subgroup of patients with juvenile psoriasis. Analysis of combined haplotypes for ERAP1 and ERAP2 also revealed differences when the patients and controls were stratified by HLA-C*06:02. An ERAP1 haplotype known to possess high enzymatic activity was associated with psoriasis if HLA-C*06:02 was present and a functional ERAP2 allele was absent. In the absence of HLA-C*06:02, an ERAP1 haplotype of low activity was conducive to psoriasis if a functional ERAP2 allele was present, but the same ERAP1 haplotype was protective if the ERAP2 allele was defective.     

Diurnal variation in platelet inhibition by clopidogrel

Morning increase in the occurrence of myocardial infarction, stroke and sudden cardiac death is a well-recognized phenomenon, which is in line with a morning enhancement of platelet aggregation. We investigated whether platelet inhibition during clopidogrel and aspirin therapy varies during the day. Fifty-nine consecutive patients (45 men and 14 women) with first ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary interventions (pPCI) on dual antiplatelet therapy were prospectively enrolled into the study. Blood samples were collected 4 days after start of clopidogrel treatment at 6.00?a.m., 10.00?a.m., 2.00?p.m. and 7.00?p.m. Arachidonic acid and adenosine diphosphate (ADP)-induced platelet aggregation were assessed by impedance aggregometry. Platelet inhibition by clopidogrel was lowest in the midmorning: median ADP-induced platelet aggregation was 55%, 17% and 27% higher at 10.00?a.m. compared to 6.00?a.m., 2.00?p.m. and 7.00?p.m., respectively (p?相似文献