A modified formalin test in mice was investigated. The pain response curve induced by 0.5% formalin was biphasic, having 2 peaks, from 0 to 5 min (first phase) and from 15 to 20 min (second phase). A low concentration of formalin was used, allowing the effects of weak analgesics to be detected. Centrally acting drugs such as narcotics inhibited both phases equally. Peripherally acting drugs such as aspirin, oxyphenbutazone, hydrocortisone and dexamethasone only inhibited the second phase. Aminopyrine and mefenamic acid which acted on both central and peripheral sites inhibited both phases, but the second phase was inhibited by lower doses. Thus, this method enables one to easily distinguish the site of action of analgesics. Furthermore, pain response in the first phase was inhibited by capsaicin-treated desensitization and Des-Arg9-(Leu8)-bradykinin (bradykinin inhibitor). The second phase was inhibited by compound 48/80 pretreatment, indomethacin and bradykinin inhibitor. Therefore, it is suggested that substance P and bradykinin participate in the manifestation of the first phase response, and histamine, serotonin, prostaglandin and bradykinin are involved in the second phase. These results indicate that the first and second phase responses induced by formalin have distinct characteristic properties, and it is a very useful method for examining pain, nociception and its modulation by pharmacological or other means.
A high potassium concentration ([K+]o) in brain tissue impedes neuronal activity, as observed in spreading cortical depression. Experimental studies were performed on mice and rats to determine the role of changes of [K+]o in cerebral concussion. In the first experiment, a 600 gm-cm impact was delivered to the vertex of the mouse skull. This impact induced arrest of spontaneous movement for 465 +/- 55.9 seconds (mean +/- SD), accompanied by apnea, bradycardia, and low-voltage electroencephalographic recordings (EEG). The injury was also frequently followed immediately by epilepsy. This impact induced an increase of cortical [K+]o from the control level of 4.1 +/- 1.8 mM to 20-30 mM, with gradual recovery within 30 minutes to the control level. In the second experiment, an impact of 9000 gm-cm was delivered to the midline parieto-occipital area of the rat and produced concussion-like phenomena similar to those elicited in mice. This level of trauma induced a significant increase of cortical [K+]o from the control level of 4.2 +/- 0.8 mM to 20-50 mM in all of the rats, and also a significant increase of brain-stem [K+]o from 3.9 +/- 0.6 to 20-30 mM in 73% of the rats. In these latter rats, the impact also induced apnea and a transient elevation of blood pressure, and resulted in low-voltage EEG recordings. In 23% of the rats in which [K+]o changes in the brain stem were not significant, the impact caused a transient reduction of blood pressure. The present study disclosed that an increase of [K+]o in the cerebral cortex and also in the brain stem is an important element in the phenomenon of concussion.
Previous randomized controlled trials (RCTs) and meta-analyses evaluated the efficacy and safety of adjunctive corticosteroids for community-acquired pneumonia (CAP). However, the results from them had large discrepancies. The eligibility criteria for the current meta-analysis were original RCTs written in English as a full article that evaluated adjunctive systemic corticosteroids adding on antibiotic therapy targeting typical and/or atypical pathogen for treating hospitalized human CAP cases. Four investigators independently searched for eligible articles through PubMed, Embase, and Cochrane databases. Random model was used. The heterogeneity among original studies and subgroups was evaluated with the I2 statistics. Of 54 articles that met the preliminary criteria, we found 10 eligible RCTs comprising 1780 cases. Our analyses revealed following pooled values by corticosteroids. OR for all-cause death: 0.80 (95% confidence interval (95% CI) 0.53–1.21) from all studies; 0.41 (95% CI 0.19–0.90) from severe-case subgroup; 0.21 (95% CI 0.0–0.74) from intensive care unit (ICU) subgroup. Length of ICU stay: −1.30 days (95% CI (−3.04)−0.44). Length of hospital stay: −0.98 days (95% CI (−1.26)–(−0.71)). Length to clinical stability: −1.16 days (95% CI (−1.73)–(−0.58)). Serious complications do not seem to largely increase by steroids. In conclusion, adjunctive systemic corticosteroids for hospitalized patients with CAP seems preferred strategies.
These data indicate that sigma-receptors may play an important role in the mechanism of injury both in cortex and striatum after 2 hours of transient focal ischemia in rats. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may influence the progression of injury in ischemic border regions.
The SNP rs3792323 in MAPKAPK3 associates with the outcome of IFN therapy in patients with HCV genotype 1b. Our functional analyses indicate that MAPKAPK3 inhibits IFN-alfa-induced antiviral activity.
We recently found that fibronectin (FN) had a functional site [YTIYVIAL sequence in the heparin-binding domain 2 (Hep 2)] that was capable of suppressing the integrin-mediated cell adhesion to extracellular matrix. However, our results also indicated that this anti-adhesive site seemed to be usually buried within the Hep 2 domain structure because of its hydrophobic nature, raising a question as to the physiological significance of the cryptic anti-adhesive activity of FN. The present study demonstrates that the cryptic anti-adhesive activity can be exposed through the physiological processes. A 30-kDa chymotryptic FN fragment derived from Hep 2 domain (Hep 2 fragment), which had no effect on adhesion of MSV-transformed nonproducer 3T3 cell line (KN(7)8) to FN, expressed the anti-adhesive activity after treatment with 6 M urea. Light scattering and circular dichroism measurements showed that the urea treatment induced the conformational change of the Hep 2 fragment from a more compact form to an unfolded one. Incubation of the Hep 2 fragment with heparin also induced similar conformational changes and expression of anti-adhesive activity. Additionally, both the urea and heparin treatments made the Hep 2 fragment and intact FN much more accessible to the polyclonal antibody (alphaIII14A), with a recognition site near the anti-adhesive site of FN. Specific cleavage of either the Hep 2 fragment or intact FN by matrix metalloproteinase 2 (MMP-2) released a 10-kDa fragment with the anti-adhesive activity, which was shown to have the exposed anti-adhesive site on the amino-terminal region. Thus, the cryptic anti-adhesive activity of FN can be expressed upon conformational change and proteolytic cleavage of Hep 2 domain.
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