Beneficial effects of NO-releasing derivative of flurbiprofen (HCT-1026) in rat model of vascular injury and restenosis.

One of the major problems related to the percutaneous transluminal coronary angioplasty technique is the renarrowing of the vessel, a phenomenon known as restenosis. NO and nonsteroidal anti-inflammatory drugs have been shown to play a role in this pathology. The main problem with the use of conventional NO donors is that they affect blood pressure and flow, and for these reasons, they cannot be used safely in clinical practice.

Inhibition of nitric oxide synthase expression by a methanolic extract of Crescentia alata and its derived flavonols.

In order to validate the use of Crescentia alata (Bignoniaceae) in the traditional medicine of Guatemala as an antiinflammatory remedy, the methanolic (MeOH) extract has been evaluated in vivo for antiinflammatory activity on carrageenin paw edema in rats and in vitro on Escherichia coli lipopolysaccharide- (LPS)-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in J774.A1 macrophage cell line. This extract exerted in vivo a significant anti-inflammatory activity at the highest dose tested.

Dexamethasone modulates hypotension induced by opioids in anaesthetised rats.

The effect of dexamethasone on hypotension induced by mu-, kappa- and delta-opioid receptor agonists was investigated in pentobarbital-anaesthetised rats. Morphine (nonselective opioid receptor agonist), DAGO (D-Ala2-N-methyl-[Phe4-Gly5-ol]enkephalin; mu-opioid receptor-selective agonist), U50-488H (trans(+/-)-3,4-dichloro-N-methyl-N-(2[1pyrrolidynyl]cyclohexyl)-benzeneacetamide; kappa-opioid receptor-selective agonist) and deltorphin II (delta-opioid receptor-selective agonist), given intravenously, 5 micromol/kg, induced hypotension in rats. This hypotension was characterised by a fall in mean arterial blood pressure in 1-2 min that recovered in 30 min for morphine and U50-488H and in 5 or 20 min for DAGO and deltorphin II, respectively.

T cell response to N-formylated peptides in humans.

We present the first evidence of a T lymphocyte response to N-formylated peptides in humans. N-formylated peptide sequences from self (mitochondrial) and foreign (microbial) antigens were used to isolate antigen-specific T cell clones from healthy individuals, including a set of monozygotic twins. The observed response differed from that previously described in mouse (CD4(+) phenotype and MHC class II restriction in humans vs.

Staphylococcus aureus bacteremia in patients with permanent pacemakers or implantable cardioverter-defibrillators.

Background: Although cardiac device infections (CDIs) are a devastating complication of permanent pacemakers or implantable cardioverter-defibrillators, the incidence of CDI in patients with bacteremia is not well defined. The objective of this study was to determine the incidence of CDI among patients with permanent pacemakers or implantable cardioverter-defibrillators who develop Staphylococcus aureus bacteremia (SAB).

Methods And Results: A cohort of all adult patients with SAB and permanent pacemakers or implantable cardioverter-defibrillators over a 6-year period was evaluated prospectively.

A standardized procedure for using human corpus cavernosum strips to evaluate drug activity.

The main problem of using human corpus cavernosum (HCC) tissue to perform bioassay is linked to its limited availability further complicated by the heterogeneous source of the tissues used. Here, we show that gender reassignment is a reliable source of human tissue without major ethical problems. Indeed, the entire corpus cavernosum is obtained from the surgery procedure, which allows creating a standardized procedure to prepare HCC strip.

Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice.

Restenosis is due to neointimal hyperplasia, which occurs in the coronary artery after percutaneous transluminal coronary angioplasty (PTCA). During restenosis, an impairment of nitric oxide (NO)-dependent pathways may occur. Concomitant hypercholesterolemia may exacerbate restenosis in patients undergoing PTCA.

HLA-DP allele-specific T cell responses to beryllium account for DP-associated susceptibility to chronic beryllium disease.

Occupational exposure to small molecules, such as metals, is frequently associated with hypersensitivity reactions. Chronic beryllium (Be) disease (CBD) is a multisystem granulomatous disease that primarily affects the lung, and occurs in approximately 3% of individuals exposed to this element. Immunogenetic studies have demonstrated a strong association between CBD and possession of alleles of HLA-DP containing glutamic acid (Glu) at position 69 in the HLA-DP beta-chain.

MICA gene triplet repeat polymorphism in patients with HLA-B27 positive and negative ankylosing spondylitis from Sardinia.

Objective: We investigated the distribution of MICA triplet repeat polymorphism in a random population and in patients with seronegative spondyloarthritis from Sardinia compared to continental Italy.

Methods: We analyzed the distribution of MICA triplet repeat polymorphism in HLA-B*2709 [not associated with ankylosing spondylitis (AS)] and B*2705 (associated with AS) haplotypes, to verify whether the strong association of MICA-A4 with HLA-B27 reported in other populations is maintained in Sardinia, and compared the distribution of MICA-A alleles in HLA-B27 negative versus HLA-B27+ patients with AS.

Results: We found that the frequency of MICA-A4 triplet repeat allele in a random Sardinia population is higher (53.

Peptide analogues as a strategy to induce tolerance in T cells with indirect allospecificity.

Background: It has been demonstrated that indirect recognition of allogeneic MHC molecules might play an important role in provoking graft rejection. Although direct recognition of allogeneic molecules on antigen presenting cells of the graft may induce a state of tolerance, the continuous presentation of processed alloantigens by specialized antigen presenting cells does not allow the same phenomenon to occur. Tolerance to interleukin-2 secreting T cells can be achieved in different ways, among these is the exposure to mutants of the wild type allopeptide.

Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings.

Spironolactone and its active metabolites canrenone and potassium canrenoate are normally used as antihypertensive drugs. Although they are classified as antagonists of aldosterone, their mechanism of action cannot be ascribed solely to the regulation of ion transport in the distal tubule of nephrons. Here we have evaluated the effects of spironolactone, canrenone, and potassium canrenoate on contractile properties of isolated rat aorta rings.

CD8(+) T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis.

HLA-B27 is highly associated with ankylosing spondylitis (AS), but the mechanism is unknown. Among the HLA-B27 alleles, B*2709, which differs by one amino acid from the susceptible B*2705, is not associated with the disease. Here, we analyze the reactivity, in patients with AS and in healthy controls carrying the B*2709 or B*2705 alleles, to an EBV epitope derived from LMP2 (236-244) and to a sequence-related self-peptide from vasoactive intestinal peptide receptor 1 (VIP1R 400-408).

Antiproliferative triterpene saponins from Trevesia palmata.

During the course of a study of plants of the family Araliaceae, antiproliferative activity was demonstrated by the crude saponin fraction of Trevesia palmata. After chromatographic purification, six new bisdesmosidic saponins (1-6), along with two known triterpenoid saponins, (7 and 8), were isolated. The structures of 1-6 were determined by (1)H-(1)H correlation spectroscopy (COSY-DQF, 1D TOCSY, 2D HOHAHA, 1D ROESY) and (1)H-(13)C (HSQC, HMBC) spectroscopy.

In vitro and in vivo TNFalpha synthesis modulation by methylguanidine, an uremic catabolyte.

This study was performed in order to examine whether the uraemic toxin, methylguanidine (MG), can modulate tumor necrosis factor alpha (TNF alpha) release by activated macrophages. In this study we have evaluated the ability of MG to influence TNF alpha release in vitro, in Escherichia coli lypopolysaccharide- (LPS)-stimulated J774 cells preincubated overnight with MG, and in vivo in rats treated with MG before and after LPS challenge. Parallel experiments employing N(G)-nitro-L-arginine methyl esther (L-NAME) were also carried out for comparison.

Involvement of ATP-sensitive potassium channels in a model of a delayed vascular hyporeactivity induced by lipopolysaccharide in rats.

We have investigated the role of ATP-sensitive potassium (K(ATP)) channels in an experimental model of a delayed phase of vascular hyporeactivity induced by lipopolysaccharide (LPS) in rats. After 24 h, from LPS treatment, in anaesthetized rats the bolus injection of phenylephrine (PE) produced an increase in mean arterial pressure (MAP) significantly (P<0.05) reduced in LPS-treated rats compared to the vehicle-treated rats.

HLA-DP molecules bind cobalt: a possible explanation for the genetic association with hard metal disease.

Metal dust inhalation induces an interstitial lung disease which may progress to pulmonary fibrosis (hard metal disease, HMD). Cobalt is believed to be the pathogenic agent of HMD. A strong genetic association of HMD with some HLA-DP alleles has been reported although the role of these molecules in the occurrence of the fibrotic disorder remains unclear.

Pacemaker lead extraction with the laser sheath: results of the pacing lead extraction with the excimer sheath (PLEXES) trial.

Objectives: The purpose of this study was to evaluate the safety and effectiveness of pacemaker lead extraction with the excimer sheath in comparison to nonlaser lead extraction.

Background: Fibrotic attachments that develop between chronically implanted pacemaker leads and to the venous, valvular and cardiac structures are the major obstacles to safe and consistent lead extraction. Locking stylets and telescoping sheaths produce a technically demanding but effective technique of mechanically disrupting the fibrosis.

Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo.

Background: The protease-activated receptor-2 (PAR-2) is expressed by vascular endothelial cells and upregulated by lipopolysaccharide (LPS) in vitro. PAR-2 is activated by a tethered ligand created after proteolytic cleavage by trypsin or experimentally by a synthetic agonist peptide (PAR-2AP) corresponding to the new amino terminus of the tethered ligand.

Methods And Results: Intravenous administration of PAR-2AP (0.

The naturally occurring polymorphism Asp116-->His116, differentiating the ankylosing spondylitis-associated HLA-B*2705 from the non-associated HLA-B*2709 subtype, influences peptide-specific CD8 T cell recognition.

HLA-B27 molecules are interesting because of their strong association with ankylosing spondylitis (AS) and reactive arthritis (ReA). A pathogenetic role for these molecules has been postulated in presenting a putative "arthritogenic" peptide to CD8 T cells. The HLA-B*2709 subtype, although differing by a single amino acid (His116-->Asp116) from the widespread and strongly AS-associated subtype HLA-B*2705, is not found in patients.

Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling.

The signaling pathway initiated by factor Xa on vascular endothelial cells was investigated. Factor Xa stimulated a 5- to 10-fold increased release of nitric oxide (NO) in a dose-dependent reaction (0.1-2.

Dynamic activation of endothelial nitric oxide synthase by Hsp90.

Heat-shock protein 90 (Hsp90) coordinates the trafficking and regulation of diverse signalling proteins, but its precise role in regulating specific cellular targets is not known. Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS.