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Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation. Leukocyte migration into tissues is vital for efficient defense against insulting pathogens and foreign antigens. Nevertheless, the same phenomenon is also crucial to inappropriate inflammation and tissue destruction in several types of acute and chronic inflammatory and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, organ transplant rejection, and ischemia-reperfusion injury. Leukocytes enter from the blood circulation into the tissues by passing through the walls of blood vessels. An essential step in this process is binding of leukocytes to the innermost layer of the blood vessel wall, the endothelium, by adhesion molecules. Multiple adhesion molecules on the leukocytes interact concertedly with their counter-receptors on the endothelium during the adhesion and the subsequent transmigration process.1,2 A change in the functional expression of adhesion molecules on the endothelial surface is an early and specific indicator of inflammation. In fact, recent studies suggest that radioactively labeled monoclonal antibodies against specific endothelial adhesion molecules can be used in the diagnosis of inflammation by nuclear imaging methods. 3,4Human vascular adhesion protein-1 (VAP-1), originally defined by 1B2 monoclonal antibody, is a 170-kd endothelial sialoglycoprotein.5 VAP-1 is inflammation inducible and mediates the early phases of interaction between lymphocytes and endothelium. 6 The expression pattern of VAP-1 in normal and inflamed human tissues has been described 7,8 and the role of VAP-1 in human leukocyte adhesion has been shown in vitro. 5,9 However, practically nothing is known about the translocation of VAP-1 from the inside of the cells to the functional position on the cell surface as well as the significance of VAP-1 in leukocyteendothelium interactions in vivo.The anti-human-VAP-1 mAb 1B2 does not recognize VAP-1 of small laboratory animals such as mouse, rat, or rabbit. However, preliminary screening experiments revealed that 1B2 antibody does recognize porcine and canine blood vessels. That encouraged us to study whether the antigens recognized by 1B2 are the porcine and canine homologues o...

Changes in endothelial permeability are crucial in the pathogenesis of many diseases. Adenosine is one of the endogenous mediators controlling endothelial permeability under normal conditions, and an endothelial cell surface enzyme CD73 is a key regulator of adenosine production. Here we report that IFN-b is a novel inducer of CD73. We found that pretreatment with IFN-b dramatically improved the vascular barrier function in lungs after intestinal ischemia-reperfusion injury in wild-type animals in vivo. IFN-b had absolutely no protective effects in CD73-deficient mice, which suffered from more severe lung damage than wild-type mice, showing that IFN-b functions strictly in a CD73-dependent manner. Most importantly, IFN-b treatment initiated after the ischemic period almost completely inhibited vascular leakage during the reperfusion. IFN-b also induced the expression and activity of CD73 and concurrently decreased vascular permeability in cultured human pulmonary endothelial cells. These data show that induction of CD73 and improvement of vascular barrier are new mechanisms for the anti-inflammatory action of IFN-b. Moreover, IFN-b treatment may be useful in alleviating vascular leakage induced by ischemia-reperfusion injury.

Background: Only a few previous studies have focused on the long-term prognosis of the patients with infective endocarditis (IE). Our purpose was to delineate factors potentially associated with the long-term outcome of IE, recurrences of IE and requirement for late valve surgery.

Objectives: To evaluate potential changes of infective endocarditis (IE) in patients treated in a Finnish teaching hospital during the past 25 years. Patients: 326 episodes of IE in 303 patients treated during 1980-2004 were evaluated for clinical characteristics and their changes over time.Results: The mean age of the patients increased with time (from 47.2 to 54.5 years, p = 0.003). Twentyfive (7.7%) episodes were associated with intravenous drug use (IVDU), with a significant increase of these episodes after 1996 (from 0 to 19 (20%), p , 0.001). Viridans streptococci were the most common causative agents of IE during 1980-1994, but after that Staphylococcus aureus was the most common pathogen (p = 0.015). The proportion of IE of the aortic valve decreased during the study (from 30 (49%) to 26 (27%), whereas the proportions of mitral (11 (18%) to 33 (35%) and tricuspid valve IE (0 to 13 (14%) increased correspondingly (p = 0.001). This was mainly due to more patients with IVDU. Chronic dialysis for renal failure as an underlying condition increased over time (from 0 to 7 (7.4%), p = 0.015) but no other predisposing conditions changed. Complications such as neurological manifestations and heart failure did not change in frequency, but the incidence of lung emboli increased (from 0% to 10.5%, p , 0.001); 83% of these emboli occurred in patients with IVDU. The proportion of patients requiring surgical treatment and mortality due to IE did not change. Conclusions: During these 25 years, the causative agents, affected valves and complications of IE changed to some degree. These changes were mainly attributed to the increase of IVDU-associated IE. Except for the increase in age, the clinical presentation and outcome in non-addicts remained substantially unchanged.

No abstract

BackgroundRadiolabeled RGD peptides detect αvβ3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvβ3 integrin is expressed in viable ischemic or injured myocardium.MethodsWe studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology.ResultsStent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvβ3 integrin that was expressed in the injured myocardial areas.ConclusionsCardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvβ3 integrin expression associated with repair of recent myocardial injury.

14( R, S)-[(18)F]Fluoro-6-thia-heptadecanoic acid ([(18)F]FTHA) is a long-chain fatty acid substrate for fatty acid metabolism. [(18)F]FTHA has been used to study fatty acid metabolism in human heart and skeletal muscle. It has been suggested that the rate of radioactivity accumulation in the myocardium reflects the beta-oxidation rate of free fatty acids (FFAs). However, the net accumulation of FFAs in tissue always represents the sum of FFA oxidation and incorporation into triglycerides. The fraction of [(18)F]FTHA entering directly into mitochondria for oxidation has not been previously measured. Eight anaesthetized pigs were studied with [(18)F]FTHA and positron emission tomography (PET). Immediately after each PET experiment, tissue samples from myocardium and skeletal muscle were taken for the isolation of mitochondria and measurements of radioactivity accumulation, and for intracellular [(18)F]FTHA metabolite analysis. Fractional [(18)F]FTHA uptake rates were calculated both by graphical analysis of PET data and by measuring (18)F in the tissue samples. Fractional [(18)F]FTHA uptake rates based on the analysis of tissue samples were 0.56+/-0.17 ml g(-1) min(-1) and 0.037+/-0.007 ml g(-1) min(-1) for myocardium and skeletal muscle (mean +/- SD), respectively. The myocardial results obtained from the PET data (0.50+/-0.11 ml g(-1) min(-1)) were similar to the values obtained from the tissue samples ( r=0.94, P=0.002). We also found that 89%+/-23% (mean+/-SD, n=7) of the (18)F entered mitochondria in myocardium, as compared with only 36%+/-15% (mean+/-SD, n=7) in skeletal muscle. Intracellular [(18)F]FTHA metabolite analysis showed that a major part of [(18)F]FTHA is metabolized in the mitochondria in the heart. Our data suggest that ~89% of [(18)F]FTHA taken up by the heart enters mitochondria. This supports the hypothesis that [(18)F]FTHA traces FFA beta-oxidation in the heart. In contrast to this, only ~36% of [(18)F]FTHA accumulated in skeletal muscle appears to directly enter mitochondria; the majority is taken up by the other cell fractions, suggesting that in skeletal muscle [(18)F]FTHA traces FFA uptake but not specifically FFA beta-oxidation.