The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis

Objective. To analyze the effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis (AS). Methods. Three hundred sixty- three white British AS patients were studied; 149 were carefully assessed for a range of clinical manifestations, and disease severity was assessed using a structured questionnaire. Limited HLA class I typing and complete HLA-DR typing were performed using DNA-based methods. HLA data from 13,634 healthy white British bone marrow donors were used for comparison. Results. A significant association between DR1 and AS was found, independent of HLA-B27 (overall odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8, P = 0.02; relative risk [RR] 2.7, 95% CI 1.5-4.8, P = 6 x 10-4 among homozygotes; RR 2.1, 95% CI 1.5-2.8, P = 5 x 10-6 among heterozygotes). A large but weakly significant association between DR8 and AS was noted, particularly among DR8 homozygotes (RR 6.8, 95% CI 1.6-29.2, P = 0.01 among homozygotes; RR 1.6, 95% CI 1.0-2.7, P = 0.07 among heterozygotes). A negative association with DR12 (OR 0.22, 95% CI 0.09-0.5, P = 0.001) was noted. HLA-DR7 was associated with younger age at onset of disease (mean age at onset 18 years for DR7-positive patients and 23 years for DR7-negative patients; Z score 3.21, P = 0.001). No other HLA class I or class H associations with disease severity or with different clinical manifestations of AS were found. Conclusion. The results of this study suggest that HLA-DR genes may have a weak effect on susceptibility to AS independent of HLA-B27, but do not support suggestions that they affect disease severity or different clinical manifestations.

The effect of HLA-DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α-tumor necrosis factor haplotype

Objective. HLA-DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA-DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes. Methods. We identified 274 HLA-DRB1*04-positive cases of RA and 271 HLA-DRB1*04-positive population controls. Each subject was typed for 6 single-nucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin a (LTA). LTA-TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program. Results. Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04. The LTA-TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA-TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3-0.8], P = 0.007), while in those with DRB1*0404, the opposite effect was observed (P = 0.007). Conclusion. These findings suggest that the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to RA.

The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood

Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bone size and mineralization was examined in 819 unrelated British Caucasian children (n = 429 boys) aged 9 years. Height, weight, pubertal status (where available), total-body and spinal bone area, bone mineral content (BMC), BMD, and area-adjusted BMC (aBMC) were assessed. Dual-energy X-ray absorptiometry (DXA)-gene associations were assessed by linear regression, with adjustment for age, gender, pubertal status, and body size parameters. There were 140, 79, 12, and 2 girls who achieved Tanner stages I-IV, respectively, and 179 and 32 boys who achieved Tanner stages I and II, respectively. The rs2306862 (N740N) coding polymorphism in exon 10 of the LRP5 gene was associated with spinal BMD and aBMC (each P = 0.01) and total-body BMD and aBMC (P = 0.04 and 0.03, respectively). Adjusting for pubertal stage strengthened associations between this polymorphism and spinal BMD and aBMC (P = 0.01 and 0.002, respectively). Individuals homozygous for the T allele had greater spinal BMD and aBMC scores than those homozygous for the C allele. A dose effect was apparent as the mean spinal BMD and aBMC of heterozygous TC individuals were intermediate between those of their TT and CC counterparts. The N740N polymorphism in exon 10 of LRP5 was associated with spinal BMD and aBMC in pre- and early pubertal children. These results indicate that LRP5 influences volumetric bone density in childhood, possibly through effects on trabecular bone formation.

Effect of upstream traffic signal on capacity of a downstream TWSC intersection

This paper investigates the platoon dispersion model that is part of the 2010 Highway Capacity Manual that is used for forecasting downstream traffic flows for analyzing both signalized and TWSC intersections. The paper focuses on the effect of platoon dispersion on the proportion of time blocked, the conflicting flow rate, and the capacity flow rate for the major street left turn movement at a TWSC intersection. The existing HCM 2010 methodology shows little effect on conflicting flow or capacity for various distances downstream from the signalized intersection. Two methods are suggested for computing the conflicting flow and capacity of minor stream movements at the TWSC intersection that have more desirable properties than the existing HCM method. Further, if the existing HCM method is retained, the results suggest that the upstream signals model be dropped from the HCM method for TWSC intersections.

Pilot study: Effect of age on visual acuity with defocus and astigmatism

PURPOSE: To investigate how distance visual acuity in the presence of defocus and astigmatism is affected by age and whether aberration properties of young and older eyes can explain any differences. METHODS: Participants were 12 young adults (mean [±SD] age, 23 [±2] years) and 10 older adults (mean [±SD] age, 57 [±4] years). Cyclopleged right eyes were used with 4-mm effective pupil sizes. Thirteen blur conditions were used by adding five spherical lens conditions (-1.00 diopters [D], -0.50 D, plano/0.00 D, +0.50 D, and +1.00 D) and adding two cross-cylindrical lenses (+0.50 DS/-1.00 DC and +1.00 D/-2.00 DC, or 0.50 D and 1.00 D astigmatism) at four negative cylinder axes (45, 90, 135, and 180 degrees). Targets were single lines of high-contrast letters based on the Bailey-Lovie chart. Successively smaller lines were read until a participant could no longer read any of the letters correctly. Aberrations were measured with a COAS-HD Hartmann-Shack aberrometer. RESULTS: There were no significant differences between the two age groups. We estimated that 70 to 80 participants per group would be needed to show significant effects of the trend of greater visual acuity loss for the young group. Visual acuity loss for astigmatism was twice that for defocus of the same magnitude of blur strength (0.33 logMAR [logarithm of the minimum angle of resolution]/D compared with 0.18 logMAR/D), contrary to the geometric prediction of similar loss. CONCLUSIONS: Any age-related differences in visual acuity in the presence of defocus and astigmatism were swamped by interparticipant variation.

Hydrogen-bonded supramolecular polymers as self-healing hydrogels: Effect of a bulky adamantyl substituent in the ureido-pyrimidinone monomer

In an attempt to generate supramolecular assemblies able to function as self-healing hydrogels, a novel ureido-pyrimidinone (UPy) monomer, 2-(N ′-methacryloyloxyethylureido)-6-(1-adamantyl)-4[1H]-pyrimidinone, was synthesized and then copolymerized with N,N-dimethylacrylamide at four different feed compositions, using a solution of lithium chloride in N,N-dimethylacetamide as the polymerization medium. The assembling process in the resulting copolymers is based on crosslinking through the reversible quadruple hydrogen bonding between side-chain UPy modules. The adamantyl substituent was introduced in order to create a “hydrophobic pocket” that may protect the hydrogen bonds against the disruptive effect of water molecules. Upon hydration to equilibrium, all copolymers generated typical hydrogels when their concentration in the hydrated system was at least 15%. The small-deformation rheometry showed that all hydrated copolymers were hydrogels that maintained a solid-like behavior, and that their extrusion through a syringe needle did not affect significantly this behavior, suggesting a self-healing capacity in these materials. An application as injectable substitutes for the eye's vitreous humor was proposed

Expression of high mobility group box 1 in inflamed dental pulp and its chemotactic effect on dental pulp cells

High mobility group box 1 protein (HMGB1) is a chromatin protein which can be released extracellularly, eliciting a pro-inflammatory response and promoting tissue repair process. This study aimed to examine the expression and distribution of HMGB1 and its receptor RAGE in inflamed dental pulp tissues, and to assess its effects on proliferation, migration and cytoskeleton of cultured human dental pulp cells (DPCs). Our data demonstrated that cytoplasmic expression of HMGB1 was observed in inflamed pulp tissues, while HMGB1 expression was confined in the nuclei in healthy dental pulp. The mRNA expression of HMGB1 and RAGE were significantly increased in inflamed pulps. In in vitro cultured DPCs, expression of HMGB1 in both protein and mRNA level was up-regulated after treated with lipopolysaccharide (LPS). Exogenous HMGB1 enhanced DPCs migration in a dose-dependent manner and induced the reorganization of f-actin in DPCs. Our results suggests that HMGB1 are not only involved in the process of dental pulp inflammation, but also play an important role in the recruitment of dental pulp stem cells, promoting pulp repair and regeneration.

The effect of thermal radiation on the natural convection boundary layer flow over a wavy horizontal surface

In this article, natural convection boundary layer flow is investigated over a semi-infinite horizontal wavy surface. Such an irregular (wavy) surface is used to exchange heat with an external radiating fluid which obeys Rosseland diffusion approximation. The boundary layer equations are cast into dimensionless form by introducing appropriate scaling. Primitive variable formulations (PVF) and stream function formulations (SFF) are independently used to transform the boundary layer equations into convenient form. The equations obtained from the former formulations are integrated numerically via implicit finite difference iterative scheme whereas equations obtained from lateral formulations are simulated through Keller-box scheme. To validate the results, solutions produced by above two methods are compared graphically. The main parameters: thermal radiation parameter and amplitude of the wavy surface are discussed categorically in terms of shear stress and rate of heat transfer. It is found that wavy surface increases heat transfer rate compared to the smooth wall. Thus optimum heat transfer is accomplished when irregular surface is considered. It is also established that high amplitude of the wavy surface in the boundary layer leads to separation of fluid from the plate.