Changes in the population and functional properties of antigen-specific rosette-forming B cells in antigen-primed mice by administration of polyclonal B-cell activator

We have demonstrated that the number of rosette-forming cells (RFC) in the spleens of mice primed with sheep red blood cells (SRBC) was markedly decreased by administration of a polyclonal B-cell activator (PBA) such as the capsular polysaccharide of Klebsiella pneumoniae (CPS-K). Most of the RFC estimated were shown to be of B-cell type with Ig-receptors specific for SRBC. The precursor activity for the generation of anti-SRBC antibody-forming cells (AFC) (plaque-forming cells (PFC)) was closely associated with these RFC. Moreover, the precursor activity for the generation of AFC of RFC in the spleens of mice primed with SRBC and then treated with CPS-K (SRBC-primed and CPS-K-treated mice), as estimated by anti-SRBC PFC responsiveness in vitro to CPS-K, was much less than that of the same number of RFC in the spleens of SRBC-primed mice not treated with CPS-K especially at an early stage after injection of CPS-K. This low anti-SRBC PFC responsiveness of individual RFC in the spleens of SRBC-primed and CPS-K-treated mice resulted neither from an increase in some suppressing activity in the spleens of these mice nor from a relative increase in the number of RFC of non-B-cell type or non-SRBC-specific RFC. The percentage of the number of rosette-forming PFC in the total number of RFC seemed to be slightly increased in SRBC-primed and CPS-K-treated mice. However, this cannot totally explain the mechanism of the low responsiveness of RFC-fraction of spleen cells from SRBC-primed and CPS-K-treated mice. It has been concluded from these results that the signal mediated by PBA such as CPS-K acts on B cells bearing Ig-receptors specific for antigen (RFC) and changes a large number of them to the cells lacking Ig-receptors (non-RFC) and at least in part to the cells bearing Ig-receptors but showing low responsiveness to generate AFC following further stimulus (modified RFC).     

Hippocampal input to preoptic thermosensitive neurons in the rat

The effects of electrical stimulation of ventral subiculum (VSB) of the hippocampus of the thermosensitive neurons in the preoptic area were studied in urethane-anesthetized rats. VSB stimulation affected thermosensitive neurons more frequently (92.1%, 58 of 63) than thermally insensitive neurons (71.4%, 55 of 77). The majority of the VSB-responsive thermosensitive neurons (33 of 44 warm-units and 11 of 14 cold-units) were initially inhibited following stimulation. The result provides further support for the involvement of hippocampus in the central control of thermoregulation.     

Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.     

Evidence for a link between mechanical and electrical alternans in acutely ischaemic myocardium of anaesthetized dogs.

In order to examine the relation between mechanical alternans and associated electrical alternans during acute myocardial ischaemia, we determined the effect of a ventricular premature beat and calcium antagonists on mechanical and electrical alternans during acute coronary occlusion in anaesthetized dogs. Isometric contractions and unipolar electrocardiograms were recorded from ischaemic myocardium. During coronary occlusion, mechanical alternans was accompanied by electrical alternans, which was an alternate change in the ST segment elevation, i.e. the higher ST and the lower ST. Electrical alternans was frequently discordant and in some cases accompanied by discordant mechanical alternans. Both discordant electrical and mechanical alternans became concordant and were potentiated after the ventricular premature beat. In all cases, concordant mechanical alternans was accompanied by concordant electrical alternans and vice versa. In this situation, the higher and the lower ST corresponded to the larger and the smaller contractions respectively. Thus, a fixed correspondence was observed between mechanical and electrical alternans. A fixed correspondence was also observed between mechanical alternans and the variation in the time taken for repolarization of the monophasic action potential. Verapamil and diltiazem inhibited both electrical and mechanical alternans. The present results support the idea that a common mechanism, such as a beat-to-beat cycle of the transmembrane and intracellular movement of calcium ions, may play a role in the mechanisms of electrical and mechanical alternans.     

Feedback suppression of staphylococcal enterotoxin-stimulated T-lymphocyte proliferation by macrophages through inductive nitric oxide synthesis.

Staphylococcal enterotoxin A (SEA)- or SEB-stimulated T-lymphocyte proliferation was suppressed by the addition of high numbers of murine peritoneal macrophages or rat peritoneal or alveolar macrophages, whereas lower numbers of murine peritoneal macrophages enhanced the T-lymphocyte response. Suppression was associated with the increase of accumulation of nitrite, a product of nitric oxide, in the culture supernatants. This macrophage-mediated suppression was totally reversed by the addition of NG-monomethyl-L-arginine, a homolog of L-arginine, indicating that macrophage-mediated suppression of T-lymphocyte proliferation was mediated through the nitric oxide-synthesizing pathway activity. Macrophages in large numbers spontaneously produced nitric oxide in culture supernatant fluids. By the addition of autologous or allogeneic spleen cells but not thymocytes to SEA- or SEB-stimulated macrophage culture, nitric oxide production was greatly increased. When T lymphocytes in spleen cells were killed by antibody before addition to macrophage culture, nitric oxide production was diminished to the basal level. These results suggest that in addition to the action to support the process of T-lymphocyte activation by SEA or SEB, macrophages display a feedback regulatory action on the SEA- or SEB-stimulated T-cell proliferative response by releasing nitric oxide through interaction between macrophages and activated T lymphocytes.     

Suplatast tosilate inhibits thymus- and activation-regulated chemokine production by antigen-specific human Th2 cells

BACKGROUND: Suplatast tosilate is an anti-allergic agent that suppresses cytokine production by human Th2 cells. OBJECTIVE: We investigated the effects of suplatast tosilate on the production of thymus- and activation-regulated chemokine (TARC) by T cells from allergic patients with asthma. METHODS: Purified protein derivative (PPD)-specific Th1 cell lines and Dermatophagoides farinae (Der f)-specific Th2 cell lines were established from nine patients with house dust mite-allergic asthma. The effects of suplatast tosilate on mRNA expression of TARC and protein production of TARC from antigen-specific Th1 or Th2 cell lines were investigated after stimulation with relevant antigens or phytohemagglutinin (PHA). In addition, the effects of IL-4, IL-10, and IFN-gamma on TARC production by Der f-specific Th2 cell lines in the presence or absence of suplatast tosilate were studied. RESULTS: Although PPD-specific Th1 cell lines did not produce TARC after stimulation with PPD antigen or PHA, stimulation of Der f-specific Th2 cell lines with Der f antigen or PHA increased production of TARC. Suplatast tosilate significantly and dose-dependently inhibited production of TARC by Der f-specific Th2 cell lines stimulated with either Der f antigen (76.5% inhibition at 100 microg/mL, P < 0.01) or PHA (81.9% inhibition at 100 microg/mL, P < 0.01). TARC production by Der f-specific Th2 cell lines was significantly increased only by activation with IL-4 but not with IL-10 or IFN-gamma; this increase in TARC production was significantly inhibited by suplatast tosilate (97.5% inhibition at 100 microg/mL, P < 0.01). CONCLUSION: Suplatast tosilate inhibits TARC production by human Th2 cells. Therefore, this agent inhibits both Th2 cytokine and Th2 chemokine and may be a useful anti-allergic agent.     

Redox-linked signal transduction pathways for protein tyrosine kinase activation

The signaling for activation of protein tyrosine kinases (PTKs) is usually started by binding of ligands to cell-surface receptors. However, recent evidence suggests the presence of ligand binding-independent signaling pathways that are mediated by oxidative stress. Oxidation and reduction of protein cysteine sulfhydryl (SH) groups may work as a molecular switch to start or to stop the signaling. It is known that oxidation of cysteine SH groups on protein tyrosine phosphatases switches off the action of protein tyrosine phosphatases. This event may not, however, signal for initial autophosphorylation of previously unphosphorylated PTKs, whereas it certainly prevents dephosphorylation of once-phosphorylated PTKs. We have suggested new mechanisms for oxidative stress-mediated PTK activation. First, cell-surface glycosylphosphatidylinositol-anchoring proteins and a phosphoglycolipid/cholesterol-enriched membrane microdomain termed a "raft" can be the direct targets of oxidative stress for inducing their clustering through an S-S-bonded or S-X-S-bonded crosslinking of cell-surface proteins and subsequent activation of raft-associating Src family PTKs. Second, intracellular specific cysteine SH groups on PTK proteins can be another target of oxidative stress for inducing a conformational change necessary for initial activation of PTKs. A possible relationship between cell-surface and intracellular events is that the former frequently induces superoxide production as the second messenger for the latter.