PPI

We have evaluated the effects of the proline homologue Aze (1) (azetidine-2-carboxylic acid) on growth of Escherichia coli strains used to over-express recombinant forms of murine myelin basic protein (rmMBP), and on the degree of misincorporation. Addition of Aze to minimal media resulted in severe diminution of growth rate, but rmMBP could still be produced and purified. Mass spectrometry indicated that a detectable proportion of the rmMBP produced had incorporated Aze instead of proline (Pro), to a maximum of three of eleven possible sites. Molecular modelling of a proline-rich region of rmMBP illustrated that the misincorporation of Aze at any site would cause a severe bend in the polypeptide chain, and that multiple Pro ? Aze substitutions would completely disrupt a poly-proline type II structure that has been conjectured to be functionally significant.

Low doses of aspirin can injure the gastric mucosa. It is not clear whether other drugs such as the antiplatelet agent clopidogrel also cause gastric mucosal injury or exacerbate aspirin-induced injury, or whether proton pump inhibitors prevent damage. METHODS: Twenty Japanese subjects with different CYP2C19 genotypes were randomly assigned to groups that were given a low dose of aspirin (100 mg; A), clopidogrel (75 mg; C), low dose of aspirin and clopidogrel (AC), or low dose of aspirin in combination with clopidogrel and rabeprazole (10 mg; ACR) once daily for 7 days. Subjects underwent gastroduodenoscopy and platelet tests on days 3 and 7; gastric mucosal damage was assessed by using the modified Lanza score (MLS). We performed 24-hour intragastric pH monitoring on day 7 of each regimen. We also analyzed the effects of the AC regimen on 30 patients with different CYP2C19 genotypes. RESULTS: Subjects in groups A, C, and AC had significantly higher levels of gastric mucosal damage on days 3 and 7, compared with baseline. The median MLS for the AC group was similar to that of the A group. Helicobacter pylori-negative subjects in the ACR group with different CYP2C19 genotypes had significant differences in MLS, intragastric pH, and platelet function. Gastric mucosal injury was inhibited equally among H pylori-positive subjects in the ACR group. Rabeprazole did not appear to affect platelet function or intragastric pH in subjects given clopidogrel. CONCLU-SIONS: Clopidogrel and low doses of aspirin cause a similar degree of gastric mucosal damage. Rabeprazole prevented this damage without reducing the antiplatelet function of clopidogrel. However, its prophylactic effect varies with CYP2C19 genotype in H pylori-negative subjects.

We studied the effects of preconceptional exposure to multiwalled carbon nanotubes (MWCNTs): mature, female C57BL/6J mice were intratracheally instilled with 67 g NM-400 MWCNT, and the following day co-housed with mature males, in breeding pairs. Time to delivery of the first litter, litter parameters, maternal inflammation and histopathology of lung and liver were recorded. In male offspring, locomotor activity, startle response, and daily sperm production (DSP) were assessed. In the dams, lung and liver bore evidence of MWCNT exposure when assessed 6 weeks and 4 months after exposure. A short delay in the delivery of the first litter was observed in exposed females. Litter parameters, behavior and DSP were similar in control and exposed groups. In conclusion, instillation of a single dose of MWCNT induced long lasting pathological changes in dam lung and liver. Theoretically, lung inflammation due to particle exposure could interfere with female reproductive parameters. Whether the observed lag in delivery of a first litter was in fact caused by exposure to MWCNT should be addressed in a study designed specifically to elucidate effects on the early processes involved in establishment of pregnancy. Exposure was not associated with changes in the assessed gestational or offspring parameters.

Background & Aims: Antibiotic resistance is a major issue in anti-Helicobacter pylori treatment. This study was aimed at assessing the efficacy of 2 therapies in patients with resistant H pylori infection. Methods: Patients who had failed 1 or more eradication regimens underwent upper gastrointestinal endoscopy and 2 antral and 2 corpus biopsy specimens were taken for histology and culture. Metronidazole, clarithromycin, and amoxicillin resistance were determined by E-test. Patients were randomly assigned to 2 therapies: 1 group received pantoprazole 40 mg, amoxicillin 1 g, levofloxacin 250 mg, all twice daily for 10 days, and the other group was treated with omeprazole 20 mg twice daily for the first week and omeprazole 20 mg twice daily, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subcitrate 240 mg twice daily for the second week. Therapeutic success was evaluated by 13 C urea breath test after 4 weeks of treatment. Results: We enrolled 44 patients in the levofloxacin-based regimen and 46 patients in the quadruple therapy. The former was successful in 31 of 44 (70%; 95% confidence interval: 53-87) and the latter in 17 of 46 (37%; 95% confidence interval: 23-47) patients, using intention-to-treat (ITT) analysis (P < .001). The rates of H pylori resistance to metronidazole, clarithromycin, and amoxicillin were 46%, 12%, and 0%, respectively. Resistance to both metronidazole and clarithromycin was found in 10% of cases. Conclusions: Triple therapy containing levofloxacin was better than quadruple therapy. The 70% success rate observed indicates that 10 days of pantoprazole, amoxicillin, and levofloxacin should be considered in patients who had failed 1 or more eradication regimens.

The purpose of this work was to explore the relation between protein-protein interactions (PPIs) and solution viscosity at high protein concentration using three monoclonal antibodies (mAbs), two of the IgG 4 subclass and one of the IgG 1 subclass. A range of methods was used to quantify the PPI either at low concentration (interaction parameter (k D ) obtained from dynamic light scattering, DLS) or at high concentration (solution storage modulus (G 0 ) from ultrasonic shear rheology). We also developed a novel method for the determination of PPI using the apparent radius of the protein at either low or high protein concentration determined using DLS. The PPI measurements were correlated with solution viscosity (measured by DLS using polystyrene nanospheres and ultrasonic shear rheology) as a function of pH (4-9) and ionic strength (10, 50 and 150 mM). Our measurements showed that the highest solution viscosity was observed under conditions with the most negative k D , the highest apparent radius and the lowest net charge. An increase in ionic strength resulted in a change in the nature of the PPI at low pH from repulsive to attractive. In the neutral to alkaline pH region the mAbs behaved differently with respect to increase in ionic strength. Two mAbs (A and B) showed little or no effect of increasing ionic strength, whereas mAb-C showed a remarkable decrease in attractive PPI and viscosity.

Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficult challenge. The cellular membrane is very effective in its role as a selectively permeable barrier. While it is essential for cell survival and function, also presents a major barrier for intracellular delivery of cargo such as therapeutic and diagnostic agents. In recent years, cell-penetrating peptides (CPPs), that are relatively short cationic and/or amphipathic peptides, received great attention as efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo such as plasmid DNA (pDNA), small interfering RNA (siRNAs), drugs, and nanoparticulate pharmaceutical carriers. This review discusses the various uptake mechanisms of these peptides. Furthermore, we discuss recent advances in the use of CPP for the efficient delivery of nanoparticles, nanocarriers, DNA, siRNA, and anticancer drugs to the cells. In addition, we have been highlighting new results for improving endosomal escape of CPP-cargo molecules. Finally, pH-responsive and activable CPPs for tumor-targeting therapy have been described.

Alterations of genetic and epigenetic features can provide important insights into the natural history of breast cancer. Although DNA methylation analysis is a rapidly developing field, a reproducible epigenetic blood-based assay for diagnosis and follow-up of breast cancer has yet to be successfully developed into a routine clinical test. The aim of this study was to review multiple serum DNA methylation assays and to highlight the value of those novel biomarkers in diagnosis, prognosis and prediction of therapeutic outcome. Serum is readily accessible for molecular diagnosis in all individuals from a peripheral blood sample. The list of hypermethylated genes in breast cancer is heterogeneous and no single gene is methylated in all breast cancer types. There is increasing evidence that a panel of epigenetic markers is essential to achieve a higher sensitivity and specificity in breast cancer detection. However, the reported percentages of methylation are highly variable, which can be partly explained by the different sensitivities and the different intra-/inter-assay coefficients of variability of the analysis methods. Moreover, there is a striking lack of receiver operating characteristic (ROC) curves of the proposed biomarkers. Another point of criticism is the fact that 'normal' patterns of DNA methylation of some tumor suppressor and other cancer-related genes are influenced by several factors and are often poorly characterized. A relatively frequent methylation of those genes has been observed in high-risk asymptomatic women. Finally, there is a call for larger prospective cohort studies to determine methylation patterns during treatment and follow-up. Identification of patterns specific for a differential response to therapeutic interventions should be useful. Only in this way, it will be possible to evaluate the predictive and prognostic characteristics of those novel promising biomarkers.

Personal space, defined as the distance individuals choose to maintain between themselves and others, is an indicator of affiliation and closeness. Most paradigms that measure personal space preferences involve explicit choice and therefore fail to examine the implicit aspects of such preferences. In the current study, we sought to investigate an implicit form of interpersonal space that is more closely related to real-life situations involving affiliation. We studied the effects of oxytocin (OT) on neural networks that involve affiliation and tested the impact on personal space preferences. In a double-blind placebo-controlled study, we asked participants to choose between two rooms that differed only in the distances between two stimuli. The stimuli were either social stimuli (two chairs) or non-social stimuli (table and plant). The behavioral results showed that OT caused participants to choose a closer space in social blocks but did not affect their choices in non-social blocks....

The bioavailability of hydrophobic drugs is critically dependent on the development of efficient and safe drug delivery vehicles. Nanoparticulate pharmaceutical carriers commonly used in delivery of active components are often non-ionic in nature. Among them polyether based amphiphiles have become increasingly relevant over the past decades. Polyether based amphiphiles exhibit good chemical stability, high water solubility, low toxicity, have decreased interaction with blood components, and are highly biocompatible; and thus have been applied in biomedical and pharmaceutical areas. The current review highlights the synthetic progression and biomedical applications of these non-ionic polyether-based amphiphilic architectures, some unresolved issues and challenges, along with the future perspective of polyether based nanocarriers for delivery of active components.

Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficult challenge. The cellular membrane is very effective in its role as a selectively permeable barrier. While it is essential for cell survival and function, also presents a major barrier for intracellular delivery of cargo such as therapeutic and diagnostic agents. In recent years, cell-penetrating peptides (CPPs), that are relatively short cationic and/or amphipathic peptides, received great attention as efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo such as plasmid DNA (pDNA), small interfering RNA (siRNAs), drugs, and nanoparticulate pharmaceutical carriers. This review discusses the various uptake mechanisms of these peptides. Furthermore, we discuss recent advances in the use of CPP for the efficient delivery of nanoparticles, nanocarriers, DNA, siRNA, and anticancer drugs to the cells. In addition, we have been highlighting new results for improving endosomal escape of CPP-cargo molecules. Finally, pH-responsive and activable CPPs for tumor-targeting therapy have been described.

The superfamily of G-protein-coupled receptors (GPCRs) could be subclassified into 7 families (A, B, large N-terminal family B-7 transmembrane helix, C, Frizzled/Smoothened, taste 2, and vomeronasal 1 receptors) among mammalian species. Cloning and functional studies of GPCRs have revealed that the superfamily of GPCRs comprises receptors for chemically diverse native ligands including (1) endogenous compounds like amines, peptides, and Wnt proteins (i.e., secreted proteins activating Frizzled receptors); (2) endogenous cell surface adhesion molecules; and (3) photons and exogenous compounds like odorants. The combined use of site-directed mutagenesis and molecular modeling approaches have provided detailed insight into molecular mechanisms of ligand binding, receptor folding, receptor activation, G-protein coupling, and regulation of GPCRs. The vast majority of family A, B, C, vomeronasal 1, and taste 2 receptors are able to transduce signals into cells through G-protein coupling. However, G-protein-independent signaling mechanisms have also been reported for many GPCRs. Specific interaction motifs in the intracellular parts of these receptors allow them to interact with scaffold proteins. Protein engineering techniques have provided information on molecular mechanisms of GPCR-accessory protein, GPCR-GPCR, and GPCR-scaffold protein interactions. Site-directed mutagenesis and molecular dynamics simulations have revealed that the inactive state conformations are stabilized by specific interhelical and intrahelical salt bridge interactions and hydrophobic-type interactions. Constitutively activating mutations or agonist binding disrupts such constraining interactions leading to receptor conformations that associates with and activate G-proteins. .no (K. Kristiansen).

The aim of this study was to describe sex differences in the behavioural effects of N,N-diethyllysergamide (LSD) (locomotor activity and other behavioural repertoire in the open field) and its effects on sensorimotor gating in rats (prepulse inhibition (PPI) of the acoustic startle reaction). Three groups of animals were analysed: males, oestral and pro-oestral phase females (EP females), and metoestral and

Understanding the function of the entorhinal cortex (EC) has been an important subject over the years, not least because of its cortical intermediary to and from the hippocampus proper, and because of electrophysiological advances which have started to reveal the physiology in behaving animals. Clearly, a lot more needs to be done but is clear to date that EC is not merely a throughput station providing all hippocampal subfields with sensory information, but that processing within EC contributes significantly to attention, conditioning, event and spatial cognition possibly by compressing representations that overlap in time. These are transmitted to the hippocampus, where they are differentiated again and returned to EC. Preliminary evidence for such a role, but also their possible pitfalls are summarised.

A prolonged period of ischaemia followed by reperfusion irreversibly damages the heart. Such reperfusion injury (RI) involves opening of the mitochondrial permeability transition pore (MPTP) under the conditions of calcium overload and oxidative stress that accompany reperfusion. Protection from MPTP opening and hence RI can be mediated by ischaemic preconditioning (IP) where the prolonged ischaemic period is preceded by one or more brief (2-5 min) cycles of ischaemia and reperfusion. Following a brief overview of the molecular characterisation and regulation of the MPTP, the proposed mechanisms by which IP reduces pore opening are reviewed including the potential roles for reactive oxygen species (ROS), protein kinase cascades, and mitochondrial potassium channels. It is proposed that IP-mediated inhibition of MPTP opening at reperfusion does not involve direct phosphorylation of mitochondrial proteins, but rather reflects diminished oxidative stress during prolonged ischaemia and reperfusion. This causes less oxidation of critical thiol groups on the MPTP that are known to sensitise pore opening to calcium. The mechanisms by which ROS levels are decreased in the IP hearts during prolonged ischaemia and reperfusion are not known, but appear to require activation of protein kinase Cε, either by receptor-mediated events or through transient increases in ROS during the IP protocol. Other signalling pathways may show cross-talk with this primary mechanism, but we suggest that a role for mitochondrial potassium channels is unlikely. The evidence for their activity in isolated mitochondria and cardiac myocytes is reviewed and the lack of specificity of the pharmacological agents used to implicate them in IP is noted. Some K + channel openers uncouple mitochondria and others inhibit respiratory chain complexes, and their ability to produce ROS and precondition hearts is mimicked by bona fide uncouplers and respiratory chain inhibitors. IP may also provide continuing protection during reperfusion by preventing a cascade of MPTP-induced ROS production followed by further MPTP opening. This phase of protection may involve survival kinase pathways such as Akt and glycogen synthase kinase 3 (GSK3) either increasing ROS removal or reducing mitochondrial ROS production.

No. Dokumen ……… No. Revisi ……… Halaman 1 dari 3 STANDAR PROSEDUR OPERASIONAL (SPO) Tanggal terbit 02-05-2018 Ditetapkan, Direktur RSUD Simeulue d r g. FARHAN NIP. 19821126 201003 1 001 PENGERTIAN Kebersihan Tangan adalah proses pembersihan kotoran dan mikroorganisme pada tangan yang di dapat melalui kontak dengan pasien, petugas kesehatan lain dan permukaan lingkungan (flora transien) dengan menggunakan sabun/antiseptik dibawah air mengalir atau menggunakan hand rub berbasis alkohol. 1.

Purpose: To estimate the association between proton-pump inhibitor (PPI) use and hip fracture. Methods: We conducted a case-control study of 6774 pairs of men aged 45 years or older, matched on age, race, and medical center. Cases sustained incident hip fractures in 1997e2006. Fracture date was index date for each case-control pair. PPI exposure was identified from electronic pharmacy records, 1991e2006. PPI use was measured as (1) ever versus never; (2) adherence; (3) duration; and recentness. Omeprazole and pantoprazole were analyzed separately using conditional logistic regression, adjusted for comorbidities. Nonusers were the referent group. Results: Eight hundred ninety-six (13.2%) cases and 713 (10.5%) controls used omeprazole before index date (matched odds ratio [OR], 1.13; 95% confidence interval [CI], 1.01e1.27). Greatest adherence (medication possession ratio > 80%) (OR, 1.33; 95% CI, 1.09e1.62), highest tertile of duration (OR, 1.23; 95% CI, 1.02e1.48), and recent use (OR, 1.22; 95% CI, 1.02e1.47) were associated with hip fracture. Six hundred ninety-four (10.2%) cases and 576 (8.5%) controls had used pantoprazole (OR, 1.10; 95% CI, 0.97e1.24). Longest duration (OR, 1.25; 95% CI, 1.02e1.53) and most recent use (OR, 1.38; 95% CI, 1.12e1.71) were associated with hip fracture. Our study suggests that PPI use and hip fractures are associated, with risk increasing with longer duration and more recent use.

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT 3 receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT 3 receptor blockade. Ketamine (3-40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed nonmatching-to-sample tasks in rats. The 5HT 3 receptor antagonist MDL 72222 (0.3-3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50-66 and 3 mg/kg, respectively) and together (12.5-25 and 1 mg/kg). The present data suggest that 5-HT 3 receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action. D

The aim of this study was to assess the association between the loss-of-function cytochrome P450 2C19 (CYP2C19)*2 variant (10 studies, 11,959 patients) or the use of proton pump inhibitors (PPIs) (13 studies, 48,674 patients) and ischemic outcomes (major adverse cardiovascular events [MACE]) in patients treated with clopidogrel.

© 2007 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología 21 Martín Gómez, MD, 1 William Otero, MD, 2 Óscar Gutiérrez, MD. 3 Tratamiento de la infección por Helicobacter pylori. Encuesta en un grupo de médicos generales y ...

Background & Aims: Antibiotic resistance is a major issue in anti-Helicobacter pylori treatment. This study was aimed at assessing the efficacy of 2 therapies in patients with resistant H pylori infection. Methods: Patients who had failed 1 or more eradication regimens underwent upper gastrointestinal endoscopy and 2 antral and 2 corpus biopsy specimens were taken for histology and culture. Metronidazole, clarithromycin, and amoxicillin resistance were determined by E-test. Patients were randomly assigned to 2 therapies: 1 group received pantoprazole 40 mg, amoxicillin 1 g, levofloxacin 250 mg, all twice daily for 10 days, and the other group was treated with omeprazole 20 mg twice daily for the first week and omeprazole 20 mg twice daily, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subcitrate 240 mg twice daily for the second week. Therapeutic success was evaluated by 13 C urea breath test after 4 weeks of treatment. Results: We enrolled 44 patients in the levofloxacin-based regimen and 46 patients in the quadruple therapy. The former was successful in 31 of 44 (70%; 95% confidence interval: 53-87) and the latter in 17 of 46 (37%; 95% confidence interval: 23-47) patients, using intention-to-treat (ITT) analysis (P < .001). The rates of H pylori resistance to metronidazole, clarithromycin, and amoxicillin were 46%, 12%, and 0%, respectively. Resistance to both metronidazole and clarithromycin was found in 10% of cases. Conclusions: Triple therapy containing levofloxacin was better than quadruple therapy. The 70% success rate observed indicates that 10 days of pantoprazole, amoxicillin, and levofloxacin should be considered in patients who had failed 1 or more eradication regimens.

Effects of steroids in acute tubulointerstitial nephritis (ATIN) are still controversial. This study shows a greater degree of improvement in renal function in steroid-treated patients with ATIN. Yet, no correlation was shown between the degree of renal recovery and delay in starting steroids.

Nicotinic acetylcholine receptors (nAChRs) in the muscle, autonomic ganglia, and brain are targets for pharmacologically administered nicotine. Several of the subunits that combine to form neuronal nicotinic receptors have been deleted by knockout or mutated by knockin in mice using homologous recombination. We will review the biochemical, pharmacological, anatomical, physiological, and behavioral phenotypes of mice with genetically altered neuronal nAChR subunits. Clinically relevant mutations in nAChR genes will also be discussed. In addition, some of the signal transduction pathways activated through nAChRs will be described in order to delineate the longer-term changes that might result from persistent activation or inactivation of nAChRs. Genetically manipulated mice have greatly increased our understanding of the subunit composition and physiological properties of nAChRs in vivo. In addition, these mice have provided a model system to determine the molecular basis for many of the pharmacological actions of nicotine on neurotransmitter release and behavior. Genetic manipulations in mice have also elucidated the role of nAChR subunits in various disease states, and suggest several avenues for drug development. D

The flagellated protozoan Giardia intestinalis is one of the most prevalent human-infective parasites with a worldwide distribution. This parasite must encyst to complete the life cycle and N-acetylgalactosamine is produced from endogenous glucose for cyst wall synthesis during the transformation. UDP-N-acetylglucosamine pyrophosphorylase in G. intestinalis (GiUAP, EC 2.7.7.23) is the fourth enzyme in the inducible pathway of N-acetylgalactosamine biosynthesis, catalysing the conversion of N-acetylglucosamine-1-P to UDP-Nacetylglucosamine. In this study the gene GiUAP was cloned and sequenced from the Portland 1 strain using PCR techniques. It has an ORF of¨1.3 kb and contains no introns. BLAST and ClustalW analysis of the deduced amino acid sequence revealed significant similarities to other eukaryotic UAPs with putative active sites identified. Southern hybridization showed that GiUAP exists as a singlecopy gene and it was shown to have two transcripts by RT-PCR and Northern hybridization. RLM-RACE identified both 5V and 3V untranslated regions and suggested the transcripts exist as a 5V -capped mRNA, with the use of two tandem polyadenylation sites to generate two unusually long giardial 3Vuntranslated regions of¨522 bp and¨3 kb. Moreover, a recombinant protein (rGiUAP) was expressed in E. coli and subjected to physical characterizations. Surprisingly the results obtained in this study were significantly different from those reported for the GiUAP in MR4 strain, suggesting this gene is under different transcription control in different strains of G. intestinalis. This report describes the molecular characterization of GiUAP and provides an opportunity to explore the control of gene expression during encystation of the parasite. D

Behavioral abnormalities related to processing negative emotions such as fear have been demonstrated in schizophrenia. The amygdala is strongly associated with fear processing, and alterations in amygdala function and structure have been demonstrated in schizophrenia. Further, functional disconnectivity has been attributed as key to the etiology of schizophrenia, with a number of lines of evidence supporting this theory. In the present study, we examine the effective connectivity corresponding to fear processing, from the amygdala to the whole brain, and compare this between patients with schizophrenia and control participants. An implicit facial emotion processing task was performed by 19 patients with schizophrenia and 24 matched controls during fMRI scanning. During the task, participants made gender judgments from facial images with either neutral or fearful emotion. Neural response to fearful images versus neutral was used as contrast of interest to estimate effective connectivity between the amygdala and the whole brain using the psycho-physiological interactions approach. This connectivity was compared between patients with schizophrenia and healthy controls. We show that when looking at fearful compared to neutral faces patients with schizophrenia show significantly reduced effective connectivity from the amygdala to a large cluster of regions including parts of the precuneus and parietal lobe, compared to healthy controls. These regions have been associated with emotion processing and high level social cognition tasks involving self related processing and mental representations about other people. The reduced amygdala connectivity in schizophrenia shown here further illuminates the neural basis for the behavioral abnormalities in emotional and social function found in the disorder.

See Covering the Cover synopsis on page 32; see editorial on page 42. BACKGROUND & AIMS: A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients' risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/ or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC. METHODS: We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I 2 test. RESULTS: The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07À1.97), but there was substantial heterogeneity among studies (I 2 , 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91À1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31À1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03À2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58À10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56À2.73), the OR for dabigatran was 1.58 (95% CI, 1.29À1.93), the OR for edoxaban was 0.31 (95% CI, 0.01À7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21À1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00À1.34), with similar trends among subgroups. CONCLUSIONS: Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.

Background & Aims: There are numerous gastroprotective strategies recommended for reducing the risk of upper gastrointestinal (GI) complications in long-term users of nonsteroidal anti-inflammatory drugs (NSAIDs). The relative efficacy of the different strategies alone or in combination is uncertain.

Randomized trials suggest highdose proton-pump inhibitors (PPIs) administered before gastroscopy in suspected upper gastrointestinal bleeding downstage bleeding ulcer stigmata. We assessed the costeffectiveness of this approach. Methods: A decision model compared high-dose IVPPI initiated while awaiting endoscopy with IVPPI administration on the basis of endoscopic findings. IVPPIs were given to all patients undergoing endoscopic hemostasis for 72 hours thereafter. Once the IV regimen was completed or for patients with low-risk endoscopic lesions, an oral daily PPI was given for the remainder of the time horizon (30 days after endoscopy). The unit of effectiveness was the proportion of patients without rebleeding, representing the denominator of the cost-effectiveness ratio (cost per no rebleeding). Probabilities and costs were derived from the literature and national databases. Results:

This paper assessed the neural systems involved in processing of dynamic facial expressions in adolescents. The processing of facial expressions changes as a function of age, and it is thus important to understand how healthy adolescent subjects process dynamic facial expressions prior to analyzing disease-related changes. We hypothesized that viewing of dynamic facial expressions with opposing valences (happy vs. fearful) induces differential activations and deactivations in the brain. 27 healthy adolescents (9 ♀, 18 ♂, mean age = 14.5 years; age range 11.6-17.3 years) were examined by using the ASSQ and K-SADS-PL and scanned with 1.5-T fMRI during viewing of dynamic facial expressions and mosaic control images. The stimuli activated the same areas as previously seen in

The dose of warfarin needed to obtain a therapeutic anticoagulation level varies widely among patients and can undergo abrupt changes for unknown reasons. Drug interactions and genetic factors may partially explain these differences. Intestinal flora produces vitamin K 2 (VK 2 ) and patients with small intestinal bacterial overgrowth (SIBO) rarely present reduced INR values due to insufficient dietary vitamin K. The present study was undertaken to investigate whether SIBO occurrence may affect warfarin dose requirements in anticoagulated patients. Based on their mean weekly dose of warfarin while on stable anticoagulation, 3 groups of 10 patients each were defined: low dose (LD, ≤ 17.5 mg/wk of warfarin); high dose (HD, from 35-70 mg/wk); and very high dose (VHD ≥ 70 mg/wk). Each patient underwent a lactulose breath test to diagnose SIBO. Plasma levels of warfarin and vitamin K-analogues were also assessed. Patients with an altered breath test were 50% in the VHD group, 10% in the HD group, and none in the LD group (P = 0.01). Predisposing factors to SIBO were more frequent in the VHD group, while warfarin interfering variables were not. VHD patients were younger and had a higher plasma vitamin K 1 (VK 1 ) concentration (P N 0.05). On the contrary, the plasma VK 2 levels tended to be lower. This pilot study suggests that SIBO may increase a patient's warfarin dose requirement by increasing dietary VK 1 absorption through the potentially damaged intestinal mucosa rather than increasing intestinal VK 2 biosynthesis. Larger studies are needed to confirm these preliminary data and to evaluate the effects of SIBO decontamination on warfarin dosage.

The liver X receptors (LXRa and LXRb) are transcription factors that control the expression of genes primarily involved in cholesterol metabolism. In the brain, in addition to normal neuronal function, cholesterol metabolism is important for APP proteolytic cleavage, secretase activities, Ab aggregation and clearance. Particularly significant in this respect is LXR mediated transcriptional control of APOE, which is the only proven risk factor for late onset Alzheimer's disease. Using a transactivation reporter assay for screening pharmacologically active compounds and off patent drugs we identified the proton pump inhibitor Lansoprazole as an LXR agonist. In secondary screens and counter-screening assays, it was confirmed that Lansoprazole directly activates LXR, increases the expression of LXR target genes in brain-derived human cell lines, and increases Abca1 and Apo-E protein levels in primary astrocytes derived from wild type but not LXRa/b double knockout mice. Other PPIs activate LXR as well, but the efficiency of activation depends on their structural similarities to Lansoprazole. The identification of a widely used drug with LXR agonist-like activity opens the possibility for systematic preclinical testing in at least two diseases-Alzheimer's disease and atherosclerosis.

PPIs), patients may have persistent symptoms of gastroesophageal reflux disease (GERD). We aimed to identify symptom types and frequency experienced by patients on PPI therapy, and to identify the type of reflux, if any, associated with these symptoms. Methods: A retrospective review was performed of 200 patients on PPI with GERD symptoms during ambulatory impedance-pH testing. The symptom index (SI) was determined for each symptom, and an SI of 50% or more was considered positive. Patients were divided into 2 groups: those with exclusively nonacid reflux (NAR) episodes and those with mixed-acid and NAR episodes. Symptom profiles were compared between these 2 groups. Results: A total of 415 symptoms were reported by the 200 patients on twice-daily PPIs. Throat clearing was most common (24%). A total of 110 (27%) were typical symptoms and 305 (73%) were atypical. Typical symptoms were more likely to have a positive SI than atypical symptoms (48% vs 25%, P < .01). Eighty-four patients (42%) had a positive SI, and 116 patients (58%) had a negative SI. One hundred patients (50%) had only NAR; the other 100 had mixed acid and NAR. Heartburn (21% vs 63%, P < .01) and nausea (8% vs 44%, P < .01) were more likely associated with reflux in the mixed-acid and NAR group. Conclusions:

Reverberation can dramatically reduce the depth of amplitude modulations which are critical for speech intelligibility. Psychophysical experiments indicate that humans' sensitivity to amplitude modulation in reverberation is better than predicted from the acoustic modulation depth at the receiver position. Electrophysiological studies on reverberation in rabbits highlight the contribution of neurons sensitive to interaural correlation. Here, we use a prepulse-inhibition paradigm to quantify the gerbils' amplitude modulation threshold in both anechoic and reverberant virtual environments. Data show that prepulse inhibition provides a reliable method for determining the gerbils' AM sensitivity. However, we find no evidence for perceptual restoration of amplitude modulation in reverberation. Instead, the deterioration of AM sensitivity in reverberant conditions can be quantitatively explained by the reduced modulation depth at the receiver position. We suggest that the lack of perceptual restoration is related to physical properties of the gerbil's ear input signals and inner-ear processing as opposed to shortcomings of their binaural neural processing.

Based on the neuromodulatory and homeostatic actions of adenosine, adenosine dysfunction may contribute to the neurobiological and clinical features of schizophrenia. The present model of adenosine dysfunction in schizophrenia takes into consideration the dopamine and glutamate hypotheses, since adenosine exerts neuromodulatory roles on these systems, and proposes that adenosine plays a role in the inhibitory deficit found in schizophrenia. Given the role of adenosine activation of adenosine A1 receptor (A1R) in mediating neurotoxicity in early stages of brain development, pre-and peri-natal complications leading to excessive adenosine release could induce primary brain changes (i.e., first hit). These events would lead to an adenosine inhibitory deficit through a partial loss of A1R that may emerge as reduced control of dopamine activity and increased vulnerability to excitotoxic glutamate action in the mature brain (i.e., second hit). Adenosine dysfunction is reasonably compatible with symptoms, gray and white matter abnormalities, progressive brain loss, pre-and peri-natal risk factors, age of onset, response to current treatments, impaired sensory gating and increased smoking in schizophrenia. Pharmacological treatments enhancing adenosine activity could be effective for symptom control and for alleviating deterioration in the course of the illness. Accordingly, allopurinol, which may indirectly increase adenosine, has been effective and well tolerated in the treatment of schizophrenia. Since much of the evidence for the adenosine hypothesis is preliminary and theoretical, further investigation in the field is warranted.

RESUMO O artigo versa sobre um estudo que tem a intenção de apresentar as principais ações que confirmam a relação entre o Índice Geral de Curso (IGC) e o Plano de Desenvolvimento Institucional (PDI) na perspectiva do Projeto Pedagógico Institucional (PPI) no contexto de faculdades isoladas localizadas no sul do estado de Santa Catarina. No escopo teórico, a pesquisa elenca aspectos que contextualizam a estrutura das faculdades isoladas, considerando a expansão proporcionada a partir de 1996 sob o advento da LDB. Elenca, ainda, considerações sobre o PDI e a sua estrutura dinâmica de seus eixos, os quais são responsáveis pelo desenvolvimento das questões operacionais e estratégicas das instituições. O trabalho, ainda em seu escopo teórico, traz assertivas que consideram o IGC um referencial no contexto avaliativo e regulatório, orientando as atividades acadêmicas e administrativas em nível institucional. A metodologia, para tanto, se esmera em uma pesquisa predominantemente qualitativa, considerando uma entrevista semiestruturada, realizada junto aos Procuradores Institucionais das IES em estudo, utilizando um roteiro como instrumento de coleta de dados. A pesquisa também se consolida como descritiva e explicativa no contexto metodológico, traduzida em análises documentais dos PDIs das instituições em estudo. Os resultados permitem concluir, entre outros aspectos, que o IGC traz influência no PPI das Instituições e orienta um processo de reflexão sobre o desenvolvimento institucional. PAlAvRAS-CHAvE: IGC. PDI. PPI.