[Analysis of factors influencing lung function in patients with pneumoconiosis].

Objective: To analyze the influencing factors of lung function in pneumoconiosis patients, and to provide reference for clinical treatment. Methods: From July 2020 to December 2020, a questionnaire survey was conducted on pneumoconiosis patients in the jurisdiction by using the "Guangdong Province Occupational Disease Prevention and Control Institute" questionnaire, and the relevant items of patients were examined. The rate of counting data is expressed, and the measurement data is expressed by mean and standard deviation. Chi-square test was used for comparison between groups, trend chi-square test was used for trend analysis of ordered classified data. Multivariate analysis was carried out with binary logistic regression model. Results: A total of 1409 pneumoconiosis patients were enrolled. The abnormal rate of lung function in pneumoconiosis patients was 68.77%. The results of trend Chi-square test showed that the abnormal rate of lung function increased with the age of exposure to dust in different age groups (Chi Sqnare Trend=64.12、8.49、24.20, P<0.05) . In univariate analysis, there were statistical significance in different dust exposure age, working age, pneumoconiosis stage, complications and occupational pneumoconiosis diseases (P<0.05) . Multiple logistic regression results showed that age of exposure to dust, years of service, stage of pneumoconiosis and complications were the main influencing factors of lung function in pneumoconiosis patients (P<0.05) . Compared with patients aged 0-30 years, patients aged 50-70 years and older had a higher rate of abnormal lung function (OR=2.16, 95%CI: 1.12~4.16; OR=4.82, 95%CI: 2.05~11.35, all P<0.05) ; Compared with patients with 0~20 years of service, patients with 20~30 years of service and more than 30 years of service had a higher rate of abnormal lung function (OR=1.58, 95%CI: 1.10~2.25; OR=1.63, 95%CI: 1.28~2.40, P<0.05) ; Compared with stage Ⅰ patients, Stage Ⅱ and Stage Ⅲ patients had a higher rate of abnormal lung function (OR=1.62, 95%CI: 1.20~2.17; OR=2.23, 95%CI: 1.40~3.55, all P<0.05) ; Compared with patients without comorbidities, patients with comorbidities had a higher rate of abnormal lung function (OR=1.68, 95%CI: 1.20~2.38, P<0.05) . Conclusion: The factors such as age of exposure to dust, working age, stage of pneumoconiosis and complications may be the influencing factors of lung function in pneumoconiosis patients.

Intra-FCY1: a novel system to identify mutations that cause protein misfolding.

Protein misfolding is a common intracellular occurrence. Most mutations to coding sequences increase the propensity of the encoded protein to misfold. These misfolded molecules can have devastating effects on cells. Despite the importance of protein misfolding in human disease and protein evolution, there are fundamental questions that remain unanswered, such as, which mutations cause the most misfolding? These questions are difficult to answer partially because we lack high-throughput methods to compare the destabilizing effects of different mutations. Commonly used systems to assess the stability of mutant proteins in vivo often rely upon essential proteins as sensors, but misfolded proteins can disrupt the function of the essential protein enough to kill the cell. This makes it difficult to identify and compare mutations that cause protein misfolding using these systems. Here, we present a novel in vivo system named Intra-FCY1 that we use to identify mutations that cause misfolding of a model protein [yellow fluorescent protein (YFP)] in Saccharomyces cerevisiae. The Intra-FCY1 system utilizes two complementary fragments of the yeast cytosine deaminase Fcy1, a toxic protein, into which YFP is inserted. When YFP folds, the Fcy1 fragments associate together to reconstitute their function, conferring toxicity in media containing 5-fluorocytosine and hindering growth. But mutations that make YFP misfold abrogate Fcy1 toxicity, thus strains possessing misfolded YFP variants rise to high frequency in growth competition experiments. This makes such strains easier to study. The Intra-FCY1 system cancels localization of the protein of interest, thus can be applied to study the relative stability of mutant versions of diverse cellular proteins. Here, we confirm this method can identify novel mutations that cause misfolding, highlighting the potential for Intra-FCY1 to illuminate the relationship between protein sequence and stability.

Molecular understanding of heteronuclear active sites in heme-copper oxidases, nitric oxide reductases, and sulfite reductases through biomimetic modelling.

Heme-copper oxidases (HCO), nitric oxide reductases (NOR), and sulfite reductases (SiR) catalyze the multi-electron and multi-proton reductions of O2, NO, and SO32-, respectively. Each of these reactions is important to drive cellular energy production through respiratory metabolism and HCO, NOR, and SiR evolved to contain heteronuclear active sites containing heme/copper, heme/nonheme iron, and heme-[4Fe-4S] centers, respectively. The complexity of the structures and reactions of these native enzymes, along with their large sizes and/or membrane associations, make it challenging to fully understand the crucial structural features responsible for the catalytic properties of these active sites. In this review, we summarize progress that has been made to better understand these heteronuclear metalloenzymes at the molecular level though study of the native enzymes along with insights gained from biomimetic models comprising either small molecules or proteins. Further understanding the reaction selectivity of these enzymes is discussed through comparisons of their similar heteronuclear active sites, and we offer outlook for further investigations.

Safety and efficacy of metal stents for malignant colonic obstruction in patients treated with bevacizumab.

BACKGROUND AND AIMS: The aim of this study was to examine clinical outcomes and adverse events (AEs) of self-expandable metal stents (SEMSs) in the management of malignant colonic obstruction (MCO). METHODS: Patients with SEMSs for MCO treated at our institution from 2007 to 2016 were included. Clinical success was defined as successful oral intake after the procedure and technical success as stent deployment across the stricture in the desired location. RESULTS: Of 199 patients, the mean age was 58, 54% were men, and 99% had stage IV cancer. MCO etiology was colorectal cancer in 82% and extrinsic compression in 17%. Technical success was achieved in 99.5% and clinical success in 89%. The SEMSs were palliative in 97% and were a bridge to surgery in 4%. MCO occurred in the left side of the colon in 90%, transverse in 4.5%, and ascending colon in 5.5%. SEMSs were placed in curved segments in 30% and straight segments in 70%. Tandem SEMSs were required in 27 patients. Forty-six patients had 48 AEs (24%), including 2% periprocedure, 15% postprocedure, and 83% after 72 hours. Stent-related AEs (n = 25) included persistent obstruction (n = 14), occlusion (n = 10), and failure of expansion (n = 1). Procedural AEs (n = 23) included minor bleeding (n = 2), perforations (n = 4), abdominal pain (n = 12), stent migration (n = 4), and respiratory insufficiency (n = 1). Repeat procedures were performed in 21 of 46 patients. After SEMSs, 48 patients underwent surgery, including resection with primary anastomosis (n = 8), resection with definitive stoma (n = 18), and diverting stoma without resection (n = 19). Mean time to surgery after SEMS placement was 175 days. Postsurgical AEs occurred in those with resections (leak, 2; infection, 2). Of 104 receiving bevacizumab, 22% had AEs, including 1 perforation compared with 3 in the nonbevacizumab group (P = .549). Mean overall survival was 5.6 months. Extrinsic compression and curved strictures were associated with poor clinical success by univariate analysis and etiology (noncolonic with poor outcome) by multivariate analysis. CONCLUSIONS: SEMSs for MCO has high technical but suboptimal clinical success. Curved strictures and extrinsic compression are associated with poor outcomes. The perforation rate was not higher in the bevacizumab compared with the nonbevacizumab group, although this should be further validated in a larger population.

Microglial recruitment of IL-1ß-producing monocytes to brain endothelium causes stress-induced anxiety.

Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1ß (IL-1ß). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1+ neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1ß signaling by caspase-1KO specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1ß. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1ß-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1ß production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.

Pathophysiology of beta2-glycoprotein I in antiphospholipid syndrome.

Since beta(2)-glycoprotein I (beta(2)GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of beta(2)GPI and anti-beta(2)GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of beta(2)GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. beta(2)GPI's epitopes for anti-beta(2)GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-beta(2)GPI antibodies are pathogenic. The pathophysiologic role of beta(2)GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of beta(2)GPI, its metabolites and autoantibodies to beta(2)GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease.

Induction of muscle weakness by local inflammation: an experimental animal model.

OBJECTIVE AND DESIGN: The objective of this study was to characterize the response of skeletal muscle to a localized inflammation induced by the inflammatory agent casein. METHODS: An inflammatory agent, casein, was injected into the right hindlimb and saline was injected into the left hindlimb of normal adult mice, once daily for six consecutive days. Inflammatory response was monitored by immunohistochemical labeling of leukocytes. Muscle protein levels were determined by electrophoresis and muscle function was determined by isometric force measurements. RESULTS: Local inflammation was induced by casein in association with the accumulation of extensive neutrophils and macrophages in the soleus muscle. This local inflammation resulted in a shift in myosin heavy chain (MHC) isoform expression and a significant reduction in total MHC concentration in the soleus. Maximal twitch and tetanic forces were significantly reduced in the inflamed soleus. Contractile function in soleus was fully restored after two weeks of recovery, along with the restoration of protein concentration and the disappearance of inflammatory cells. CONCLUSION: This study establishes a unique and robust model in which mechanisms of local inflammation induced muscle protein degradation, reduction of contractile force, and subsequent recovery from this condition can be further studied.

A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells.

RNA interference constitutes a powerful tool for biological studies, but has also become one of the most challenging therapeutic strategies. However, small interfering RNA (siRNA)-based strategies suffer from their poor delivery and biodistribution. Cell-penetrating peptides (CPPs) have been shown to improve the intracellular delivery of various biologically active molecules into living cells and have more recently been applied to siRNA delivery. To improve cellular uptake of siRNA into challenging cell lines, we have designed a secondary amphipathic peptide (CADY) of 20 residues combining aromatic tryptophan and cationic arginine residues. CADY adopts a helical conformation within cell membranes, thereby exposing charged residues on one side, and Trp groups that favor cellular uptake on the other. We show that CADY forms stable complexes with siRNA, thereby increasing their stability and improving their delivery into a wide variety of cell lines, including suspension and primary cell lines. CADY-mediated delivery of subnanomolar concentrations of siRNA leads to significant knockdown of the target gene at both the mRNA and protein levels. Moreover, we demonstrate that CADY is not toxic and enters cells through a mechanism which is independent of the major endosomal pathway. Given its biological properties, we propose that CADY-based technology will have a significant effect on the development of fundamental and therapeutic siRNA-based applications.

Localized inflammation in peripheral tissue signals the CNS for sickness response in the absence of interleukin-1 and cyclooxygenase-2 in the blood and brain.

The CNS can be activated by both local and systemic inflammation, resulting in the manifestation of sickness symptoms. The pathways by which the CNS is activated under these two conditions, however, may differ. In this study, we injected casein into the peritoneal cavity (i.p.) or into an s.c. air pouch of mice to induce restricted local inflammation. Both routes of casein injection caused fever and reduced locomotor activity. These responses were not accompanied by the statistically significant induction of the inflammatory cytokine interleukin-1 (IL-1) in the blood and brain. Further, these responses were produced without the induction of brain cyclooxygenase-2 (COX-2), which has been implicated as an obligatory step in systemic inflammation-induced activation of the CNS. Induction of IL-1, interleukin-6 (IL-6), and COX-2, however, was found consistently at the sites of casein injection. The local inflammation-induced febrile and locomotor activity responses were blunted in animals deficient in functional Toll-like receptor 4 (TLR4), type I interleukin-1 receptor (IL-1R1), IL-6, or COX-2. Therefore, the observed febrile and locomotor activity effects appear to require local, but not central, IL-1, IL-6, and COX-2. These findings suggest that local inflammation can activate the CNS via pathways distinguishable from those mediating systemic inflammation-induced CNS activation.

Light controllable siRNAs regulate gene suppression and phenotypes in cells.

Small interfering RNA (siRNA) is widely recognized as a powerful tool for targeted gene silencing. However, siRNA gene silencing occurs during transfection, limiting its use is in kinetic studies, deciphering toxic and off-target effects and phenotypic assays requiring temporal, and/or spatial regulation. We developed a novel controllable siRNA (csiRNA) that is activated by light. A single photo removable group is coupled during oligonucleotide synthesis to the 5' end of the antisense strand of the siRNA, which blocks the siRNA's activity. A low dose of light activates the siRNA, independent of transfection resulting in knock down of specific target mRNAs and proteins (GAPDH, p53, survivin, hNuf2) without stimulating non-specific effects such as regulated protein kinase PKR and induction of the interferon response. We demonstrate survivin and hNuf2 csiRNAs temporally knockdown their mRNAs causing multinucleation and cell death by mitotic arrest, respectively. Furthermore, we demonstrate a dose-dependent light regulation of hNuf2 csiRNA activity and resulting phenotype. The light controllable siRNAs are introduced into cells using commercially available reagents including the MPG peptide based delivery system. The csiRNAs are comparable to standard siRNAs in their transfection efficiency and potency of gene silencing. This technology should be of interest for phenotypic assays such as cell survival, cell cycle regulation, and cell development.

Peripheral injection of lipopolysaccharide prevents brain recruitment of leukocytes induced by central injection of interleukin-1.

I.c.v. injection of interleukin-1beta induces infiltration of leukocytes into the brain. I.p. injection of bacterial endotoxin lipopolysaccharide induces the expression of interleukin-1 in the CNS without causing the entry of leukocytes into the brain. This suggests that during systemic inflammation trafficking of potentially damaging leukocytes into the CNS is inhibited. In this study, we investigated the effects of peripheral injection of lipopolysaccharide on brain leukocyte recruitment induced by i.c.v.-interleukin-1 in mice. I.c.v.-interleukin-1 induced widespread infiltration of leukocytes into the brain 16 h after the injection. Pretreatment with i.p.-lipopolysaccharide 2 h before the i.c.v. interleukin-1 injection completely blocked interleukin-1-induced leukocyte infiltration, whereas i.p.-LPS only attenuated the effect of interleukin-1 if it was given 12 h before i.c.v. interleukin-1 injection. I.p.-lipopolysaccharide given 24 h before i.c.v. interleukin-1 injection did not alter interleukin-1 induced leukocyte infiltration. I.c.v.-interleukin-1 induced expression of p- and e-selectins in brain vasculatures prior to the appearance of leukocytes in the brain parenchyma. Induction of p- and e-selectin was inhibited by the pretreatment of i.p.-lipopolysaccharide 2 h, but not 24 h, before i.c.v.-interleukin-1 injection. I.c.v.-interleukin-1-induced leukocyte infiltration was diminished in both e- and p- selectin knockout animals. These results suggest that systemic inflammation actively inhibits recruitment of leukocytes by CNS. Inhibition of the expression of p- and e-selectins is a mechanism by which peripheral inflammation regulate CNS leukocyte recruitment.

Photoperiod alters hypothalamic cytokine gene expression and sickness responses following immune challenge in female Siberian hamsters (Phodopus sungorus).

Rodents that live in changing environments display different immune responses mediated in part by photoperiod (day length) cues. Siberian hamsters maintained in winter-like (short) photoperiods display smaller physiological and behavioral responses to immune challenges as compared with hamsters housed in summer-like (long) photoperiods. We hypothesized that these different response patterns are attributable to altered cytokine production in the hypothalamus in response to photoperiod changes. Female hamsters were housed in long or short days for 10 weeks to induce photoperiodic alterations, then injected with either LPS (a bacterial endotoxin) or saline. Fever and food intake were assessed 3 h post-injection; hypothalami and blood were collected 3, 6, and 12 h post-injection. LPS induced lower fever and reduction in food intake responses in short-day hamsters as compared with long-day hamsters. Additionally, short-day hamsters reduced IL-1beta and Tnfalpha expression in the hypothalamus 6 h after LPS injection, as measured by quantitative RT-PCR. Plasma estradiol concentrations did not differ between long- and short-day hamsters. These data suggest that differences in cytokine production in the hypothalamus may underlie the photoperiod-induced differences in sickness responses, and that these changes are not mediated by estradiol.

Photoperiod alters the time course of brain cyclooxygenase-2 expression in Siberian hamsters.

Fever is initiated by activation of the arachidonic acid cascade and the biosynthesis of prostaglandins within the brain. Inducible cyclooxygenase (COX-2) is a rate-limiting enzyme in prostaglandin synthesis, and the number of blood vessels expressing COX-2 correlates with elevated body temperature following peripheral lipopolysaccharide (LPS). Despite its importance in host defense, fever is energetically expensive and we hypothesized that fever may be limited by available metabolic resources. During winter, when competing metabolic demands are constrained by low temperatures and food availability, it was predicted that fever duration would be reduced in seasonally breeding Siberian hamsters (Phodopus sungorus). We measured LPS-induced COX-2 expression in blood vessels of hamsters to test whether photoperiodic alterations in fever duration are centrally mediated, or whether they reflect changes in peripheral modulation of body temperature. Hamsters housed in long, 'summer-like' or short, 'winter-like' day lengths for 10 weeks were injected with LPS, and brains were collected 2, 4, or 8 h later. COX-2 expression was comparably increased in long- and short-day hamsters by 2 h and 4 h post-LPS; however, short-day hamsters exhibited significantly fewer COX-2-positive cells and blood vessels by 8 h post-LPS compared to long-day hamsters, corresponding with reduced fever duration in short-day hamsters. Cortisol concentrations increased more than two-fold in short-day compared to long-day hamsters by 4 h; this increase may have contributed to the decrease in COX-2 expression observed by 8 h in short days. We conclude that short photoperiods significantly altered the time course of central COX-2 protein expression in hamsters in a manner consistent with reduced fever duration.

Connecting cytokines and brain: a review of current issues.

Cytokines have been a multi-disciplinary research focus for over 2 decades. To date, there have been more than 15,000 articles published concerning the relationship between cytokines and the central nervous system (CNS). Over half of these articles have been published in the last 5 years. From such vast number of studies, two major topics emerge as the critical issues: 1) how do cytokines modulate the functions of the CNS? 2) what is the role of cytokines in the pathogenesis of neurological diseases? Thus far, it has been clearly established that cytokines can alter the functions of the CNS in specific manners, invoking CNS-controlled autonomic, neuroendocrine, and behavioral responses. Induced expression of cytokines has also been found in the CNS during brain injury and infection, contributing to the immunological processes at this "immunologically privileged" site. Furthermore, increasing evidence points to the potential involvement of cytokines in the induction and modulation of an array of neurological diseases ranging from Alzheimer's disease to chronic fatigue syndrome. Despite such progress, however, substantial obstacles remain for both the basic understanding and the potential clinical exploitation of how cytokines interact with CNS. In this review, we will attempt to synopsize the current theories and evidence regarding the answers to the above-mentioned critical questions. These issues will be reviewed not only in isolation, as most of the original reports focused on only one of the questions, but also in parallel such that inter-issue insights may be gained.

Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice.

Zinc status in patients with Type I diabetes is significantly lower than healthy controls. Whether zinc supplementation can prevent the onset of Type I diabetes is unknown. Recent studies have suggested that the generation of reactive oxygen species (ROS) is a cause of beta cell death leading to Type I diabetes. In addition, we found that activation of NFkappaB (a ROS-sensitive transcription factor that regulates immune responses) may be the key cellular process that bridges oxidative stress and the death of beta cells. Zinc is a known antioxidant in the immune system. Therefore, this study is designed to test whether an increase in dietary zinc can prevent the onset of Type I diabetes by blocking NFkappaB activation in the pancreas. The results show that high zinc intake significantly reduced the severity of Type I diabetes (based on hyperglycemia, insulin level, and islet morphology) in alloxan and streptozotocin-induced diabetic models. Zinc supplementation also inhibited NFkappaB activation and decreased the expression of inducible NO synthase, a downstream target gene of NFkappaB. It is concluded that zinc supplementation can significantly inhibit the development of Type I diabetes. The ability of zinc to modulate NFkappaB activation in the diabetogenic pathway may be the key mechanism for zinc's protective effect. Inhibition of the NFkappaB pathway may prove to be an important criterion for choosing nutritional strategies for Type I diabetes prevention.

Social stress increases the susceptibility to endotoxic shock.

The influence of social disruption stress (SDR) on the susceptibility to endotoxic shock was investigated. SDR was found to increase the mortality of mice when they were challenged with the bacterial endotoxin lipopolysaccharide (LPS). Histological examination of SDR animals after LPS injection revealed widespread disseminated intravascular coagulation in the brain and lung, extensive meningitis in the brain, severe hemorrhage in the lung, necrosis in the liver, and lymphoid hyperplasia in the spleen, indicating inflammatory organ damage. In situ hybridization histochemical analysis showed that the expression of the glucocorticoid receptor mRNA was down-regulated in the brain and spleen of SDR animals while the ratio of expression of AVP/CRH-the two adrenocorticotropic hormone secretagogue, increased. After LPS injection, the expression of pro-inflammatory cytokines, IL-1beta and TNF-alpha, was found significantly higher in the lung, liver, spleen, and brain of the SDR mice as compared with the LPS-injected home cage control animals. Taken together, these results show that SDR stress increases the susceptibility to endotoxic shock and suggest that the development of glucocorticoid resistance and increased production of pro-inflammatory cytokines are the mechanisms for this behavior-induced susceptibility to endotoxic shock.

Spatiotemporal induction patterns of cytokine and related immune signal molecule mRNAs in response to intrastriatal injection of lipopolysaccharide.

The brain's response to a direct immune challenge was examined by in situ hybridization histochemistry. Lipopolysaccharide (bacterial endotoxin) injected acutely into rat striatum induced mRNA expression for inhibitory factor kappaBalpha, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, IL-12 p35, inducible nitric oxide synthase, IL-1 receptor antagonist, and the type 1 IL-1 receptor. Expression patterns were evaluated at select time points ranging from 15 min to 3 days post-injection. Rats injected with vehicle alone were used to control for mechanical effects. Following lipopolysaccharide administration, a wave of mRNA induction within brain parenchyma radiated outward from the injection site, generally peaking in intensity at the 16-h time point. The individual profiles of cytokine mRNA induction patterns reveal that the brain's immune response to local inflammatory stimulation is quite elaborate and in many ways resembles the progression of cytokine induction customary of localized inflammation in peripheral tissues.

Induction of IkappaBalpha mRNA expression in the brain by glucocorticoids: a negative feedback mechanism for immune-to-brain signaling.

Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induces brain mRNA expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha and the cytokine-responsive immediate-early gene IkappaBalpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of IkappaBalpha mRNA in the brain after peripheral LPS injection is caused by the feedback action of glucocorticoids has not been determined. In this study, we examined the mRNA expression of IkappaBalpha and IL-1beta in the rat brain by in situ hybridization histochemistry. Injection of the glucocorticoid agonist dexamethasone induced IkappaBalpha mRNA expression in the brain in a pattern identical to that of LPS injection. LPS but not dexamethasone also induced IL-1beta mRNA expression. Pretreatment with dexamethasone 30 min before LPS injection enhanced the expression of IkappaBalpha mRNA in the brain in a dose-dependent manner. Immobilization of rats for 2 hr (which raises glucocorticoid levels) also induced IkappaBalpha mRNA expression without inducing the expression of IL-1beta. Brain IkappaBalpha expression induced by peripheral LPS injection was attenuated by pretreatment of rats with the glucocorticoid antagonist RU-486. Finally, increased expression of IL-1beta mRNA in the brain was observed at 4 hr after peripheral LPS injection in adrenalectomized rats compared with sham-operated rats. These results reveal that in the brain glucocorticoids selectively induce IkappaBalpha mRNA expression, which serves as a negative feedback mechanism for peripheral LPS-induced synthesis of proinflammatory cytokines. Such an inhibitory control mechanism may be important for preventing prolonged expression of proinflammatory cytokines in the brain after peripheral immune challenge.

Imageability and word recognition in the left and right visual fields: a signal detection analysis.

Identifying the information processing constraints that determine whether or not imagery moderates visual field asymmetries is essential for constructing a dynamic model of hemispheric interaction during language processing. In this investigation, we manipulated the global experimental context in which imageable and nonimageable words were presented by contrasting mixed and blocked word lists using a lateralized lexical decision task. Signal detection analyses were employed to assess whether global stimulus context and imageability differentially affect word discriminability (d prime) and response bias (log beta) across visual fields. Both discriminability and response bias varied with imageability and stimulus context, but to a comparable extent across visual fields. This suggests that both hemispheres are sensitive to the global context in which words are presented, and can adjust processing based not only on semantic characteristics of the words themselves, but also on the variability of items in the stimulus environment.