Systemically elevated Th1-, Th2- and Th17-associated chemokines in psoriasis vulgaris before and after ultraviolet B treatment.

Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation.

Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility.

NACHT leucine-rich repeat- and PYD-containing (NLRP)3 protein controls the inflammasome by regulating caspase-1 activity and interleukin (IL)-1ß processing. The contribution of IL-1ß in the pathogenesis of psoriasis is well recognized. Polymorphisms in NLRP3 and caspase recruitment domain-containing protein (CARD)8, a negative regulator of caspase-1 activity, have been associated with susceptibility to common inflammatory diseases, such as Crohn's disease and rheumatoid arthritis. To investigate the role for genetic variants in the NLRP3 inflammasome in psoriasis susceptibility. In a patient sample comprising 1988 individuals from 491 families and 1002 healthy controls, genotypes for four selected single-nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and CARD8 (one SNP) were determined by TaqMan(®) Allelic Discrimination. Using the transmission disequilibrium test (TDT), a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis was demonstrated (P = 0.015). Using logistic regression analysis in 741 patients with psoriasis and 1002 controls, the CARD8 rs2043211 genotype was significantly different in cases and controls in overall terms [OR 1.3 (1.1-1.5), P = 0.004] and for both genders. Our data support the hypothesis that the inflammasome plays a role in psoriasis susceptibility.

The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering.

The endogenous fibrinolytic system and the ability of the endothelium to release tissue-plasminogen activator (t-PA) play a pivotal role to protect humans from atherothrombotic events. We have recently reported that the decreased capacity for t-PA release in hypertension is restored with chronic blood pressure lowering. Thus, we explored if acute blood pressure lowering has the same effect. The capacity for acute t-PA release was investigated in the perfused-forearm model during stimulation by intra-arterial substance P 8 pmol/min in hypertensive subjects. The procedure was then repeated during acute blood pressure lowering (n = 9) induced by sodium nitroprusside (SNP) infusion or during placebo infusion (n = 3). SNP lowered mean arterial pressure from 108.6 (2.6) to 83.0 (2.6) (mean and SEM) mmHg (P < 0.001). Substance P induced significant increase in t-PA release during both high- and low-pressure conditions (P < 0.01, ANOVA). Peak t-PA release rate was 199 (77) and 167 (41) (mean and SEM) ng/min/l tissue, and accumulated t-PA release was 2,395 (750) and 2,394 (473) ng, during high- and low-pressure conditions, respectively. t-PA release and hemodynamic responses were almost identical during high- and low-pressure conditions (P = ns, for all). Acute blood pressure lowering does not restore stimulated t-PA release from the endothelium in hypertensive subjects. These findings are in contrast to previously described effects of chronic blood pressure treatment. Although data need to be confirmed in a larger study, they suggest that high blood pressure decreases the cellular t-PA pool rather than interferes with release mechanisms of the protein.

Suppression of endothelial t-PA expression by prolonged high laminar shear stress.

Primary hypertension is associated with an impaired capacity for acute release of endothelial tissue-type plasminogen activator (t-PA), which is an important local protective response to prevent thrombus extension. As hypertensive vascular remodeling potentially results in increased vascular wall shear stress, we investigated the impact of shear on regulation of t-PA. Cultured human endothelial cells were exposed to low (< or =1.5 dyn/cm(2)) or high (25 dyn/cm(2)) laminar shear stress for up to 48 h in two different experimental models. Using real-time RT-PCR and ELISA, shear stress was observed to time and magnitude-dependently suppress t-PA transcript and protein secretion to approximately 30% of basal levels. Mechanistic experiments revealed reduced nuclear protein binding to the t-PA specific CRE element (EMSA) and an almost completely abrogated shear response with pharmacologic JNK inhibition. We conclude that prolonged high laminar shear stress suppresses endothelial t-PA expression and may therefore contribute to the enhanced risk of arterial thrombosis in hypertensive disease.

Prevalence of back pain, its effect on functional ability and health-related quality of life in lower limb amputees secondary to trauma or tumour: a comparison across three levels of amputation.

BACKGROUND AND OBJECTIVES: The prevalence of back pain and its effect on function and health-related quality of life across three levels of lower limb amputation secondary to trauma or tumour was studied. STUDY DESIGN: Cross-sectional survey. METHODS: Forty-six lower limb amputees, aged 19-78 years, participated. The Roland Morris disability questionnaire (RMDQ) and the short form 36 health survey (SF-36) were used. RESULTS: Participants reported more back pain after amputation than before (p < 0.001). There was a significant association between back pain daily or several times/week and severe or moderate disability reporting on the RMDQ (p = 0.003). On the SF-36, the group as a whole scored significantly lower in health-related quality of life with regard to physical functioning, role physical, bodily pain, general health, social functioning and the physical component summary (PCS), and significantly higher in the mental component summary (MCS) compared to normative Swedish data. When all three levels of amputation were compared, no statistically significant differences were found in the RMDQ or SF-36 results. CONCLUSIONS: There was a high prevalence of back pain after amputation. Almost all participants having back pain daily or several times per week reported severe or moderate disability on the RMDQ. The group as a whole scored significantly lower for health-related quality of life in the PCS and significantly higher in the MCS compared to normative Swedish data. CLINICAL RELEVANCE: The high prevalence of back pain, and the significant association between back pain daily or several times per week and severe or moderate disability on the RMDQ, and the negative correlation between RMDQ and SF-36, may have clinical relevance with regard to rehabilitation and follow-up of lower limb amputation.