The sigma(B)-dependent promoter in front of the rsbV gene of Bacillus subtilis is induced approximately 5-fold in response to (1) the addition of 4% ethanol, (2) carbon starvation, and (3) phosphorous starvation. Binding sites for the global carbon and nitrogen regulators, CcpA and TnrA, were mutated, and the consequences of their loss and that of CcpA or TnrA were studied using rsbV-lacZ fusions. These responses proved to be dependent on CcpA, TnrA, and their putative binding sites upstream of the promoter. Induction in response to glucose limitation was largely abolished by loss of CcpA or the upstream region, while induction in response to phosphorous limitation was largely abolished only by the upstream mutations. The results suggest that CcpA directly influences the carbon starvation response and that both proteins exert indirect effects on all three stress responses. The integrity of the DNA sequence is important for all three responses.

PURPOSE: The role of fibroblast growth factor (FGF) in orbital fibroblasts (OFs) is rarely known. In this study, we investigated the effect of FGF10 on fibrosis and the inflammation mechanism of Graves orbitopathy (GO). METHODS: Orbital tissue from GO (n = 15) and non-GO (n = 15) was obtained for this study. The mRNA and protein expression levels of FGF10 and FGF receptor 2b (FGFR2b) in orbital tissue were determined by real-time polymerase chain reaction, western blot analysis, and confocal microscopy. The effects of FGF10 on transforming growth factor (TGF)-β1 induced fibrotic proteins and interleukin (IL)-1β- or tumor necrosis factor (TNF)-α- induced inflammatory proteins were investigated using recombinant human (rh) FGF10 and small interfering (si) RNA transfection against FGF10. RESULTS: FGF10 and FGFR2b mRNA expression levels were significantly lower in GO orbital tissues than in non-GO orbital tissues (p = 0.009 and 0.005, respectively). Immunostaining of FGF10 in orbital adipose tissues showed differences in FGF10 expression between GO and control samples. Immunostaining of FGF10 was very weak in the orbital tissues of GO patients. TGF-β1-induced fibronectin, collagen Iα, α-smooth muscle actin protein expression in GO OFs was attenuated by rhFGF10 treatment and increased by knockdown of FGF10 via siFGF10 transfection. Similarly, IL-1β- or TNF-α-induced IL-6, IL-8, and cyclooxygenase-2 protein production in GO OFs was either blocked by rhFGF10 treatment or further upregulated by inhibition of FGF10 via siFGF10 transfection. CONCLUSIONS: Our data demonstrate that FGF10 has beneficial effects on the inflammatory and fibrotic mechanisms of GO in primary cultured OFs, providing new insights into GO pathology and the discovery of FGF10 as a promising novel therapeutic application for the treatment of GO.

The oxidation hypothesis of atherosclerosis proposes that oxidized LDL is a major causative factor in the development of atherosclerosis. Although this hypothesis has received strong mechanistic support and many animal studies demonstrated profound atheroprotective effects of antioxidants, which reduce LDL oxidation, the results of human clinical trials with antioxidants were mainly negative, except in selected groups of patients with clearly increased systemic oxidative stress. We propose that even if reducing lipoprotein oxidation in humans might be difficult to achieve, deeper understanding of mechanisms by which oxidized LDL promotes atherosclerosis and targeting these specific mechanisms will offer novel approaches to treatment of cardiovascular disease. In this review article, we focus on oxidized cholesteryl esters (OxCE), which are a major component of minimally and extensively oxidized LDL and of human atherosclerotic lesions. OxCE and OxCE-protein covalent adducts induce profound biological effects. Among these effects, OxCE activate macrophages via toll-like receptor-4 (TLR4) and spleen tyrosine kinase and induce macropinocytosis resulting in lipid accumulation, generation of reactive oxygen species and secretion of inflammatory cytokines. Specific inhibition of OxCE-induced TLR4 activation, as well as blocking other inflammatory effects of OxCE, may offer novel treatments of atherosclerosis and cardiovascular disease. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder.

Strongly Interacting Massive Particles (SIMPs) have recently been proposed as light thermal dark matter relics. Here we consider an explicit realization of the SIMP mechanism in the form of vector SIMPs arising from an SU(2)X hidden gauge theory, where the accidental custodial symmetry protects the stability of the dark matter. We propose several ways of equilibrating the dark and visible sectors in this setup. In particular, we show that a light dark Higgs portal can maintain thermal equilibrium between the two sectors, as can a massive dark vector portal with its generalized Chern-Simons couplings to the vector SIMPs, all while remaining consistent with experimental constraints.

We report 3 patients who presented with abnormal pancreatic contents that were initially nondiagnostic but were eventually found to have urate crystal deposition consistent with pancreatic tophaceous gout. Our first case involved an ICU patient who had fever of unknown origin and refractory pancreatic pseudocyst. The other 2 patients presented with abdominal pain associated with a pancreatic mass which mimicked malignancy. After further investigation, we were able to identify pancreatic tophaceous gout as the diagnosis. Initiation of therapy led to resolution of pancreatitis in the first patient and resolution of abdominal pain and decrease in size of a pancreatic mass in the other 2 patients. The recognition of clinical gout involving the pancreas has important implications in the evaluation and care of these patients who are at high risk for tophaceous gout. In addition, the importance of specimen preparation that preserves crystals for viewing is discussed.

Abstract Background Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE. Methods SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits. Results Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC. Conclusion These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.

Cholesterol is a structural component of cellular membranes, which is transported from liver to peripheral cells in the form of cholesterol esters (CE), residing in the hydrophobic core of low-density lipoprotein. Oxidized CE (OxCE) is often found in plasma and in atherosclerotic lesions of subjects with cardiovascular disease. Our earlier studies have demonstrated that OxCE activates inflammatory responses in macrophages via toll-like receptor-4 (TLR4). Here we demonstrate that cholesterol binds to myeloid differentiation-2 (MD-2), a TLR4 ancillary molecule, which is a binding receptor for bacterial lipopolysaccharide (LPS) and is indispensable for LPS-induced TLR4 dimerization and signaling. Cholesterol binding to MD-2 was competed by LPS and by OxCE-modified BSA. Furthermore, soluble MD-2 in human plasma and MD-2 in mouse atherosclerotic lesions carried cholesterol, the finding supporting the biological significance of MD-2 cholesterol binding. These results help understand the molecular basis of TLR4 activation by OxCE and mechanisms of chronic inflammation in atherosclerosis.

Background

Musculoskeletal ultrasound (MSUS) and the multi-biomarker disease activity (MBDA) score are outcome measures that may aid in the management of rheumatoid arthritis (RA) patients. This study evaluated tofacitinib response by MSUS/MBDA scores and assessed whether baseline MSUS/MBDA scores or their early changes predict later clinical response.

Methods

Twenty-five RA patients treated with tofacitinib were assessed at baseline, 2, 6 and 12-weeks. Power doppler (PDUS) and gray scale (GSUS) ultrasound scores, MBDA score, clinical disease activity index (CDAI), and disease activity score (DAS28) were obtained. Pearson correlations and multiple linear regression models were used to evaluate associations and identify predictors of response to therapy.

Results

MSUS, MBDA scores, CDAI, and DAS28 improved significantly over 12 weeks (p < 0.0001). Baseline MSUS and MBDA score correlated with each other, and with 12-week changes in CDAI/DAS28 (r = 0.45-0.62, p < 0.05), except for GSUS with DAS28. Two-week change in MSUS correlated significantly with 12-week changes in CDAI/DAS28 (r = 0.42-0.57, p < 0.05), except for early change in PDUS with 12-week change in CDAI. Regression analysis demonstrated significant independent associations between baseline PDUS/MBDA score and 6-week change in CDAI/DAS28, with adjustment for baseline CDAI/DAS28 (all p < 0.05); and between baseline MBDA scores and 12-week change in DAS28 (p = 0.03).

Conclusions

RA patients treated with tofacitinib for 12 weeks demonstrated improvement by clinical, imaging, and biomarker end-points. Baseline PDUS and MBDA score were predictive of CDAI and DAS28 responses. This is the first study to evaluate early measurements of MSUS and MBDA score as predictors of clinical response in RA patients treated with tofacitinib.

Trial registration

ClinicalTrials.gov NCT02321930 (registered 12/22/2014).