Serum from Mycobacterium bovis BCG-infected mice that had been challenged with lipopolysaccharide (LPS) exhibited a marked ability to induce gamma interferon (IFN-y) in cultures of spleen cells of normal mice in the presence of interleukin-2 (IL-2). The inducing activity became detectable in the circulatory system about 90 min after LPS challenge, disappeared at around 5 h, and was observable upon 640x dilution of the serum. Addition of monoclonal anti-IL-2 receptor antibody to the culture inhibited the induction by the serum. The activity induced high levels of IFN-y even in nylon wool-nonadherent cells, while concanavalin A failed to do so. Serum from uninfected mice challenged with LPS contained no such activity. The molecular weight of the active substance, estimated by gel filtration, was about 70,000. There were pronounced differences among mouse strains in the activities of the sera prepared, which paralleled the amounts of IFN-y produced in vivo. However, the levels of IFN-y produced in whole spleen cells and in nylon wool-nonadherent cells from mice of various strains were the same when stimulated with competent serum. These results indicate the existence of an unidentified factor that induces IFN-y in cooperation with IL-2 in macrophage-depleted splenocytes. They also suggest that IFN-,y production in vivo is not genetically controlled at the lymphocyte level but, rather, at the level of synthesis of the unknown factor.

A protein factor which induces high levels of gamma interferon (IFN-y) in resting splenic nonadherent cells was isolated from the sera of mice with generalized inflammation caused by endotoxic shock. The factor was highly purified by ammonium sulfate precipitation followed by ion-exchange column chromatography on DEAE-Sepharose, molecular sieving on Ultrogel AcA 44, and hydrophobic column chromatography with phenyl-Sepharose. It was further purified to apparent homogeneity by polyacrylamide gel electrophoresis. It induced IFN-y production in a dose-dependent manner in the presence of interleukin-2, monoclonal anti-CD3 antibody (anti-CD3 MAb), or concanavalin A (ConA) in spleen cells deprived of plastic plate-and nylon wool-adherent cells. Anti-CD3 MAb induced the highest level of production of the three. The factor, interleukin-2, anti-CD3 MAb, or ConA alone induced a trace of or no detectable IFN-y in these cells. The factor also exhibited an accessory function during proliferation in these cells in the presence of a suboptimal dose of ConA. However, the factor failed to stimulate IFN-y production when staphylococcal enterotoxin A, a superantigenic T-cell mitogen, was employed. Treatment with pronase or heat abolished these activities. These studies confirm the existence of a soluble protein factor which is able to exhibit a novel accessory function in IFN-y production in resting T or natural killer cells. It will be of interest to compare this factor with the recently cloned human natural killer stimulatory factor (NKSF/IL-12).

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Extracellular zinc, which is released from hippocampal neurons in response to brain ischaemia, triggers morphological changes in microglia. Under ischaemic conditions, microglia exhibit two opposite activation states (M1 and M2 activation), which may be further regulated by the microenvironment. We examined the role of extracellular zinc on M1 activation of microglia. Pre-treatment of microglia with 30–60 μM ZnCl2 resulted in dose-dependent increases in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNFα) secretion when M1 activation was induced by lipopolysaccharide administration. In contrast, the cell-permeable zinc chelator TPEN, the radical scavenger Trolox, and the P2X7 receptor antagonist A438079 suppressed the effects of zinc pre-treatment on microglia. Furthermore, endogenous zinc release was induced by cerebral ischaemia–reperfusion, resulting in increased expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, without hippocampal neuronal cell loss, in addition to impairments in object recognition memory. However, these effects were suppressed by the zinc chelator CaEDTA. These findings suggest that extracellular zinc may prime microglia to enhance production of pro-inflammatory cytokines via P2X7 receptor activation followed by reactive oxygen species generation in response to stimuli that trigger M1 activation, and that these inflammatory processes may result in deficits in object recognition memory.

Our placebo-controlled study demonstrated that acotiamide significantly increased both gastric accommodation and gastric emptying in Japanese FD patients. Acotiamide also improved the patients' dyspeptic symptoms and anxiety score. Clinical Trials Registry no: UMIN000013544.

Angiotensin II in the CNS facilitates micturition reflex by inhibiting central GABAergic activity and activating the AT receptor/PLC/PKC/NADPH oxidase/superoxide anion pathway.

Background/AimsGastric motility abnormalities have been considered to be pathophysiological features of functional dyspepsia (FD) that are closely related to dyspepsia symptoms, especially postprandial distress syndrome (PDS). The aims of this study are to (1) investigate the prevalence of gastric motility disorders and (2) evaluate the association between gastric motility abnormalities and dyspeptic symptoms using gastric scintigraphy in the PDS type of FD. MethodsForty healthy subjects and 94 PDS type FD patients were enrolled in the study. The volunteers and patients ingested a radiolabeled (technetium-99m) solid test meal, and scintigraphic images were recorded. Gastric accommodation and emptying were assessed by scintigraphic imaging. The patients' dyspeptic symptoms were also explored using self-completed symptom questionnaires with 10 variables (4 scales, 0-3 points) at the same time. ResultsIn 94 Japanese FD patients, the prevalence of impaired gastric accommodation and delayed emptying were 14.9% (14/94) and 10.6% (10/94), respectively. Gastric motility abnormalities were seen in 25.5% (24/94) of FD patients. There was no association between gastric motility abnormalities and dyspeptic symptoms. ConclusionsGastric motility abnormalities were seen in 25.5% of Japanese PDS type FD patients. However, there was no association between gastric motility abnormalities and dyspeptic symptoms on gastric scintigraphy.

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