Circulating levels of interleukin-6, vascular endothelial growth factor, YKL-40, matrix metalloproteinase-3, and total aggrecan in spondyloarthritis patients during 3 years of treatment with TNFα inhibitors

The objectives of the study were to investigate short and long-term changes and relations to treatment response of plasma interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), YKL-40, matrix metalloproteinase-3 (MMP-3), and total aggrecan in patients with spondyloarthritis (SpA) treated with tumor necrosis factor-alpha (TNFα) inhibitors and to compare with levels in healthy subjects. Biomarkers were measured in an observational cohort of 49 SpA patients (ankylosing spondylitis, n = 32, and psoriatic arthritis, n = 17) initiating TNFα inhibitor therapy (infliximab, n = 38; etanercept, n = 8; and adalimumab, n = 3) and compared with levels in healthy subjects. Clinical parameters and biomarkers were measured at baseline, weeks 2, 6, and every 6–12 weeks for up to 3 years. Patients with co-morbidities (n = 4), missing baseline samples (n = 3), and adverse events (n = 5) were excluded. Patients with SpA had compared with healthy subjects elevated IL-6 (median 8.5 ng/l (range, 0.98–64) vs. 1.3 (0.33–26)), VEGF (105 ng/l (22–752) vs. 45 (12–351)), YKL-40 (74 μg/l (14–572) vs. 43 (20–184)), and MMP-3 (43 μg/l (9.1–401) vs. 16 (2.5–47), p ≤ 0.001), whereas total aggrecan was lower (662 μg/l (223–2,219) vs. 816 (399–2,190),p ≤ 0.001). Two weeks after first treatment, all biomarker levels changed towards normal levels (p ≤ 0.03) in clinical responders (n = 24), and persistent reductions over 3 years were found in IL-6, VEGF, YKL-40, and MMP-3. Only MMP-3 decreased (p ≤ 0.02) in non-responders (n = 13). The study demonstrated changes of plasma IL-6, VEGF, YKL-40, MMP-3, and total aggrecan and a potential value for monitoring disease activity and treatment response in SpA patients. Larger prospective studies are required to clarify clinical utility of these biomarkers.     

Fibrin clot structure in patients with end-stage renal disease

Fibrin clots with reduced permeability, increased clot stiffness and reduced fibrinolysis susceptibility may predispose to cardiovascular disease (CVD). Little is known, however, about the structure of fibrin clots in patients with end-stage renal disease (ESRD). These patients suffer from a high risk of CVD in addition to their chronic low-grade inflammation. Using permeability, compaction and turbidity studies in 22 ESRD patients and 24 healthy controls, fibrin clots made from patient plasma were found to be less permeable (p < 0.001), less compactable (p < 0.001), and less susceptible to fibrinolysis (p < 0.001) than clots from controls. The maximum rate of turbidity increase was also higher for the patients than controls (p < 0.001), and scanning electron microscopy revealed higher clot density of fibrin fibers in clots from patients than clots from controls (p < 0.001). Patients had higher plasma concentrations of fibrinogen, C-reactive protein and interleukin 6 than controls. These plasma markers of inflammation correlated significantly with most of the fibrin structure characteristics observed in the patients. In contrast, plasma markers of azothemia showed no such correlations. The results suggest that in ESRD patients fibrin clots are significantly different from healthy controls, and that the fibrin structure characteristics in the patients are associated primarily with the inflammatory plasma milieu rather than with level of azothemia.     

Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups

Background  

A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers.     

The outermost N‐terminal region of tapasin facilitates folding of major histocompatibility complex class I

Tapasin (Tpn) is an ER chaperone that is uniquely dedicated to MHC‐I biosynthesis. It binds MHC‐I molecules, integrates them into peptide‐loading complexes, and exerts quality control of the bound peptides; only when an “optimal peptide” is bound will the MHC‐I be released and exported to the cell surface for presentation to T cells. The exact mechanisms of Tpn quality control and the criteria for being an optimal peptide are still unknown. Here, we have generated a recombinant fragment of human Tpn, Tpn_1–87 (representing the 87 N‐terminal and ER‐luminal amino acids of the mature Tpn protein). Using a biochemical peptide–MHC‐I‐binding assay, recombinant Tpn_1–87 was found to specifically facilitate peptide‐dependent folding of HLA‐A*0201. Furthermore, we used Tpn_1–87 to generate a monoclonal antibody, αTpn_1–87/80, specific for natural human Tpn and capable of cellular staining of ER localized Tpn. Using overlapping peptides, the epitope of αTpn_1–87/80 was located to Tpn_40–44, which maps to a surface‐exposed loop on the Tpn structure. Together, these results demonstrate that the N‐terminal region of Tpn can be recombinantly expressed and adopt a structure, which at least partially resembles that of WT Tpn, and that this region of Tpn features chaperone activity facilitating peptide binding of MHC‐I.     

The pituitary-Leydig cell axis before and after orchiectomy in patients with stage I testicular cancer

Introduction

This study investigates the pituitary-Leydig cell axis in patients with stage I testicular germ cell cancer (TGCC) followed with surveillance only, in order to evaluate the risk of Leydig cell dysfunction one year after orchiectomy.

Patients and methods

A retrospective evaluation of reproductive hormones in patients with unilateral stage I TGCC (N = 72) without relapse diagnosed between 1990 and 2008. A group of healthy males (N = 706) served as controls.

Results

Before orchiectomy there were no significant differences in luteinizing hormone (LH) and testosterone (T) levels between human chorionic gonadotropin (hCG)-negative patients and controls, although 33% of the patients were outside the 97.5 percentile when using bivariate LH/T evaluation. At 1-year follow-up there was a significant increase in LH (ΔLH = 2.04 IU/L, p < 0.001), and 57% of the patients had an LH/T relation outside the 97.5 percentile.

Conclusion

Patients with stage I TGCC are at increased risk of having an LH/T relation outside the normal range one year after orchiectomy, suggesting insufficient Leydig-cell function. Whether a proportion of these patients will develop manifest hypogonadism and benefit from androgen therapy is yet to be clarified.     

Accessing the mental space-Spatial working memory processes for language and vision overlap in precuneus

The "overlapping systems" theory of language function argues that linguistic meaning construction crucially relies on contextual information provided by "nonlinguistic" cognitive systems, such as perception and memory. This study examines whether linguistic processing of spatial relations established by reading sentences call on the same posterior parietal neural system involved in processing spatial relations set up through visual input. Subjects read simple sentences, which presented two agents in relation to each other, and were subsequently asked to evaluate spatial (e.g., "Was he turned towards her?") and equally concrete nonspatial content (e.g., "Was he older than her?"). We found that recall of the spatial content relative to the nonspatial content resulted in higher BOLD response in a dorsoposterior network of brain regions, most significantly in precuneus, strikingly overlapping a network previously shown to be involved in recall of spatial aspects of images depicting similar scenarios. This supports a neurocognitive model of language function, where sentences establish meaning by interacting with the perceptual and working memory networks of the brain.     

Frontal eye fields involved in shifting frame of reference within working memory for scenes

Working memory (WM) evoked by linguistic cues for allocentric spatial and egocentric spatial aspects of a visual scene was investigated by correlating fMRI BOLD signal (or "activation") with performance on a spatial-relations task. Subjects indicated the relative positions of a person or object (referenced by the personal pronouns "he/she/it") in a previously shown image relative to either themselves (egocentric reference frame) or shifted to a reference frame anchored in another person or object in the image (allocentric reference frame), e.g. "Was he in front of you/her?" Good performers had both shorter response time and more correct responses than poor performers in both tasks. These behavioural variables were entered into a principal component analysis. The first component reflected generalised performance level. We found that the frontal eye fields (FEF), bilaterally, had a higher BOLD response during recall involving allocentric compared to egocentric spatial reference frames, and that this difference was larger in good performers than in poor performers as measured by the first behavioural principal component. The frontal eye fields may be used when subjects move their internal gaze during shifting reference frames in representational space. Analysis of actual eye movements in three subjects revealed no difference between egocentric and allocentric recall tasks where visual stimuli were also absent. Thus, the FEF machinery for directing eye movements may also be involved in changing reference frames within WM.