Oligonucleotide-targeting periostin ameliorates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-4 years after diagnosis. It is the most frequent form of a group of interstitial pneumonias of unknown etiology. Current available therapies prevent deterioration of lung function but no therapy has shown to improve survival. Periostin is a matricellular protein of the fasciclin 1 family. There is increased deposition of periostin in lung fibrotic tissues. Here we evaluated whether small interfering RNA or antisense oligonucleotide against periostin inhibits lung fibrosis by direct administration into the lung by intranasal route. Pulmonary fibrosis was induced with bleomycin and RNA therapeutics was administered during both acute and chronic phases of the disease. The levels of periostin and transforming growth factor-ß1 in airway fluid and lung tissue, the deposition of collagen in lung tissue and the lung fibrosis score were significantly reduced in mice treated with siRNA and antisense against periostin compared to control mice. These findings suggest that direct administration of siRNA or antisense oligonucleotides against periostin into the lungs is a promising alternative therapeutic approach for the management of pulmonary fibrosis.

Circulating fibrocytes correlate with the asthma control test score.

BACKGROUND: Bronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting ß2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. METHODS: There were 20 patients with asthma and seven healthy controls. The number of CD45(+)Collagen I(+) circulating fibrocytes was assessed in the peripheral blood by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short-acting ß2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. CONCLUSION: The results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma.

Spontaneous chemiluminescence production, lipid peroxidation, and covalent binding in rat hepatocytes exposed to acetaminophen.

Spontaneous chemiluminescence associated with the cell injury was observed in the isolated rat hepatocyte suspension during acetaminophen (APAP) metabolism, indicating the occurrence of oxidative stress. APAP apparently affected the hepatocytes in various manners. APAP, at low concentrations (1-2 mM), damaged the hepatocytes due to lipid peroxidation provoked during APAP metabolism, while at high concentrations (5-50 mM), APAP protected the hepatocytes due to a chemical antioxidant effect of the unmetabolized APAP that remained in the medium because of the saturation of APAP metabolism. The covalent binding of APAP to the hepatocytes increased with APAP concentration up to 50 mM without loss of cell viability. When an overdose of APAP was administered to rats, the APAP plasma concentration was around 1-3 mM, which corresponded to the concentration range where lipid peroxidation occurred in the isolated hepatocytes. Thus, it seems likely that lipid peroxidation contributes to the APAP-induced hepatotoxicity in the early stage of the toxic process.

Percutaneous transluminal coronary angioplasty for morphologic left anterior descending artery lesion in a patient with dextrocardia. A case report and literature review.

A case report of percutaneous transluminal coronary angioplasty (PTCA) to treat coronary atherosclerotic lesions in a patient with dextrocardia associated with situs inversus totalis is presented. The patient was a sixty-two-year-old man who was admitted with a diagnosis of congestive heart failure. Cardiac catheterization was performed. Left ventriculography showed mild hypokinesis in segments 2 and 3 with ejection fraction of 63%. Coronary arteriography revealed 74% stenosis in segment 7 of the left anterior descending (LAD) artery. PTCA for this lesion was performed. Successful dilation was achieved with the residual stenosis in the LAD reduced from 74% to 34%. Performance of PTCA in patients with dextrocardia is extremely rare, and only 8 cases have been reported to date. However, by visualizing the procedure as a mirror image and choosing a guide catheter that permits good engagement, it appears possible to perform it like ordinary PTCA.

Unusual right coronary artery runoff with right and left main coronary artery aneurysm. A case report.

A rare case of unusual right coronary artery runoff with right and left main coronary artery aneurysm is presented. The discussion is mainly from the etiologic point of view.

Excitation and inhibition via adenosine receptors of the twitch response to electrical stimulation in isolated guinea pig ileum.

The effects of adenosine and its related compounds on the cholinergic twitch response were examined in electrically stimulated guinea pig ileum. Adenosine (3 x 10(-7)-10(-5) M) and an adenosine A1-receptor agonist N6-cyclohexyladenosine (CHA, 10(-8)-10(-6) M) suppressed the twitch. Conversely, the A2a-receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N- ethylcarboxamidoadenosine (CGS 21680, 10(-9)-10(-7) M) potentiated the twitch in half the preparations examined. The A1-antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), which per se did not affect the twitch, recovered the attenuated twitch caused by CHA (10(-7) M) or adenosine (10(-6) M) and converted it into a potentiated twitch. These results suggest the presence of adenosine A1- and A2a-receptors coupled negatively and positively, respectively, to acetylcholine release in the preparation.

Effects of the adenosine A1-receptor antagonist on defecation, small intestinal propulsion and gastric emptying in rats.

We examined the effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and (R)-7,8-dihydro-8-ethyl-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1 -i]purin- 5(4H)-one (KF20274), selective adenosine A1-receptor antagonists, on the gastrointestinal propulsion in rats, as compared with those of the laxative bisacodyl. DPCPX and KF20274 (p.o.) dose-dependently increased the fecal pellet output, whereas these drugs at the dose that increased defecation did not affect small intestinal propulsion or gastric emptying. Bisacodyl increased defecation and slowed gastric emptying without any influence on small intestinal propulsion. Bisacodyl, but not DPCPX or KF20274, induced diarrhea at the dose inducing defecation. The present results suggest that the adenosine A1-receptor antagonist selectively enhances the lower gastrointestinal propulsion, resulting in defecation without diarrhea.

[Two cases of peripartum cardiomyopathy].

Two cases of peripartum cardiomyopathy, a rare type of dilated cardiomyopathy, are reported. A 36-year-old woman developed congestive heart failure 1 month after delivering her third child. Cardiac catheterization revealed diffuse hypokinesis of the left ventricle and an ejection fraction of 28%. The second study, 20 months later, demonstrated an ejection fraction of 46%. Endomyocardial biopsy showed mild interstitial edema. A 42-year-old woman developed toxemia during pregnancy. She delivered her second child at 38 weeks of gestation. Two weeks later, she developed congestive heart failure. Cardiac catheterization demonstrated diffuse hypokinesis of left ventricle with an ejection fraction of 40%. Endomyocardial biopsy revealed dense fibrosis. Follow-up angiography performed 8 months later showed similar findings with an ejection fraction of 34%. These two cases suggest the importance of evaluation of endomyocardial biopsy to determine the degree of interstitial fibrosis that may reflect the prognosis for patients with peripartum cardiomyopathy confirmed by measurements of ejection fraction.

Possible physiological role of endogenous adenosine in defecation in rats.

Evacuated feces after intraperitoneal administration of selective adenosine receptor antagonists were evaluated in rats. The selective adenosine A1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (100-300 micrograms/kg i.p.) and (R)-7,8-dihydro-8-ethyl-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1 -i]purin- 5(4H)-one (KF20274) (30-300 micrograms/kg i.p.), significantly increased defecation, whereas the selective adenosine A2 receptor antagonist 4-amino-8-chloro-1-phenyl[1,2,4]triazolo[4,3-a]quinoxaline (CP-66,713) failed to cause a significant increase at up to 10 mg/kg i.p. The defecation caused by DPCPX (100 micrograms/kg) was markedly alleviated by (2S)-N6-(2-endo-norbornyl)adenosine ((S)-ENBA) (30-300 micrograms/kg s.c.), a selective adenosine A1 receptor agonist, but not influenced by 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) (30-1000 micrograms/kg s.c.), a selective adenosine A2 receptor agonist. These results suggest that endogenous adenosine plays a physiological role in sustained inhibition of defecation via adenosine A1 receptors.

Effects of KW-5805, a new antiulcer agent, on experimental gastric and duodenal ulcers, gastric mucosal lesions by necrotizing agents and gastric acid secretion.

Effects of KW-5805, a new antiulcer agent, on various experimental ulcers, necrotizing agent-induced gastric lesions and gastric acid secretion in rats were compared with those of pirenzepine and cimetidine. KW-5805 showed antiulcer activities against experimental gastric and duodenal ulcers (ED50 = 1.2-10.0 mg/kg, p.o.). KW-5805 effectively inhibited gastric lesions induced by various necrotizing agents (ED50 = 4.5-39.8 mg/kg, p.o.). In addition, the cytoprotective effect of KW-5805 was not affected by indomethacin, but reserved by N-ethylmaleimide. These antiulcer and cytoprotective effects of KW-5805 were more potent than those of pirenzepine and cimetidine. In pylorus-ligated rats, intraduodenal KW-5805 administration at 30 mg/kg showed a weak antisecretory effect, which was 3-10 times less potent than those of pirenzepine and cimetidine. In rats with acute gastric fistula, intravenous injection of KW-5805 reduced methacholine-stimulated gastric acid secretion at doses of 10 and 30 mg/kg and inhibited tetragastrin-induced acid secretion at 30 mg/kg. These results indicate that KW-5805 has potent and broad antiulcer properties, which are probably exerted by its potent cytoprotective effect in addition to its antisecretory effect.

Susceptibility to adenosine agonists of giant migrating contraction induced by glycerol enema in anesthetized rats.

The present study examined whether adenosine agonists influence the occurrence of giant migrating contractions (GMCs) induced by glycerol enema (65%, 2 ml/kg) in rats. Catheter pressure transducers were used to measure the colonic luminal manometric alterations. The adenosine A1 agonists (2S)-N6-(2-endo-norbornyl)adenosine ((S)-ENBA) (10 micrograms/kg, i.v.) and N6-cyclohexyladenosine (30 micrograms/kg, i.v.) abolished the GMCs, whereas the adenosine A2 agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) (30-300 micrograms/kg, i.v.) failed to influence the GMCs. The suppressive action of (S)-ENBA on the GMCs was entirely counteracted by the peripheral adenosine antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg, i.v.). The present observations suggest that the adenosine A1 agonist suppresses the GMCs via peripheral adenosine receptors.

Enhancement by KW-5092, a novel gastroprokinetic agent, of the gastrointestinal motor activity in dogs.

KW-5092 ([1-[2-[[[5-(piperidinomethyl)-2- furanyl]methyl]amino]ethyl]-2-imidazolidinylidene) propanedinitrile fumarate) is a novel gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory activity and acetylcholine (ACh) release facilitatory activity. The present study examined the effects of KW-5092 on gastrointestinal (GI) motor activity in dogs. In anesthetized dogs, KW-5092 at 0.03 to 1 mg/kg, i.v. dose-dependently enhanced the gastric antral and the colonic motor activity. Neostigmine, an AChE inhibitor, enhanced the motor activity at 0.03 and 0.1 mg/kg, i.v. Ranitidine, a histamine H2-receptor antagonist with AChE inhibitory activity and ACh release facilitatory activity, enhanced the motor activity but decreased blood pressure at 1 to 10 mg/kg, i.v. In conscious dogs, KW-5092 at 0.03 to 1 mg/kg, i.v. or 1 to 10 mg/kg, p.o. dose-dependently enhanced the gastric antral, duodenal, ileal and the colonic motor activities. Neostigmine at 0.1 mg/kg, i.v. or 3 mg/kg, p.o. enhanced the duodenal, ileal and colonic motor activities, but induced excitement, slavering, vomiting and diarrhea. Ranitidine at 3 mg/kg, i.v. enhanced the gastric antral and colonic motor activities, but induced collapse or akinesia. The present results suggest that KW-5092 enhances the GI motor activity in a wide range from the gastric antrum to the colon and does not induce behavioral and cardiovascular side effects. KW-5092 may be a useful drug for the treatment of GI motility dysfunctions.

Colonic giant migrating contractions induced by glycerol enema in anesthetized rats.

Colonic motility was measured with three catheter pressure transducers that were inserted into the descending colon at the distance of 4 cm, 6 cm and 8 cm from the anal verge in anesthetized rats. Colonic infusion of glycerol (65%, 2 ml/kg) induced large phasic pressure changes with high amplitude and long duration. Some of the pressure changes propagated over all the three recording sites, appearing to be equivalent to giant migrating contractions. These glycerol-induced large propulsions were abolished by lidocaine (5%, 2 ml/kg, intracolon), hexamethonium (10 mg/kg, i.v.) or clonidine (30 micrograms/kg, i.v.); and they were almost entirely suppressed by atropine (3 mg/kg, i.v.), suggesting the principal involvement of the cholinergic neural pathway.

Coronary artery ectasia--a case report and literature review.

A case report of coronary artery ectasia is presented. A middle-aged man was admitted with sudden onset of respiratory arrest which is a rather rare occurrence. Relevant articles are reviewed, and discussion mainly concerns the etiologic and pathophysiologic point of view.

Monoclonal antibodies against human platelet membrane glycoprotein IIIa and collagen-induced platelet activation.

Two monoclonal antibodies against human platelet membrane glycoprotein IIIa (GPIIIa) were obtained. One monoclonal antibody, designated as 1B1, was found to inhibit both collagen-induced platelet aggregation and release reactions. This antibody also inhibited the binding of 125I-labeled collagen to human platelets. On the other hand, the other antibody, designated as B10, had no effect on platelet activation induced by a number of physiological stimulants including collagen. Direct binding studies involving 125I-labeled 1B1 or B10 demonstrated that the binding sites for these antibodies on unstimulated platelets have dissociation constants of 4.2 and 14.0 nM, respectively. The binding of 125I-labeled 1B1 or B10 to platelets was not inhibited by the other antibody. Purified 1B1 and B10 were covalently coupled to Affi-Gel and then proteolytic fragments of GPIIIa were applied to the Affi-Gel immunoadsorbent columns. Of the several proteolytic fragments, the 56 kilodaltons (kDa) fragment obtained on digestion with V8 protease bound to both of the columns. The 69 and 55 kDa fragments obtained with BrCN bound to only the 1B1 Affi-Gel column, while the 63 kDa fragment obtained with chymotrypsin only bound to the B10-Affi-Gel column. Based on the partial amino acid sequences of these fragments and the amino acid sequence of GPIIIa (C. A. Fitzgerald, B. Steiner, S. C. Rall, Jr., S. Lo and D. R. Phillips, J. Biol. Chem., 262, 3936 (1987), the epitopes for 1B1 and B10 were concluded to be located at amino acids 335 to 582 and 206 to 335, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Augmentation of the gastric mucosal defense mechanism induced by KW-5805, a novel antiulcer agent.

KW-5805 (a new antiulcer agent), given p. o. at 30 mg/kg to rats, significantly increased the amount of gastric adherent mucus and mucosal glycoproteins. Gastric mucosal glucosamine synthetase activity was significantly enhanced by KW-5805 (30 mg/kg, p. o.). KW-5805 (10, 30 mg/kg, p. o.) significantly suppressed the decrease of gastric mucosal blood volume and oxygen sufficiency induced by hemorrhagic shock. The agent also significantly inhibited the extravasation of Evans blue into the gastric mucosa after ischemia-reinfusion. In conclusion, KW-5805 increased biosynthesis, storage and secretion of gastric mucus and improved the gastric mucosal hemodynamics.

Pheochromocytoma and Ca++ channel blocker.

This is a case report of a 57-year-old woman who was diagnosed as suffering from pheochromocytoma on the basis of serum catecholamine levels, the results of abdominal echography and CT scanning. Her fluctuating blood pressure was treated successfully by intravenous administration of diltiazem. Diltiazem elicits a marked reduction in vascular resistance. There was no evidence that diltiazem affects catecholamine secretion levels, as reported by others for nifedipine.

Alcoholic cardiomyopathy--acetaldehyde poisoning rat: myocardial and serum enzyme changes in acute exposure.

In order to clarify the pathogenesis of alcoholic cardiomyopathy, acetaldehyde (Ach) was administered to rats using the inhalation method. Serum enzyme changes and structural alterations of the heart were observed at various time intervals after 2 ml of Ach exposure for 2 hours. Possible myocardium-related enzymes, such as glutamic oxaloacetic transaminase, lactic dehydrogenase and creatine phosphokinase, were elevated within 24 hours and then returned almost to the previous levels. The most significant change seen using light microscopy was a prominent contraction band scattered throughout the specimen in the groups exposed for 12 and 24 hours, respectively. Ultrastructually, mitochondrial swelling and crystal disarray concomitant with myofibrillar change (swelling of Z-band) were observed. The former was seen most prominently immediately after exposure, while the latter was observed 24 hours after exposure. The significance of these findings and the difference between alcoholic cardiomyopathy and ischemic lesions were discussed.

Complications of valvular surgery--5 cases report with special reference to the conduction system--.

Five interesting autopsy cases of post-valvular replacement death are reported and discussed with special reference to disturbances of the conduction system. The most important acute changes are hemorrhages; the significance of a venous hemorrhage is emphasized. Chronic changes are collagenization of conduction system. One case of mycotic valvulitis, probably due to aspergillus, and one case of dissecting aneurysm probably related to previous valve replacement surgery are included.

Single coronary artery with myocardial infarction and AV block.

A case of single coronary artery with myocardial infarction was found in a 77-year-old woman. Study of the conductive system in this case did not show any abnormalities that could be correlated with the terminal clinical episode of heart block. In seven anatomically proven cases reported, the single coronary artery arose from the right aortic sinus, which suggests a possible causal relationship to infarction.