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Acute haemorrhagic lesions in the oesophagus, stomach and duodenum (‘stress ulcers’) occur relatively often under clinical conditions and are always dangerous to the patient (lethality rate about 70%). Since conservative and surgical treatment are without significant success up to now, prevention by adaptation to stressors or by administration of drugs seems mandatory. An improved technique for producing acute gastric lesions in rats by immobilization and a new method for assessing this disease in the animals is presented in this communication. High precision is obtained within a single experimental series especially from day to day. Since histamine was suggested to be involved in the pathogenesis of stress ulcer disease, (+)-catechin, a rather specific inhibitor of specific histidine decarboxylase from rat stomach, was tested in immobilized rats. It prevented the formation of acute gastric lesions by 80% in seven series of experiments lasting for half a year. Since the drug has low toxicity in man, it is recommended for clinical trials.

Disease states such as arthritis may interact with the kinetics of β-blockers. Acebutolol (AC) is a chiral β-blocker which is available as a racemate. The beneficial properties of AC, however, is attributed mainly to theS-(+)-enantiomer. The disposition of AC enantiomers and their active, chiral metabolites, diacetolol (DC) were examined after oral administration to healthy and adjuvant-induced arthritic (AA) female Sprague-Dawley rats. Arthritis was induced by tail base injection ofMycobacterium butyricum. Swelling of hind and forepaws were apparent in 10–16 days in AA but not controls. Control and AA rats were sacrificed at 0.5, 1, 2, 4, 6 and 8 h after a 25 mg/kg oral AC dose and blood was collected (n=6). Significant three to tenfold increases in the initial plasma concentrations (0.5–2h) of AC were observed in AA. Enantiomers were equally affected, thus ACS∶R ratio was not changed. Higher plasma concentrations of the metabolite were only significant at 2h. The ratio of DC∶AC, however, was unaffected by AA. The DCS∶R ratio was significantly decreased at 0.5 and 1 h in AA. The limited protein binding of AC (10%) was neither stereoselective nor affected by AA. Reduced intrinsic clearance in AA may be responsible for these observations.

Alpha 1 antitrypsin (α1-AT) is the major plasma protease inhibitor. Radioiodinated α1-AT binds to human lymphocytes. The binding is fast and reversible, and the cells can be saturated with a maximum of approximately 1.2×106 molecules of α1-AT per lymphocyte. The receptor for α1-AT is a surface-associated protease. Adition of α1-AT completely inhibits cell surface proteolytic activity. Furthermore α1-AT decreases3H-thymidine incorporation into lymphocytes stimulated by B or T cell mitogens or by allogeneic cells. Since α1-AT was shown to be produced by activated monocytes and to bind to lymphocytes, it is likely to represent a mediator of monocyte-lymphocyte interactions.

Recent findings indicate that chemical stimulation of the porcine skin with capsaicin evokes a flare response similar to that observed in man. The aim of the present study was to elucidate whether chemical stimulation of cutaneous capsaicin-sensitive nerve endings with mustard oil produces neurogenic inflammatory reactions in the pig. The application of mustard oil onto the abdominal skin of domestic pigs resulted in a pronounced flare response. After a previous intravenous injection of a solution of Evans blue, the skin area in contact with the irritant turned dark blue, indicating a marked extravasation of albumin. Quantitative estimation of the dye content of the skin supported this conclusion. The technique of vascular labelling revealed a delicate network of small subepidermal blood vessels in histological preparations after the application of mustard oil following a previous intravenous injection of colloidal silver. Labelled blood vessels were not noted outside the treated area. The present results show that mustard oil produces a strong cutaneous inflammatory response in the pig, and suggest that the porcine skin provides a valuable model for study of the significance of capsaicinsensitive sensory nerves in vascular and other cutaneous reactions.

Toll-like receptors (TLR’s) are critical receptors that promote innate immune responses to pathogen-associated molecular patterns. Activation of TLR’s leads to production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α. This study investigates whether peripheral blood monocyte expression of TLR’s is disturbed in patients with chronic hepatitis C and whether levels of expression of these molecules are significantly correlated with hepatitis C virus (HCV) genotype, viral load, hepatic necroinflammatory activity, histological stage and circulating TNF-α concentrations. In 18 non-cirrhotic patients with biopsy-proven, virologically-confirmed chronic hepatitis C and 32 controls, we measured expression of TLR2 and TLR4 on peripheral blood monocytes. HCV genotype, viral load, serum alanine aminotransferase (ALT) levels, histological stage of disease and circulating TNF-α and endotoxin levels were also determined. Peripheral blood monocyte expression of TLR2 and TLR4 were significantly increased in patients with chronic hepatitis C compared to controls, irrespective of HCV genotype or histological stage of disease. Circulating levels of TNF-α were also significantly increased in patients with chronic hepatitis C. In both the overall study cohort and patients with chronic hepatitis C, monocyte expression of TLR2, but not of TLR4, correlated significantly with serum TNF-α levels. In patients with chronic hepatitis C, monocyte expression of TLR2, but not of TLR4, also correlated significantly with serum ALT levels. Expression of TLR’s was not significantly correlated with viral load. Up-regulation of peripheral blood monocyte expression of TLR2 and TLR4 occurs in patients with chronic hepatitis C. Increased monocyte expression of TLR2, but not of TLR4, correlates significantly with both increased circulating TNF-α levels and hepatic necroinflammatory activity in this disorder.

This study was designed to determine the effects of different calcium concentrations on the perfused isolated guinea-pig heart preparation subjected to cardiac anaphylaxis. Following challenge both physiological and biochemical effects were determined on hearts from guinea-pigs previously sensitized to ovalbumin. Perfusion media containing either 1, 2.54 or 5 mM of calcium was used. In comparison to nonsensitized controls challenged to ovalbumin, challenged sensitized hearts (CSH) perfused with 1 mM Ca2+ showed an initial increase indF/dt, a prolonged rise in H.R. and depressed coronary flow. Raising the calcium concentration to either 2.54 or 5 mM in CSH preparations resulted in a marked increase in the release of lactate dehydrogenase (LDH) into the coronary effluent and depressed coronary flow. Perfusing CSH preparations with increasingly higher calcium concentrations more often produced severe tachyarrhythmias and fibrillation. The highest level of histamine released into the coronary effluent occurred immediately following challenge and then declined exponentially over the next 20 min. Both challenge and the administration of histamine induced an immediate but transient increase in H.R., a rise indF/dt, and LDH release. The infusion of histamine produced an increase in coronary flow, but on porcine tubular coronary arterial segments only a direct constricting effect was obtained. The prior administration of cimetidine (10−5 M) attenuated the rise in LDH anddF/dt in CSH and nonsensitized preparations infused with histamine (3 μg). However, although cimetidine did not affect the decreased coronary flow in CSH preparations, it initially attenuated the rise in coronary flow in preparations infused with histamine. These results suggest that calcium enhances the liklihood of tachyarrhythmias in cardiac anaphylaxis. The release of LDH in histamine-infused preparations and those CSH preparations perfused with 2.54 and 5 mM calcium-containing medias also suggests the possibility that calcium enhances the damaging effects on the myocardial cell in cardiac anaphylaxis.

Endothelial protein C receptor (EPCR) plays a pivotal role in augmenting Protein C activation by the thrombin–thrombomodulin complex. The activity of EPCR is markedly changed by ectodomain cleavage and release as the soluble protein (sEPCR). The EPCR shedding is mediated by the tumor necrosis factor-α converting enzyme (TACE). Epi-sesamin (ESM), from the roots of Asarum siebodlii, is known to exhibit anti-allergic and anti-fungal activities. However, little is known about the effects of ESM on EPCR shedding. We investigated this issue by monitoring the effects of ESM on phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and cecal ligation and puncture (CLP)-mediated EPCR shedding. Data showed that ESM induced potent inhibition of PMA, TNF-α, IL-1β, and CLP-induced EPCR shedding, likely through suppression of TACE expression. In addition, treatment with ESM resulted in a reduction of PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). Given these results, ESM should be viewed as a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of EPCR shedding.