Dissociated linkage of cytokine-inducing activity and cytotoxicity to different domains of listeriolysin O from Listeria monocytogenes

Listeriolysin O (LLO), a cholesterol-binding cytolysin of Listeria monocytogenes, exhibits cytokine-inducing and cytolytic activities. Because the cytolytic activity was abolished by cholesterol treatment but the cytokine-inducing activity was not, these activities appeared to be linked to different domains of the LLO molecule. In this study, we constructed recombinant full-length LLO (rLLO529) and various truncated derivatives and examined their cytolytic, cholesterol-binding, and gamma interferon (IFN-gamma)-inducing activities. rLLO529 exhibited both IFN-gamma-inducing and cytolytic activities. Four truncated rLLOs possessing different C termini, which did not exert either cytolytic or cholesterol-binding activity, stimulated IFN-gamma production in normal spleen cells. However, a truncated rLLO corresponding to domain 4 (rLLO416-529) did not exhibit IFN-gamma-inducing activity, whereas it did bind to immobilized cholesterol. In addition, though the hemolysis induced by rLLO529 was inhibited by rLLO416-529, such inhibition was not detected upon rLLO529-induced IFN-gamma production. These data indicated that domain 4 was responsible for binding of LLO to membrane cholesterol followed by oligomerization and pore formation by the entire LLO molecule. In contrast, the other part of LLO, corresponding to domain 1-3, was essential for IFN-gamma-inducing activity. These findings implied a novel aspect of the function of LLO as a bacterial modulin.     

Low-dose maintenance steroid treatment could reduce the relapse rate in patients with type 1 autoimmune pancreatitis: a long-term Japanese multicenter analysis of 510 patients

Journal of Gastroenterology - The effect of maintenance steroid treatment (MST) in reducing the risk of relapse in patients with autoimmune pancreatitis (AIP) remains under debate. The aim of this...     

EUS elastography combined with the strain ratio of tissue elasticity for diagnosis of solid pancreatic masses

Background

Recently, the usefulness of endoscopic ultrasound (EUS) elastography has been reported for the diagnosis of pancreatic lesions. In the present study, we retrospectively assessed EUS elastography as a diagnostic tool by evaluating tissue elasticity distribution and elasticity semiquantification, using the strain ratio (SR) of tissue elasticity, in patients with pancreatic masses.

Methods

One hundred and nine patients who underwent EUS elastography between September 2006 and May 2009 were retrospectively evaluated. The final diagnosis was chronic pancreatitis (CP) in 20 patients [6 with non-mass-forming pancreatitis, 7 with mass-forming pancreatitis (MFP), and 7 with autoimmune pancreatitis (AIP)], pancreatic cancer (PC) in 72, pancreatic neuroendocrine tumor (PNET) in 9, and normal pancreas in 8. The tissue elasticity distribution calculation was performed in real time, and the results were represented in color in fundamental B-mode imaging. In addition, we performed quantification using the SR (non-mass area/mass area).

Results

Elastography for all PC patients showed intense blue coloration, indicating malignant lesions. In contrast, MFP presented with a mixed coloration pattern of green, yellow, and low-intensity blue. Normal controls showed an even distribution of green to red. The mean SR was 23.66?±?12.65 for MFP and 39.08?±?20.54 for PC (P?Conclusions Endoscopic ultrasound elastography is a promising diagnostic tool for defining the tissue characteristics of pancreatic masses. In addition, semiquantitative analysis of elasticity using the SR may allow the differentiation of MFP from PC.     

Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo

Global brain state dynamics regulate plasticity in local cortical circuits, but the underlying cellular and molecular mechanisms are unclear. Here, we demonstrate that astrocyte Ca(2+) signaling provides a critical bridge between cholinergic activation, associated with attention and vigilance states, and somatosensory plasticity in mouse barrel cortex in vivo. We investigated first whether a combined stimulation of mouse whiskers and the nucleus basalis of Meynert (NBM), the principal source of cholinergic innervation to the cortex, leads to enhanced whisker-evoked local field potential. This plasticity is dependent on muscarinic acetylcholine receptors (mAChR) and N-methyl-d-aspartic acid receptors (NMDARs). During the induction of this synaptic plasticity, we find that astrocytic [Ca(2+)](i) is pronouncedly elevated, which is blocked by mAChR antagonists. The elevation of astrocytic [Ca(2+)](i) is crucial in this type of synaptic plasticity, as the plasticity could not be induced in inositol-1,4,5-trisphosphate receptor type 2 knock-out (IP(3)R2-KO) mice, in which astrocytic [Ca(2+)](i) surges are diminished. Moreover, NBM stimulation led to a significant increase in the extracellular concentration of the NMDAR coagonist d-serine in wild-type mice when compared to IP(3)R2-KO mice. Finally, plasticity in IP(3)R2-KO mice could be rescued by externally supplying d-serine. Our data present coherent lines of in vivo evidence for astrocytic involvement in cortical plasticity. These findings suggest an unexpected role of astrocytes as a gate for cholinergic plasticity in the cortex.