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PPI
Terms modified by PPI Selected AbstractsChronic toxicity and responses of several important enzymes in Daphnia magna on exposure to sublethal microcystin-LRENVIRONMENTAL TOXICOLOGY, Issue 3 2005Wei Chen Abstract In the current study, the toxicological mechanisms of microcystin-LR and its disadvantageous effects on Daphnia magna were examined. Survival rate, number of newborn, activity of several important enzymes [glutathione S-transferase (GST), lactate dehydrogenase (LDH), phosphatases, and glutathione], accumulated microcystins, and ultrastructural changes in different organs of Daphnia were monitored over the course of 21-day chronic tests. The results indicated that low concentrations of dissolved microcystin had no harmful effect on Daphnia. On the contrary, stimulatory effects were detected. In the presence of toxin at high dosage and for long-term exposure, GST and glutathione levels decreased significantly. The decreased enzyme activity in the antioxidant system probably was caused by detoxification reactions with toxins. And these processes of detoxification at the beginning of chronic tests may enable phosphatases in Daphnia magna to withstand inhibition by the toxins. At the same time, we also found that the LDH activity in test animals increased with exposure to microcystin-LR, indicating that adverse effects occurred in Daphnia. With microcystin given at a higher dosage or for a longer exposure, the effect on Daphnia magna was fatal. In the meantime, microcystin began to accumulate in Daphnia magna, and phosphatase activity started to be inhibited. From the ultrastructure results of cells in D. magna, we obtained new information: the alimentary canal may be the target organ affected by exposure of microcystins to D. magna. The results of the current study also suggested that the oxidative damage and PPI (protein phosphatase inhibition) mechanisms of vertebrates also are adapted to Daphnia. © 2005 Wiley Periodicals, Inc. Environ Toxicol 20: 323,330, 2005. [source] Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle responseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2007Linda E. Campbell Abstract Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMG-recorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating. [source] Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 7 2010T. V. Lipina Significant advances have been made in understanding the role of disrupted-in-schizophrenia-1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia-related behavior in mutant mice (DISC1-L100P). We investigated here the role of DA in the expression of schizophrenia-related endophenotypes in the DISC1-L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1-L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1-fold increase in the proportion of striatal Dreceptors without significant changes in DA release in vivo in the striatum of DISC1-L100P mutants in response to the low dose of amphetamine. The D2 receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1-L100P mutants. Taken together, our findings show the role of DISC1 in D2 -related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia. [source] GLT-1 upregulation impairs prepulse inhibition of the startle reflex in adult ratsGLIA, Issue 7 2009Michele Bellesi Abstract We tested the hypothesis that glutamate transporter GLT-1 (also known as EAAT2) plays a role in the regulation of prepulse inhibition (PPI) of the acoustic startle reflex, a simple form of information processing which is reduced in schizophrenia. To do this, we studied PPI in rats treated with ceftriaxone (200 mg/kg/day for 8 days), an antibiotic that selectively enhances GLT-1 expression and activity. We showed that ceftriaxone-induced GLT-1 upregulation is associated with impaired PPI of the startle, that this effect is reversed by dihydrokainate, a GLT-1 antagonist, that GLT-1 expression correlates negatively with PPI, and that PPI normalizes when GLT-1a levels return to baseline. Our data indicate that GLT-1 regulates PPI of the startle reflex. © 2008 Wiley-Liss, Inc. [source] Double-Dose, New-Generation Proton Pump Inhibitors Do Not Improve Helicobacter pylori Eradication RateHELICOBACTER, Issue 6 2007Hyo Sun Choi Abstract Background: Up to present, omeprazole plus two antibiotics are used for Helicobacter pylori eradication therapy . Few studies have compared double-dose new-generation, proton pump inhibitors (PPI) with omeprazole. Therefore, we conducted a randomized, prospective study to evaluate differences in H. pylori eradication rates by PPI type. Material and Methods: Between January 2006 and December 2006, 576 consecutive patients with proven H. pylori infection were enrolled prospectively. Four different PPIs [omeprazole 20 mg b.i.d. (old generation), or pantoprazole 40 mg b.i.d., rabeprazole 20 mg b.i.d., or esomeprazole 40 mg b.i.d. (new generation)] were added to clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) for 1 week. Results: By intention-to-treat analysis, no difference was found between the eradication rates of these four PPIs: 64.9% (omeprazole, n = 148), 69.3% (pantoprazole, n = 140), 69.3% (rabeprazole, n = 140), and 72.9% (esomoprazole, n = 148). When eradication rates were analyzed according to whether patients had an ulcer or not on a per-protocol basis, no difference was found between the eradication rates of the four PPIs. However, side-effects were more common in the esomeprazole-based triple therapy group than in the other groups (p < .05). Conclusions: No convincing evidence was obtained that double-dose new-generation PPIs have better H. pylori eradication rates and tolerability than omeprazole. [source] Helicobacter pylori"Rescue" Therapy After Failure of Two Eradication TreatmentsHELICOBACTER, Issue 5 2005Javier P. Gisbert ABSTRACT Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face Helicobacter pylori treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final , overall , eradication rate. After failure of a combination of proton pump inhibitor (PPI), amoxicillin, and clarithromycin, the use of empirical quadruple therapy (PPI,bismuth,tetracycline,metronidazole), has been generally used as the optimal second-line therapy. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several "rescue" therapies are consecutively given. It seems that performing culture even after a second eradication failure may not be necessary, as it is possible to construct an overall strategy to maximize H. pylori eradication, based on the different possibilities of empirical treatment (when antibiotic susceptibilities are unknown). Thus, if one does not want to perform culture before the administration of the third treatment after failure of the first two, different empirical treatments exist, including regimens based on: 1, amoxicillin (amoxicillin,PPI at high doses); 2, amoxicillin plus tetracycline (PPI,bismuth,tetracycline,amoxicillin, or ranitidine,bismuth,citrate,tetracyline,amoxicillin); 3, rifabutin (rifabutin,amoxicillin,PPI); 4, levofloxacin (levofloxacin,amoxicillin,PPI); and 5, furazolidone (furazolidone,bismuth,tetracycline,PPI). [source] Recent Use of Proton Pump Inhibitor-Based Triple Therapies for the Eradication of H. pylori: A Broad Data ReviewHELICOBACTER, Issue 2 2003Hans-Joachim Ulmer abstract Introduction. For the eradication of Helicobacter pylori a 1-week triple therapy combining proton pump inhibitors with two antibiotics has been recommended as a gold standard therapy. However, a recent broad data review on the efficacy of the different regimens is missing. Therefore, the aim of this study was to systematically review the recent literature. Methods. We undertook a broad data review of the efficacy of nine different 7-day triple therapies consisting of a proton pump inhibitor (lansoprazole, pantoprazole, omeprazole) in its standard dosage and two antibiotics. Relevant original papers on H. pylori eradication in adults, published in English or German between 1995 and 2000, were identified from MEDLINE searches. Studies were reviewed and selected according to predefined criteria. Results. Our predefined criteria were fulfilled by 79 full paper articles including 112 study arms with 8383 patients on intention-to-treat, or 6787 patients on per-protocol basis, respectively. The mean eradication rates unweighted or weighted by the number of patients in the study arm vary from 71.9% to 83.8% for intention-to-treat analysis and from 78.5% to 91.2% for per-protocol analysis. Conclusions. All nine PPI based triple therapy regimens are very effective in H. pylori eradication. The current literature review underlines that the use of either lansoprazole, omeprazole, or pantoprazole combined with two antibiotics yield similar high eradication rates. [source] High Efficacy of Ranitidine Bismuth Citrate, Amoxicillin, Clarithromycin and Metronidazole Twice Daily for Only Five Days in Helicobacter pylori EradicationHELICOBACTER, Issue 2 2001Javier P. Gisbert ABSTRACT Aim. The combination of a proton pump inhibitor (PPI) or ranitidine-bismuth-citrate (Rbc) and two antibiotics for 7,10 days are, at present, the preferred treatments in Helicobacter pylori eradication. However, therapies for fewer than 7 days have been scarcely evaluated and it is unknown whether the length of treatment can be shortened, without a lost of efficacy, if three instead of two antibiotics are used. The aim of our study was to evaluate the efficacy of Rbc plus three antibiotics for only 5 days in H. pylori eradication. Methods. We prospectively studied 80 patients (34% duodenal ulcer, 66% functional dyspepsia) infected by H. pylori. At endoscopy, biopsies were obtained for histological study and rapid urease test, and a 13C-urea breath test was carried out. Urea breath test was repeated 4 weeks after completing eradication treatment with Rbc [400 mg twice a day (bid)], amoxicillin (1 g bid), clarithromycin (500 mg bid) and metronidazole (500 mg bid). All drugs were administered together after breakfast and dinner for 5 days only, and no treatment was administered thereafter. Compliance with therapy was determined from the interrogatory and the recovery of empty envelopes of medications. Results. In 79 out of the 80 patients, H. pylori eradication success or failure was assessed after therapy (one patient was lost from follow-up). All but one of these 79 patients took all the medications (one patient stopped treatment on the day 3 due to nausea/vomiting). Per protocol eradication was achieved in 72/78 (92%; 95% CI, 84,96%) and in 72/80 (90%; 81,95%) by intention-to-treat. Therapy was more effective in patients with duodenal ulcer than in those with functional dyspepsia [100% (87,100%) vs. 85% (73,92%) by intention-to-treat; p < .05]. Adverse effects were described in ten patients (12%), and included the perception of a metallic taste (eight patients), nausea/vomiting (two patients, one of them abandoned the treatment due to this), and diarrhea (two patients). Conclusion. The combination of Rbc, amoxicillin, clarithromycin and metronidazole for only 5 days represents a promising therapy for H. pylori infection, due to its high efficacy, simple posology, low cost and excellent tolerance. [source] Synthesis, and Helix or Hairpin-Turn Secondary Structures of ,Mixed' ,/, -Peptides Consisting of Residues with Proteinogenic Side Chains and of 2-Amino-2-methylpropanoic Acid (Aib)HELVETICA CHIMICA ACTA, Issue 9 2006Dieter Seebach Abstract Twelve peptides, 1,12, have been synthesized, which consist of alternating sequences of , - and , -amino acid residues carrying either proteinogenic side chains or geminal dimethyl groups (Aib). Two peptides, 13 and 14, containing 2-methyl-3-aminobutanoic acid residues or a ,random mix' of ,-, ,2 -, and ,3 -amino acid moieties were also prepared. The new compounds were fully characterized by CD (Figs.,1 and 2), and 1H- and 13C-NMR spectroscopy, and high-resolution mass spectrometry (HR-MS). In two cases, 3 and 14, we discovered novel types of turn structures with nine- and ten-membered H-bonded rings forming the actual turns. In two other cases, 8 and 11, we found 14/15 -helices, which had been previously disclosed in mixed ,/, -peptides containing unusual , -amino acids with non-proteinogenic side chains. The helices are formed by peptides containing the amino acid moiety Aib in every other position, and their backbones are primarily not held together by H-bonds, but by the intrinsic conformations of the containing amino acid building blocks. The structures offer new possibilities of mimicking peptide,protein and protein,protein interactions (PPI). [source] pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidityINTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Angelo De Milito Abstract Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg,1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients. [source] Proton pump inhibitor omeprazole use is associated with low bone mineral density in maintenance haemodialysis patientsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2 2009A. Kirkpantur Summary Objective:, Limited studies have shown that proton pump inhibitor (PPI) therapy may decrease bone density or insoluble calcium reabsorption through induction of hypochlorhydria. However, PPI therapy may also reduce bone resorption via inhibition of osteoclastic vacuolar proton pumps. The aim of this study was to determine whether the opposing effects of PPI therapy may cause clinically important alterations in bone mineral densitometry (BMD) parameters in maintenance haemodialysis patients. Methods:, Sixty-eight maintenance haemodialysis patients were enrolled in this study. Patients were classified into two groups involving users of PPI therapy (omeprazole 20 mg/day, group 1, n = 36 patients) and non-users of acid suppression drugs (group 2, n = 32 patients). Patients had radius, hip and spine BMD assessed by dual-energy X-ray absorptiometry. Results:, The mean duration of PPI therapy with omeprazole was 27 ± 5 months. The users of PPI therapy had lower values of bone mineral density and T -scores at the anatomical regions than non-users of acid suppression drugs. Serum calcium and phosphate levels, calcium-phosphate product and serum intact parathormone levels and the ratio of users of vitamin D therapy were similar among groups. A mutivariable adjusted odds ratio for lower bone density associated with more than 18 months of omeprazole, when all the potential confounders were considered, was 1.31 in the proximal radius, 0.982 in the femur neck, 0.939 in the trochanter and 1.192 in the lumbal spine. Conclusion:, The present data suggest that PPI therapy should be cautiously prescribed in maintenance haemodialysis patients, especially with lower BMD values. [source] Free energy and structure of polyproline peptides: An ab initio and classical molecular dynamics investigationINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 15 2010Mahmoud Moradi Abstract Depending on their environment, polyproline peptides form chiral helices that may be either left- (PPII) or right-handed (PPI). Here, we have characterized both the structure and free energy landscapes of Ace-(Pro)n -Nme (n an integer less than 13) peptides, in vacuo and in implicit water environments. Both ab initio and classical molecular dynamics methods were used. In terms of the latter, we used a recently developed Adaptively Biased Molecular Dynamics (ABMD) method in conjunction with three different force fields (ff99, ff99SB, ff03) and two different Generalized Born models for the implicit solvent environment. Specifically, the ABMD method provides for an accurate description of the free energy landscapes in terms of a set of collective variables, which were carefully chosen as to reflect the "slow modes" of the polyproline peptides. These are primarily based on the cis - trans isomerization associated with the prolyl bonds. In agreement with recent experimental results, the peptides form not only the pure PPII or PPI structures but also a large number of stable conformers having more or less similar free energies, whose distributions we have characterized. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [source] Implementation and evaluation of MPI-based parallel MD programINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 1 2001R. Trobec Abstract The message-passing interface (MPI)-based object-oriented particle,particle interactions (PPI) library is implemented and evaluated. The library can be used in the n -particle simulation algorithm designed for a ring of p interconnected processors. The parallel simulation is scalable with the number of processors, and has the time requirement proportional to n2/p if n/p is large enough, which guarantees optimal speedup. In a certain range of problem sizes, the speedup becomes superlinear because enough cache memory is available in the system. The library is used in a simple way by any potential user, even with no deep programming knowledge. Different simulations using particles can be implemented on a wide spectrum of different computer platforms. The main purpose of this article is to test the PPI library on well-known methods, e.g., the parallel molecular dynamics (MD) simulation of the monoatomic system by the second-order leapfrog Verlet algorithm. The performances of the parallel simulation program implemented with the proposed library are competitive with a custom-designed simulation code. Also, the implementation of the split integration symplectic method, based on the analytical calculation of the harmonic part of the particle interactions, is shown, and its expected performances are predicted. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 84: 23,31, 2001 [source] Immobilisation of the Pyrphos Ligand on Soluble Hyperbranched Supports and Use in Rhodium-Catalysed Hydrogenation in Ionic LiquidsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 5 2009Jutta Abstract The immobilisation of the pyrphos ligand has been extended from highly symmetric dendrimers to less regular structured hyperbranched poly(ethylene imines). Cationic dendritic pyrphos-rhodium(norbornadiene) [pyrphos-Rh(NBD)] complexes have been synthesised using poly(propylene imine) (PPI) and poly(amido amine) (PAMAM) dendrimers as supports bearing between 4 and 64 potential catalytically active sites at their periphery as well as pyrphos-Rh(NBD) complexes tethered to hyperbranched poly(ethylene imines) carrying on average 9 to 139 functionalities located throughout the whole supporting structure. These immobilised systems have been used as catalysts for the hydrogenation of Z -methyl ,-acetamidocinnamate. With the PPI, PAMAM, and hyperbranched poly(ethylene imine)-bound pyrphos-Rh(NBD) omplexes as catalysts, hydrogenations were carried out in methanol, and a decrease in activity and selectivity was observed with increasing size of the macromolecular support. Furthermore, the polycationic catalysts were tested in a liquid/liquid-biphasic system consisting of the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate {[BMIM] [BF4]} and isopropyl alcohol. Using the PPI-, PAMAM-, and PEI-immobilised systems, a strong negative "dendritic effect" with increasing molecular size was observed with respect to the catalytic activity, the stereoinduction, and the recyclability. The PPI-bound rhodium(I)-complexes of generations one and two showed good reusability; even after triple recycling, with no loss of activity or selectivity being noted. It has been demonstrated that in this case the catalytic behaviour of hyperbranched systems is essentially similar to that of the related dendritic model system. [source] Immobilisation of the BINAP Ligand on Dendrimers and Hyperbranched Polymers: Dependence of the Catalytic Properties on the Linker UnitADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 4 2009Jutta Abstract A series of immobilised Carbo-BINAP ligands has been synthesised using poly(propylene imine) (PPI) dendrimers as soluble supports. They contain up to 64 BINAP ligands at their periphery without an additional linking unit. Despite the high steric requirements of the ligand, all dendrimers could be completely functionalised, resulting in the immobilised systems in good yields. Furthermore, the immobilisation strategy that worked out for the fixation of AMINAP ligands with additional linking units as well as of Carbo-BINAP ligands without additional linking units on dendrimers has thus been extended to less regularly hyperbranched poly(ethylene imines) (PEI) as soluble supports. In that way it has been possible to attach on average 9, 26, and 138 Glutaroyl-AMINAP or Carbo-BINAP ligands to PEIs of different molecular weights. The catalytic properties of these systems in the copper-catalysed hydrosilylation of acetophenone were investigated. The dendritic PPI-bound Carbo-BINAP ligands displayed a strong dependence of enantioselectivity and activity on the generation of the dendrimer. For the Carbo-BINAP and Glutaroyl-AMINAP ligands immobilised on the hyperbranched polymers, however, activities and enantioselectivities comparable to those of the mononuclear catalysts were found. The macromolecular, immobilised BINAP ligands could be recycled several times without any observable loss of activity or enantioselectivity. [source] Quantitative Analysis of the Duration of Slow Conduction in the Reentrant Circuit of Ventricular Tachycardia After Myocardial InfarctionJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 9 2008YI-GANG LI M.D. Background: Few data are available to define the circuits in ventricular tachycardia (VT) after myocardial infarction and the conduction time (CT) through the zone of slow conduction (SCZ). This study assessed the CT of the SCZ and identified different reentrant circuits. Methods: During VTs, concealed entrainment (CE) was attempted. The SCZ was identified by a difference between postpacing interval (PPI) and VT cycle length (VTcl) ,30 ms. Since the CT in the normally conducting part of the VT circuit is constant during VT and CE, a CE site within the reentrant circuit with (S-QRS)/PPI , 50% was classified as an inner reentry in which the entire circuit was within the scar, and a CE site with (S-QRS)/PPI < 50% as a common reentry in which part of the circuit was within the scar and part out of the scar. Results: CE was achieved in 20 VTs (12 patients). Six VTs (30%) with a (S-QRS)/PPI ,50% were classified as inner reentry and 14 VTs (70%) with a (S-QRS)/PPI <50% during CE mapping as common reentry. The EG-QRS interval (308 ± 73 ms vs 109 ± 59 ms, P < 0.0001) was significantly longer and the incidence of systolic potentials higher (4/6 vs 0/12, P < 0.001) in the inner reentry group. For the 14 VTs with a common reetry, the CT of the SCZ was 348 ± 73 ms, while the CT in the normal area was 135 ± 50 ms. Conclusion: According to the proposed classification, 30% of VTs after myocardial infarction had an entire reentrant circuit within the scar. In VTs with a common reentrant circuit, the CT of the SCZ is approximately four times longer than the CT in the normal area, accounting for more than 70% of VTcl. [source] A Novel Pacing Maneuver to Localize Focal Atrial TachycardiaJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2007F.R.A.C.P., UWAIS MOHAMED M.B.B.S. Background: Although focal atrial tachycardias cannot be entrained, we hypothesized that atrial overdrive pacing (AOP) can be an effective adjunct to localize the focus of these tachycardias at the site where the post-pacing interval (PPI) is closest to the tachycardia cycle length (TCL). Methods: Overdrive pacing was performed in nine patients during atrial tachycardia, and in a comparison group of 15 patients during sinus rhythm. Pacing at a rate slightly faster than atrial tachycardia in group 1 and sinus rhythm in group 2 was performed from five standardized sites in the right atrium and coronary sinus. The difference between the PPI and tachycardia or sinus cycle length (SCL) was recorded at each site. The tachycardia focus was then located and ablated in group 1, and the atrial site with earliest activation was mapped in group 2. Results: In both groups the PPI-TCL at the five pacing sites reflected the distance from the AT focus or sinus node. In group 1, PPI-TCL at the successful ablation site was 11 ± 8 msec. In group 2, PPI-SCL at the site of earliest atrial activation was 131 ± 37 msec (P < 0.001 for comparison). In groups 1 and 2, calculated values at the five pacing sites were proportional to the distance from the AT focus or sinus node, respectively. Conclusions: The PPI-TCL after-AOP of focal atrial tachycardia has a direct relationship to proximity of the pacing site to the focus, and may be clinically useful in finding a successful ablation site. [source] Estimation of Entrainment Response Using Electrograms from Remote Sites: Validation in Animal and Computer Models of Reentrant TachycardiaJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2003PETER E. HAMMER M.S. Estimation of Entrainment Response. Introduction: Studies suggest that entrainment response (ER) of reentrant tachycardia to overdrive pacing can be estimated using signals from sites other than the paced site. Methods and Results: A formula for estimation of ER using remote sites against the difference between the postpacing interval (PPI) and tachycardia cycle length (TCL) determined solely from the paced site signal was validated in experimental data and using a simple two-dimensional cellular automata model of reentry. The model also was used to study the behavior and features of entrained surfaces, including the resetting of tachycardia phase by single premature paced stimuli. Experimental results from 1,484 remote sites in 115 pacing sequences showed the average of the median ER estimate error at each pacing site was,2 ± 5 msec, and the median ER estimate was within 10 msec of PPI,TCL for 94% of pacing sites. From simulation results, ER at the paced site was accurately estimated from >99.8% of 20,764 remote sites during pacing at 24 sites and three paced cycle lengths. Intervals measured from remote electrograms revealed whether the site was activated orthodromically or nonorthodromically during pacing, and results of simulations illustrated that the portion of the surface activated nonorthodromically during pacing increased with distance from the pacing site to the circuit. The phenomenon of nonorthodromic activation of reentrant circuits predicted by modeling was discernible in measurements taken from the animal model of reentrant tachycardia. Results also showed that, for single premature stimuli that penetrated the tachycardia circuit, phase reset of the tachycardia was linearly related to distance between the central obstacle and the paced site. Conclusion: The ER is a complex but predictable perturbation of the global activation sequence of reentrant tachycardias. This predictability allows calculations of the response from anywhere on the perturbed surface. These findings suggest new techniques for measurement of the ER, which may lend themselves to computer-based methods for accurate and rapid mapping of reentrant circuits. [source] In GERD patients, mucosal repair associated genes are upregulated in non-inflamed oesophageal epitheliumJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5 2009D. R. De Vries Abstract Previous studies addressing the effects of acid reflux and PPI therapy on gene expression in oesophageal epithelium concentrated on inflamed tissue. We aimed to determine changes in gene expression in non-inflamed oesophageal epithelium of GERD patients. Therefore, we included 20 GERD patients with pathological total 24-hr acid exposure of 6,12% and SAP , 95%. Ten patients discontinued PPI treatment (PPI-), 10 took pantoprazole 40 mg bid (PPI+). Ten age/sex-matched healthy controls were recruited. Biopsies were taken from non-inflamed mucosa 6 cm and 16 cm proximal to the squamocolumnar junction (SCJ). Gene expression profiling of biopsies from 6 cm was performed on Human Genome U133 Plus 2.0 arrays (Affymetrix). Genes exhibiting a fold change >1.4 (t-test P -value < 1E, 4) were considered differentially expressed. Results were confirmed by real-time RT-PCR. In PPI- patients, 92 microarray probesets were deregulated. The majority of the corresponding genes were associated with cell,cell contacts, cytoskeletal reorganization and cellular motility, suggesting facilitation of a migratory phenotype. Genes encoding proteins with anti-apoptotic or anti-proliferative functions or stress-protective functions were also deregulated. No probesets were deregulated in PPI+ patients. QPCR analysis of 20 selected genes confirmed most of the deregulations in PPI- patients, and showed several deregulated genes in PPI+ patients as well. In the biopsies taken at 16 cm QPCR revealed no deregulations of the selected genes. We conclude that upon acid exposure, oesophageal epithelial cells activate a process globally known as epithelial restitution: up-regulation of anti-apoptotic, anti-oxidant and migration associated genes. Possibly this process helps maintaining barrier function. [source] Nateglinide and glibenclamide metabolic effects in naïve type 2 diabetic patients treated with metforminJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2009G. Derosa MD PhD Summary Background and objective:, Most antidiabetic agents target only one of several underlying causes of diabetes. The complementary actions of the glinides and the biguanides may give optimal glycemic control in patients with type 2 diabetes mellitus. The aim of the present study was to compare the effects of nateglinide plus metformin with glibenclamide plus metformin on glucose and lipid metabolism, and haemodynamic parameters in patients with type 2 diabetes mellitus. Methods:, We enrolled 248 type 2 diabetic patients. Patients were randomly assigned to receive nateglinide (n = 124) or glibenclamide (n = 124), after 6 months of run-in, in which we titrated nateglinide (starting dose 180 mg/day), glibenclamide (starting dose 7·5 mg/day), and metformin (starting dose 1500 mg/day). The final doses were (mean ± standard deviation), 300 ± 60, 12·5 ± 2·5, and 2500 ± 500 mg/day, respectively. We followed these patients for 1 year after titration. We assessed body mass index (BMI), fasting (FPG) and post-prandial (PPG) plasma glucose, glycosylated haemoglobin (HbA1c), fasting (FPI) and post-prandial (PPI) plasma insulin, homeostasis model assessment (HOMA) index, and lipid profile [total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), apolipoprotein A-I (Apo A-I), and apolipoprotein B (Apo B)], systolic blood pressure (SBP), and diastolic blood pressure (DBP). All variables were evaluated at baseline and after 3 and 6 months in the run-in period, and at baseline, and after 3, 6, 9 and 12 months for both treatment groups. Results and discussion:, Body mass index did not show any significant change during the study. We observed a significant improvement from baseline to 1 year on HbA1c (P < 0·01 vs. baseline and vs. glibenclamide group, respectively), FPG (P < 0·01 vs. baseline), PPG (P < 0·01 vs. baseline), and on HOMA index (P < 0·05 vs. baseline) in the nateglinide group. In the glibenclamide group, we found significant changes in HbA1c (P < 0·05 vs. baseline), FPG (P < 0·01 vs. baseline), PPG (P < 0·05 vs. baseline), and HOMA index (P < 0·05 vs. baseline). No significant change was observed in TC, LDL-C, HDL-C, Tg, Apo A-I, Apo B, SBP, DBP and HR in either group after 3, 6, 9 and 12 months. These effects of nateglinide and glibenclamide on insulin-resistance parameters are in agreement with previous reports. Contrarily to previous reports, we did not observe any significant BP change in patients treated with glibenclamide. Although both nateglinide and glibenclamide attenuated PPG and HOMA index, they did not have significant effects on lipid metabolism, as already shown in subjects with type 2 diabetes and good glycemic control. Conclusion:, Nateglinide improved glycemic control better than glibenclamide in combination with metformin. [source] Metformin,pioglitazone and metformin,rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndromeJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2006G. Derosa MD PhD Summary Background and objective:, Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin. The combination of metformin with thiazolidinediones is less well studied. The aim of the present study was to assess the differential effect, and tolerability, of metformin combined with pioglitazone or rosiglitazone on glucose, coagulation and fibrinolysis parameters in patients with type 2 diabetes mellitus and metabolic syndrome. Methods:, This 12-month, multicentre, double-blind, randomized, controlled, parallel-group trial was conducted at three study sites in Italy. We assessed patients with type 2 diabetes mellitus (duration ,6 months) and with metabolic syndrome. All patients were required to have poor glycaemic control with diet, or experienced adverse effects with diet and metformin, administered up to the maximum tolerated dose. Patients were randomized to receive either pioglitazone or rosiglitazone self-administered for 12 months. We assessed body mass index (BMI), glycaemic control [glycosylated haemoglobin (HbA1c), fasting and postprandial plasma glucose and insulin levels (FPG, PPG, FPI, and PPI respectively), homeostasis model assessment (HOMA) index], lipid profile [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG)], lipoprotein (a) [Lp(a)] and homocysteine (HCT) at baseline and at 3, 6, 9 and 12 months of treatment. Results and discussion:, No BMI change was observed at 3, 6, 9 and 12 months in either group. Significant HbA1c decreases were observed at 9 and 12 months in both groups. After 9 and 12 months, mean FPG and PPG levels decreased in both groups. Decreases in FPI and PPI were observed at 9 and 12 months compared with the baseline in both groups. Furthermore, in both groups, the HOMA index improved but only at 12 months. Significant TC, LDL-C, HDL-C, TG improvement was present in the pioglitazone group at 12 months compared with the baseline values, and these variations were significantly different between groups. No TC, LDL-C, TG improvement was present in the rosiglitazone group after 12 months. Significant Lp(a) and HCT improvement was present in the pioglitazone group at 12 months compared with the baseline values, and Lp(a) change was significant compared with the rosiglitazone group. Significant HCT decrease was observed in the rosiglitazone group at the end of the study. In our type 2 diabetic patients, both drugs were safe and effective for glycaemic control and improving HCT plasma levels. However, long-term treatment with metformin plus pioglitazone significantly reduced Lp(a) plasma levels, whereas metformin + rosiglitazone did not. Conclusion:, For patients with type 2 diabetes mellitus and metabolic syndrome, combined treatment with metformin and rosiglitazone or pioglitazone is safe and effective, However, the pioglitazone combination also reduced the plasma Lp(a) levels whereas the rosiglitazone combination did not. [source] Personality and psychopathology in an impulsive aggressive college sampleAGGRESSIVE BEHAVIOR, Issue 1 2006Laura E. Helfritz Abstract Certain personality traits have been associated with impulsive aggression in both college and community samples, primarily irritability, anger/hostility, and impulsivity. The literature regarding the psychopathology associated with impulsive aggression is relatively sparse and strongly emphasizes DSM-IV-TR [APA, 2000] Axis II personality disorders, although some comorbidity with Axis I clinical disorders has been reported. The current study compares impulsive aggressive (IA) college students with their non-aggressive peers on several self-report measures of personality and psychopathology. Personality results were as predicted, with IAs scoring higher than controls on measures of impulsivity and aggression. Additionally, the Psychopathic Personality Inventory (PPI), which was given for exploratory purposes, revealed a unique pattern of psychopathic traits in impulsive aggression that contained key differences from the callous-unemotional profile seen in premeditated aggression. Contrary to our hypothesis that a specific pattern of psychopathology (personality disorders, bipolar disorder, and adult attention deficit hyperactivity disorder) would emerge for impulsive aggression, IAs scored significantly higher than controls on nearly every clinical scale of the Personality Assessment Inventory (PAI; Somatic Complaints, Anxiety, Anxiety-Related Disorders, Depression, Mania, Schizophrenia, Borderline Features, Antisocial Features, Alcohol Problems, and Drug Problems), indicating a global elevation of psychopathology. In conclusion, while the personality traits and behaviors that characterize impulsive aggression are relatively consistent across individuals, its associated psychopathology is unexpectedly variable. Aggr. Behav. 00:1,10, 2005. © 2005 Wiley-Liss, Inc. [source] Comparison of one-week and two-week empirical trial with a high-dose rabeprazole in non-cardiac chest pain patientsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2009Jeong Hwan Kim Abstract Background:, In patients with non-cardiac chest pain (NCCP), the optimal duration of an empirical trial with a high-dose proton pump inhibitor (PPI) is unclear. We aimed to compare the efficacy of one-week and two-week PPI trial in patients with weekly or more than weekly NCCP and to determine its optimal duration for diagnosing gastroesophageal reflux disease (GERD)-related NCCP. Methods:, Forty-two patients with at least weekly NCCP were enrolled. The baseline symptoms were assessed using a daily symptom diary for seven days. Also, esophago-gastro-duodenoscopy and 24 h esophageal pH monitoring were performed for the diagnosis of GERD. Then, patients were treated with rabeprazole 20 mg twice daily for 14 days. To assess NCCP improvement during the PPI trial, the first week and the second week symptom diary were kept for 1,7 and 8,14 days. The PPI test was considered positive if a symptom score improved (50% compared to the baseline. Results:, There was no significant difference for a positive PPI test between GERD-related NCCP group (n = 8, 50%) and non GERD-related NCCP group (n = 6, 23%) during the first week of the PPI test. However, during the second week, GERD-related NCCP had a higher positive PPI test (n = 13, 81%) than non GERD-related NCCP (n = 7, 27%) (P = 0.001) with a sensitivity and specificity of 81% and 62%, respectively. Conclusions:, The rabeprazole empirical trial was diagnostic for patients with GERD-related NCCP, and its optimal duration was determined to be at least two weeks. [source] Effect of the CYP2C19 polymorphism on the eradication rate of Helicobacter pylori infection by 7-day triple therapy with regular proton pump inhibitor dosageJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8pt1 2008Jung Mook Kang Abstract Background and Aim:, Proton pump inhibitors (PPI) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) in the liver. We investigated whether the CYP2C19 genotype plays a role in the eradication rate of Helicobacter pylori (H. pylori) infection in patients receiving pantoprazole- or esomeprazole-based triple therapy. Methods:, A total of 327 patients infected with H. pylori were treated with either pantoprazole or esomeprazole, plus amoxicillin and clarithromycin for 7 days. The presence of the CYP2C19 genotype was determined by pyrosequencing. Results:, The overall H. pylori eradication rate was 85%; 82.6% for the PAC regimen, and 88.3% for the EAC regimen; the differences were not statistically significant. The overall eradication rate in the poor metabolizer groups (PM) was significantly higher than in the extensive metabolizer groups (EM) (97.4% vs 83.3%; P = 0.016). The eradication rates in the EM and PM groups were 80.8% and 95.7% for the PAC regimen and 86.8% and 100% for the EAC regimen, respectively. Conclusion:, The results of this study suggest that the CYP2C19 genotype status may play a role in the H. pylori eradication rate in patients receiving pantoprazole or esomeprazole-based triple therapy. [source] Low-dose intravenous pantoprazole for optimal inhibition of gastric acid in Korean patientsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2007Jung-Hwan Oh Abstract Background and Aim:, Proton-pump inhibitor (PPI) therapy for bleeding ulcers is more efficacious in Asian patients than in non-Asian patients. The aim of this study was to evaluate the efficacy of various doses of pantoprazole on intragastric acidity in Korean patients. Methods:, A prospective randomized study was conducted in 52 patients either with bleeding peptic ulcers after successful endotherapy or who received endoscopic mucosal resection for gastric neoplasms. Patients were randomized into two doses of intravenous pantoprazole: 40 mg q.d. and 40 mg b.i.d. We compared these results with our preliminary study utilizing high-dose pantoprazole (80 mg + 8 mg/h). The potential contribution of CYP2C19 genetic polymorphisms and the presence of Helicobacter pylori were also assessed. Results:, Pantoprazole 40 mg b.i.d. and high-dose pantoprazole demonstrated better inhibition of intragastric acid than pantoprazole q.d. (P < 0.05). The pantoprazole 40 mg q.d. group exhibited significant variations in acid inhibition correlating with CYP2C19 genotype. Median 24 h pH values did not differ significantly between the pantoprazole b.i.d. and high-dose pantoprazole groups, regardless of H. pylori infection status. A median intragastric pH < 6.0 was observed in only three of 28 patients in the 40 mg b.i.d. group; these three patients were extensive metabolizers. Conclusion:, A 40 mg b.i.d. dose of pantoprazole is sufficient to maintain pH > 6.0 in Korean patients, except for patients with extensive metabolizing CYP2C19 genotypes. [source] Gastro-oesophageal reflux disease in AsiaJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2000Khean-Lee Goh Abstract Gastro-oesophageal reflux disease (GORD) occurs more frequently in Europe and North America than in Asia but its prevalence is now increasing in many Asian countries. Many reasons have been given for the lower prevalence of GORD in Asia. Low dietary fat and genetically determined factors, such as body mass index and maximal acid output, may be important. Other dietary factors appear to be less relevant. Increased intake of carbonated drinks or aggravating medicines may influence the increasing rates of GORD in some Asian countries but no strong evidence links other factors, such as the age of the population, smoking or alcohol consumption, to GORD. The management of GORD in Asia is similar to that in Europe and North America but the lower incidence of severe oesophagitis in Asia may alter the approach slightly. Also, because Asians tend to develop stomach cancer at an earlier age, endoscopy is used routinely at an earlier stage of investigation. Gastro-oesophageal reflux disease is essentially a motility disorder, so short-term management of the disease can usually be achieved using prokinetic agents (or histamine (H2)-receptor antagonists). More severe and recurrent GORD may require proton pump inhibitors (PPI) or a combination of prokinetic agents and PPI. The choice of long-term treatment may be influenced by the relative costs of prokinetic agents and PPI. © 2000 Blackwell Science Asia Pty Ltd [source] Trial of fenobam, an mGluR5 antagonist, in adults with Fragile X SyndromeJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008R. Hagerman Background: Recent advances in the study of the Fragile X knockout mouse model have demonstrated enhanced activity of the metabolic glutamate receptor 5 (mGluR5) pathway. The use of mGluR5 antagonists has rescued behavioural, cognitive and dendritic structural abnormalities in the knockout mouse. An initial phase II trial in adults with FXS was approved by the FDA. Method: We have completed this initial trial of fenobam (50 mg to 150 mg/dose) in twelve adults with FXS (mean age 23.9 (SD 5.4; range 18.7,30.7 years) seen either at UC Davis MIND Institute or at RUSH, University in Chicago, to assess safety, side-effects, and metabolism after a single dose. Results: Outcome measures included prepulse inhibition (PPI) and a continuous performance task (CPT). All patients tolerated this single dose without significant side-effects. The metabolism of fenobam in patients with FXS is similar to controls and peaks at approximately 180 minutes after oral dose. Fifty percent of the patients had a 20% or more improvement in PPI that is significantly different from test-retest changes in PPI previously reported in individuals with FXS (p = 0.03). This effect was more pronounced in males. The majority of patients scored at ceiling on the CPT so it was not a helpful measure to assess medication benefits. Conclusion: This work documents the safety and aspects of the metabolism of fenobam in patients with FXS and will facilitate further expansion of fenobam trials in patients with FXS. Although fenobam is a targeted treatment for FXS, subgroups of autism may also benefit from fenobam treatment. [source] Organic dyes as small molecule protein,protein interaction inhibitors for the CD40,CD154 costimulatory interactionJOURNAL OF MOLECULAR RECOGNITION, Issue 1 2010Peter Buchwald Abstract It is becoming increasingly clear that small molecules can often act as effective protein,protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40,CD154 costimulatory interaction with activities in the low micromolar (µM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (,G0/nonhydrogen atom,=,0.8,kJ/NnHa) approaching the average of known promising small-molecule PPI inhibitors (,1.0,kJ/NnHa). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1,TNF- , interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40,CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general. Copyright © 2009 John Wiley & Sons, Ltd. [source] Serotonin transporter, 5-HT1A receptor, and behavior in DBA/2J mice in comparison with four inbred mouse strainsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 16 2009Nina K. Popova Abstract Prepulse inhibition (PPI), the reduction in acoustic startle produced when it is preceded by a weak prepulse stimulus, is impaired in schizophrenic patients. The DBA/2J mouse strain displayed deficient PPI and is therefore suggested as an experimental animal model for the loss of sensorimotor gating in schizophrenia. Brain serotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder and schizophrenia. In the present study, behavior, 5-HT transporter (5-HTT) mRNA level, 5-HT1A receptor mRNA level, and 5-HT1A receptor density in the brain regions were studied in DBA/2J mice in comparison with four inbred mouse strains (CBA/Lac, C57BL/6, BALB/c, and ICR). A decrease in 5-HTT mRNA level in the midbrain and a reduced density of 5-HT1A receptors in the frontal cortex without significant changes in 5-HT1A receptor mRNA level in DBA/2J mice were found. It was shown that, along with decreased PPI, DBA/2J mice demonstrated considerably reduced immobility in the tail suspension test and in the forced swim test. No significant interstrain differences in intermale aggression, or in light-dark box and elevated plus-maze tests, were found. The results suggested the involvement of decreased 5-HTT gene expression and 5-HT1A receptor density in genetically defined PPI deficiency and showed a lack of any association between PPI deficiency and predisposition to aggressive, anxiety, and depressive-like behaviors. © 2009 Wiley-Liss, Inc. [source] Activation of phosphoinositide-3 kinase/Akt pathway by FeSO4 in rat cerebral cortex synaptic endingsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2007Romina M. Uranga Abstract The aim of this work was to study the involvement of the phosphoinositide-3-kinase (PI3K)/Akt pathway in synaptic endings incubated under oxidative stress conditions. Synaptosomes purified from rat cerebral cortex were exposed to FeSO4 (50 ,M) for different periods of time. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenate (LDH) leakage were significantly affected after 5 min of incubation in the presence of FeSO4, with respect to control conditions. In whole synaptosomes incubated in the presence of [,- 32P]ATP, phosphoinositide (PPI) labeling was increased after 5 min of Fe2+ exposure. This effect was prevented by the specific PI3K inhibitor LY294002. Anti-p85 immunoprecipitates (IPs) obtained from synaptosomes preincubated with Fe2+ (5 min) showed a PI3K activity two-fold higher than the activity recovered under control conditions. Additionally, Akt activation was temporally coincident with PI3K activation. LY294002 was not able to prevent the LDH leakage and diminution of MTT reduction induced by Fe2+. Our results demonstrate that free iron provokes the early activation of PI3K/Akt pathway, but this activation is not sufficient for protecting synaptic endings from oxidative damage. © 2007 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||||||||