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The introduction of Augmented Reality (AR) has attracted several developments, although the people's experience of AR has not been clearly studied or contrasted with the human experience in 2D and 3D environments. Here, the directional task was applied in 2D, 3D, and AR using simplified stimulus in video games to determine whether there is a difference in human answer reaction time prediction using context stimulus. Testing of the directional task adapted was also done. Research question: Are the main differences between 2D, 3D, and AR able to be predicted using Markov chains? Methods: A computer was fitted with a digital acquisition card in order to record, test and validate the reaction time (RT) of participants attached to the arranged RT for the theory of Markov chain probability. A Markov chain analysis was performed on the participants' data. Subsequently, the way certain factors influenced participants RT amongst the three tasks time on the accuracy of the participants was sought in the three tasks (environments) were statistically tested using ANOVA. Results: Markov chains of order 1 and 2 successfully reproduced the average reaction time by participants in 3D and AR tasks, having only 2D tasks with the variance predicted with the current state. Moreover, a clear explanation of delayed RT in every environment was done. Mood and coffee did not show significant differences in RTs on a simplified videogame. Gender differences were found in 3D, where endogenous directional goals are in 3D, but no gender differences appeared in AR where exogenous AR buttons can explain the larger RT that compensate for the gender difference. Our results suggest that unconscious preparation of selective choices is not restricted to current motor preparation. Instead, decisions in different environments and gender evolve from the dynamics of preceding cognitive activity can fit and improve neurocomputational models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mugruza-Vassallo, Granados-Domínguez, Flores-Benites and Córdova-Berríos.)

Risk taking (RT) is an essential component in decision-making process that depicts the propensity to make risky decisions. RT assessment has traditionally focused on self-report questionnaires. These classical tools have shown clear distance from real-life responses. Behavioral tasks assess human behavior with more fidelity, but still show some limitations related to transferability. A way to overcome these constraints is to take advantage from virtual reality (VR), to recreate real-simulated situations that might arise from performance-based assessments, supporting RT research. This article presents results of a pilot study in which 41 individuals explored a gamified VR environment: the Spheres & Shield Maze Task (SSMT). By eliciting implicit behavioral measures, we found relationships between scores obtained in the SSMT and self-reported risk-related constructs, as engagement in risky behaviors and marijuana consumption. We conclude that decontextualized Virtual Reality Serious Games are appropriate to assess RT, since they could be used as a cross-disciplinary tool to assess individuals' capabilities under the stealth assessment paradigm.

Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1. In normal conditions, CPT1C down-regulates SAC1 catalytic activity, allowing efficient GluA1 trafficking to the plasma membrane. However, under low malonyl-CoA levels, such as during glucose depletion, CPT1C-dependent inhibition of SAC1 is released, facilitating SAC1's translocation to ER-TGN contact sites to decrease TGN PI(4)P pools and trigger GluA1 retention at the TGN. Results reveal that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and provide the first report of a SAC1 inhibitor. Moreover, they shed light on how nutrients can affect synaptic function and cognition., (© 2020 Casas et al.)

Anterograde transport of late endosomes or lysosomes (LE/Lys) is crucial for proper axon growth. However, the role of energetic nutrients has been poorly explored. Malonyl-CoA is a precursor of fatty acids, and its intracellular levels highly fluctuate depending on glucose availability or the energy sensor AMP-activated protein kinase (AMPK). We demonstrate in HeLa cells that carnitine palmitoyltransferase 1C (CPT1C) senses malonyl-CoA and enhances LE/Lys anterograde transport by interacting with the endoplasmic reticulum protein protrudin and facilitating the transfer of Kinesin-1 from protrudin to LE/Lys. In cultured mouse cortical neurons, glucose deprivation, pharmacological activation of AMPK or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at the axon terminal, and shortens axon length in a CPT1C-dependent manner. These results identify CPT1C as a new regulator of anterograde LE/Lys transport in response to malonyl-CoA changes, and give insight into how axon growth is controlled by nutrients., Competing Interests: MP, RF, MC, MP, MB, PH, JD, AR, DS, HH, HS, CR, NC No competing interests declared, (© 2019, Palomo-Guerrero et al.)

Introduction: Training on impression disinfection is often limited to brief explanations in the clinic. This investigation assessed knowledge on this topic amongst clinical students in our university, produced a pill of knowledge to suit their needs, and evaluated its impact and acceptance., Material and Methods: A pre-post study was designed to identify knowledge gaps using an anonymous, voluntary self-applied questionnaire before and after watching an audio-visual clip (pill of knowledge). All 136 students in the school were invited to enter the study (estimated sample size: 116)., Results: Participants: 109 (26.6% in 3rd year; 37.6% in 4th year and 39.4% in 5th year). Participation dropped 10.29% (n = 95) in the post-intervention survey. Knowledge improvement was higher for those impression materials included in the pill. Most students (68.4%) reported to know more about impression disinfection after the pill and 70.5% felt more able to achieve correct disinfection. The pill was particularly well received (86.3%). All students would recommend it to their peers, and 93.5% are willing to receive pills on other topics., Discussion: Our results disclosed an important gap in knowledge, which can be filled by a single, brief and concise pill adapted to the intended audience. Once made readily available through digital repositories, it may help solve this problem, given the ubiquitous presence of mobile devices., Conclusions: Our results found pills of knowledge as a useful approach to facilitating undergraduates' learning process. This method, using suitable information and communication technologies, has the potential to improve the performance on certain clinical tasks., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recovery of new samples of Montezumella amenosi Vía, 1959 and Moianella cervantesi Ossó Domínguez, 2013, with preserved cephalic appendages and ventral features, now allows for new and complete revision of Montezumellidae, an extinct eubrachyuran family that appeared in the Middle Eocene and lived until the Neogene. New data on antennular and antennal features, as well as additional data on the sternal and pleonal features of the females, have been analyzed. As a result, Montezumellidae is removed from Cancroidea, where it was previously placed. In view of the unique set of characters that this family presents, no other superfamily of Eubrachyura, fossil or recent, can accommodate it. Therefore, a new superfamily is proposed for it. Despite several basal characters that this group presents, its possible origins or phylogenetic relationships are not clear. Neither, based on the present fossil record, no relationships with potential ancestors or descendants can be suggested.

Understanding how people behave when facing hazardous situations, how intrinsic and extrinsic factors influence the risk taking (RT) decision making process and to what extent it is possible to modify their reactions externally, are questions that have long interested academics and society in general. In the spheres, among others, of Occupational Safety and Health (OSH), the military, finance and sociology, this topic has multidisciplinary implications because we all constantly face RT situations. Researchers have hitherto assessed RT profiles by conducting questionnaires prior to and after the presentation of stimuli; however, this can lead to the production of biased, non-realistic, RT profiles. This is due to the reflexive nature of choosing an answer in a questionnaire, which is remote from the reactive, emotional and impulsive decision making processes inherent to real, risky situations. One way to address this question is to exploit VR capabilities to generate immersive environments that recreate realistic seeming but simulated hazardous situations. We propose VR as the next-generation tool to study RT processes, taking advantage of the big four families of metrics which can provide objective assessment methods with high ecological validity: the real-world risks approach (high presence VR environments triggering real-world reactions), embodied interactions (more natural interactions eliciting more natural behaviors), stealth assessment (unnoticed real-time assessments offering efficient behavioral metrics) and physiological real-time measurement (physiological signals avoiding subjective bias). Additionally, VR can provide an invaluable tool, after the assessment phase, to train in skills related to RT due to its transferability to real-world situations.

A fundamental understanding of the Ostwald ripening effect (ORE) during the mechanochemical synthesis of PbTe nanostructures is presented. The ripening process involves the coarsening of larger particles from those of smaller size; this phenomenon was systematically evaluated at different stages of milling by microscopy analyses (AFM, TEM, STEM and HRTEM). At the early stage of milling, smaller particles and quantum dots are eventually dissolved to lower the total energy assciated with their surfaces. The ripening process - during milling - involves short-range mass transfer among particles. HRTEM analyses allowed us to identify that coarsening occurs by thermo-mechanically activated cooperative mechanisms. The detachment of the atoms from smaller particles to form bigger ones plays a major role in the particle coarsening. It was found that the coarsening process was not limited to crystalline nanostructures; so grain boundaries, edge dislocations and boundaries among crystalline and amorphous phases also play an important role to determine how species migration contributes to generate coarse particles. Those serve as sites for inducing coarsening in an equivalent way as surfaces do. Secondary ion mass spectrometry and elemental chemical mapping (EDX-STEM) revealed that both the purity and the chemical homogeneity of the PbTe nanostructures are prominent features of this material. Additionally, a direct band gap enhancement (780 nm) compared to bulk PbTe (3859 nm) was detected. It occurred due to the quantum confinement effect, lattice imperfections and even surface properties of the nanostructures. It is important to point out that the whole optical behaviour of the PbTe nanostructures was dependent upon the embedded nanoparticles and quantum dots in the clusters and coarse particles ranging from 15 nm to 35 nm.

Objectives: The treatment of non muscle invasive bladder cancer (NMIBC) continues to be a challenge. Hyperthermia (HT) combined with intravesical chemotherapy is used to enhance the effects of chemotherapy., Methods: A review of the publications was carried out to synthesize the adverse effects (AE) reported by the use of chemohyperthermia (QHT) with Mitomycin-C (MMC). The most relevant data are exposed for each of the devices currently used in the QHT., Results: SYNERGO®: The dropout rate varied between 3-40%, and the AE rate is up to 88%. The most common AEs were pain (2-40%), thermal reaction of the posterior wall (13-100%), bladder spasms (2-32%), dysuria (3-60%) and hematuria (2-62%). COMBAT BRS®: The dropout rate is 3-11%. The AEs reported were CTCAE Grade 1-2: Pain 13-27%, bladder spasms 6-27%and hematuria 3-20% are the most relevant. In general, CTCAE grade 3-4 toxicity is not reported. UNITHERMIA®: The dropout rate is 7-12%. The AEs described are: Pain 6-23%, bladder spasms 6-23%, hematuria 9-11, frequency 15-25% and allergy 6-11%. The majority of toxicities are CTCAE grade 1-2 (17-53%), with grade 3-4 in 9-15% and Grade 5 in 0-2%. QHT adds little to the AEs of the treatment with MMC. It neither adds severe effects, nor increases dropouts significantly, and does not increase the incidence of allergic reactions. The comparative study between BCG and QHT-MMC, is less likely to present urinary frequency, nocturia, incontinence, hematuria, fever, fatigue and arthralgia in patients in the QHT group., Conclusions: QHT has proven to be a safe alternative for the treatment of intermediate and high risk NMIBC, with AE mainly grade 1-2. The AEs reported have little variation with respect to the dose of MMC used, presenting different "profiles" related to the device used for its administration. The treatments with QHTMMC are well tolerated, without adding significantly more AE than the instillations of MMC alone and presenting a better toxicity profile than those reflected in the literature with respect to the treatment with BCG.

Background: Lower gastrointestinal bleeding (LGIB) is an event that has shown an increase in complications and mortality rates in the last decades. Although some factors associated with poor outcome have been identified, there are several yet to be evaluated., Objective: To identify risk factors for poor outcome in patients with LGIB in the Hospital Edgardo Rebagliati Martins of Lima, Peru., Material and Methods: A prospective analytic observational cohort study was made, and a census was conducted with all patients with acute LGIB between January 2010 and December 2013. The main variables were heart rate ≥100/min, systolic blood pressure <100 mmHg and low hematocrit (≤35%) at admission. Poor outcome was defined as any of the following: death during hospital stay, bleeding requiring transfusion of ≥4 blood packs, readmission within one month of hospital discharge, or the need for hemostatic surgery., Results: A total of 341 patients with LGIB were included, of which 27% developed poor outcome and 2% died. Variables found to be statistically related to poor outcome were: heart rate ≥ 100/min at admission (RR: 1.75, IC 95% 1.23- 2.50), systolic blood pressure <100 mmHg at admission (RR: 2.18, IC 95% 1.49-3.19), hematocrit ≤35% at admission (RR: 1.98, IC 95% 1.23-3.18) and LGIB of unknown origin (RR: 2.74, IC 95% 1.73-4.36)., Conclusions: Elevated heart rate at admission, systolic hypotension at admission, low hematocrit at admission and having a LGIB of unknown origin are factors that increase the risk of developing poor outcome, and these patients should be monitored closely due to their higher risk of complications.

A new genus and species of brachyuran crab from the Upper Eocene (Priabonian) strata in Basa Valley (Huesca, northern Spain) assignable to the superfamily Dromioidea, Basadromia longifrons n. gen., n. sp., adds to current knowledge of the morphological diversity and geographical-stratigraphical distribution of the superfamily. The main characters of the new form, such as the orbitofrontal construction with two median teeth and an rostral tooth situated in a lower plane, two minor frontal (inner orbital) teeth, well-marked cervical and branchial grooves, general carapace outline, and the shape and distribution of dorsal regions, confirm placement in Dromioidea. Unique features, such as the four conspicuous frontal teeth, lateral margins of carapace with small, subtle spines, the reduced length of the posterior margin, disposition of dorsal grooves, and peculiar shape and distribution of the dorsal regions (mainly protogastric and epibranchial), warrants the erection of a new genus and new species. In the absence of ventral features the new taxon is tentatively assigned to the family Dromiidae after detailed comparison with both fossil and extant members.

Background: The most commonly used second-line Helicobacter pylori eradication regimens are bismuth-containing quadruple therapy and levofloxacin-containing triple therapy, both offering suboptimal results. Combining bismuth and levofloxacin may enhance the efficacy of rescue eradication regimens., Aims: To evaluate the efficacy and tolerability of a second-line quadruple regimen containing levofloxacin and bismuth in patients whose previous H. pylori eradication treatment failed., Methods: This was a prospective multicenter study including patients in whom a standard triple therapy (PPI-clarithromycin-amoxicillin) or a non-bismuth quadruple therapy (PPI-clarithromycin-amoxicillin-metronidazole, either sequential or concomitant) had failed. Esomeprazole (40 mg b.d.), amoxicillin (1 g b.d.), levofloxacin (500 mg o.d.) and bismuth (240 mg b.d.) was prescribed for 14 days. Eradication was confirmed by (13) C-urea breath test. Compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by questionnaires., Results: 200 patients were included consecutively (mean age 47 years, 67% women, 13% ulcer). Previous failed therapy included: standard clarithromycin triple therapy (131 patients), sequential (32) and concomitant (37). A total of 96% took all medications correctly. Per-protocol and intention-to-treat eradication rates were 91.1% (95%CI = 87-95%) and 90% (95%CI = 86-94%). Cure rates were similar regardless of previous (failed) treatment or country of origin. Adverse effects were reported in 46% of patients, most commonly nausea (17%) and diarrhoea (16%); 3% were intense but none was serious., Conclusions: Fourteen-day bismuth- and levofloxacin-containing quadruple therapy is an effective (≥90% cure rate), simple and safe second-line strategy in patients whose previous standard triple or non-bismuth quadruple (sequential or concomitant) therapies have failed., (© 2015 John Wiley & Sons Ltd.)

Background: Aim was to evaluate the efficacy and tolerability of a moxifloxacin-containing second-line triple regimen in patients whose previous Helicobacter pylori eradication treatment failed., Methods: Prospective multicentre study including patients in whom a triple therapy or a non-bismuth-quadruple-therapy failed. Moxifloxacin (400mg qd), amoxicillin (1g bid), and esomeprazole (40 mg bid) were prescribed for 14 days. Eradication was confirmed by (13)C-urea-breath-test. Compliance was determined through questioning and recovery of empty medication envelopes., Results: 250 patients were consecutively included (mean age 48 ± 15 years, 11% with ulcer). Previous (failed) therapy included: standard triple (n = 179), sequential (n = 27), and concomitant (n = 44); 97% of patients took all medications, 4 were lost to follow-up. Intention-to-treat and per-protocol eradication rates were 82.4% (95% CI, 77-87%) and 85.7% (95% CI, 81-90%). Cure rates were similar independently of diagnosis (ulcer, 77%; dyspepsia, 82%) and previous treatment (standard triple, 83%; sequential, 89%; concomitant, 77%). At multivariate analysis, only age was associated with eradication (OR = 0.957; 95% CI, 0.933-0.981). Adverse events were reported in 25.2% of patients: diarrhoea (9.6%), abdominal pain (9.6%), and nausea (9.2%)., Conclusion: 14-day moxifloxacin-containing triple therapy is an effective and safe second-line strategy in patients whose previous standard triple therapy or non-bismuth quadruple (sequential or concomitant) therapy has failed, providing a simple alternative to bismuth quadruple regimen., (Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Alzheimer's disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level.

Background: Elevations of cardiac troponin I (cTnI) not associated with acute coronary syndrome (ACS) have been reported in patients with chronic kidney disease (CKD) stage 5 or end-stage renal disease (ESRD). The aim of this study was to determine the prevalence of elevated cTnI in patients with CKD stage 3 to 5 in conditions other than ACS., Methods: The study population consisted of 426 patients with CKD stage 3 to 5 (estimated glomerular filtration rate < 60 mL/minute/1.73m2 calculated with the MDRD-4 equation) admitted with symptoms of ACS but finally this diagnosis was ruled out with determinations of cTnI and medical history, physical examination, and electrocardiography. Levels of cTnI in serum were measured at admission, at 6 - 12 hours and at 6 months with two different analytical methods (Access and Vidas analyzers). Patients were assigned into the following two groups according to the clinical diagnosis: 1) patients with Other Cardiac Diseases (OCD) and 2) patients with Other Noncardiac Diseases (ONCD)., Results: The OCD group included 140 patients (33%) and the ONCD group included 286 patients (67%). We found elevated cTnI (higher than 99th percentile) with the Access and Vidas analyzers in 32% of patients. The prevalence of elevated cTnI was higher in patients with CKD stage 5 or ESRD. In the OCD group, the most common diagnoses were congestive heart failure (52.1%) and atrial fibrillation (20%), whereas in the ONCD group they were arterial hypertension (8.4%) and cerebrovascular accident (8.1%). The rate of mortality in patients with CKD stage 3 to 5 was 17% but was higher in patients with CKD stage 5 (40%)., Conclusions: Elevations of cTnI not associated with ACS were common in patients with CKD stage 3 to 5, and there was an increase in mortality with higher concentrations of cTnI.

In this work we propose a protocol for estimating the effect of pH on the docking performance to BACE-1, which affords the charge state of the inhibitor as well as the protonation state of all ionisable residues in the protein at a given pH value. To the best of our knowledge, this is the first report of a protocol predicting the BACE-1 ligand docking poses not only at the neutral pH at which most crystallographic structures were obtained, but also at the optimal pH of the enzyme (in the acidic range), at which most of the BACE-1 binding affinity assays are performed. We have applied this protocol to a set of 23 fragment-like BACE-1 ligands that span four orders of magnitude in their binding affinities. The pK a values of the BACE-1 acidic residues deviate substantially from the estimates for model compounds in solution and display a ligand dependent variability, especially in the case of the catalytic Asp dyad residues. This outcome should have a strong bearing on the design of protocols for docking based BACE-1 screening campaigns. Finally, we were able to find an explanation for the poor docking success rate of some fragments based on the availability of anchoring points, a rationale that could help to improve hit rates in BACE-1 screening campaigns.

Background: Coronary angiography (CA) has been the gold standard technique for studying coronary artery disease. It is based on the analysis of bidimensional orthogonal projections that may not be optimal to estimate determinate coronary segments. Rotational angiography "Xperswing" (DARCA) is a new technique that allows the visualization of the coronary arteries from multiple views, with a single contrast injection. The aim of this study is to evaluate the coronary lesions quantification with DARCA., Methods: Quantitative coronary analysis of significant coronary stenosis (>50%) was performed. Every lesion was measured in two different projections: the "optimal projection", obtained by DARCA and defined by the operator as the one with a better lesion qualification, and the "standard projection", corresponding to the usual projection closer to the optimal one in obliquity and angulation. Measures were performed twice and by two independent operators. Intra- and inter-observer correlation was estimated by Kappa index and variables were compared with t Student test (SPSS 14.0)., Results: 205 lesions in 147 patients were analyzed. Kappa coefficient intra-observer was 0.80 and 0.86 respectively with an inter-observer correlation index of 0.72. Lesion length and maximal diameter of the vessel were significantly greater in the group of RA. In the segments analysis, calculated length was longer for the first diagonal branch, first marginal obtuse artery, middle circumflex, middle and distal RCA and posterior descending artery, with greater reference diameters for proximal LAD and distal RCA. There were no significant differences for coronary stenosis grade., Conclusions: RA XperSwing provides a better visualization of coronary arteries improving lesions characterization, with longer measured lesions length and greater vessel diameters, especially in coronary segments with more angulation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aspartic proteases (AP) are a family of important hydrolytic enzymes in medicinal chemistry, since many of its members have become therapeutical targets for a wide variety of diseases from AIDS to Alzheimer. The enzymatic activity of these proteins is driven by the Asp dyad, a pair of active site Asp residues that participate in the hydrolysis of peptides. Hence, the protonation state of these and other acidic residues present in these enzymes determines the catalytic rate and the affinity for an inhibitor at a given pH. In the present work we have reviewed the effect of the protonation states of the titratable residues in AP's both on catalysis and inhibition in this family of enzymes. The first section focuses on the details of the catalytic reaction mechanism picture brought about by a large number of kinetic, crystallographic and computational chemistry analyses. The results indicate that although the mechanism is similar in both retroviral and eukaryotic enzymes, there are some clear differences. For instance, while in the former family branch the binding of the substrate induces a mono-ionic charge state for the Asp dyad, this charge state seems to be already present in the unbound state of the eukaryotic enzymes. In this section we have explored as well the possible existence of low barrier hydrogen bonds (LBHB's) in the enzymatic path. Catalytic rate enhancement in AP's could in part be explained by the lowering of the barrier for proton transfer in a hydrogen bond from donor to acceptor, which is a typical feature of LBHB's. Review of the published work indicates that the experimental support for this type of bonds is rather scarce and it may be more probable in the first stages of the hydrolytic mechanism in retroviral proteases. The second section deals with the effect of active site protonation state on inhibitor binding. The design of highly potent AP inhibitors, that could be the basis for drug leads require a deep knowledge of the protonation state of the active site residues induced by their presence. This vital issue has been tackled by experimental techniques like NMR, X-ray crystallography, calorimetric and binding kinetic techniques. Recently, we have developed a protocol that combines monitoring the pH effect on binding affinities by SPR methods and rationalization of the results by molecular mechanics based calculations. We have used this combined method on BACE-1 and HIV-1 PR, two important therapeutic targets. Our calculations are able to reproduce the inhibitor binding trends to either enzyme upon a pH increase. The results indicate that inhibitors that differ in the Asp dyad binding fragments will present different binding affinity trends upon a pH increase. Our calculations have enabled us to predict the protonation states at different pH values that underlie the above mentioned trends. We have found out that these results have many implications not only for in silico hit screening campaigns aimed at finding high affinity binders, but also (in the case of BACE-1) for the discovery of cell active compounds.

The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: The aim of our study was to evaluate cut-off values for acute coronary syndrome (ACS) diagnosis in patients with chronic renal failure (CRF) for the cardiac biomarkers cardiac troponin I (cTnI) and creatine kinase MB isoenzyme (CK-MB) as compared to the cut-off values proposed by the manufacturers and those frequently used in the laboratory., Method: We performed a prospective study in patients with CRF with a glomerular filtration rate estimated by the MDRD-4 equation <60 mL/min and admitted with suspected acute coronary syndrome due to clinical history, physical examination, and electrocardiography. cTnI and CK-MB measurements were assessed upon hospitalisation and six months later using two different analytical methods (for cTnI: Access® and Vidas® analysers, and for CK-MB: Access® and Vitros® analysers)., Results: During the study period, 484 patients with CRF and suspected ACS were assessed. ACS was diagnosed in 12% of patients (58/484), while we found other cardiac pathologies (OCP) in 29% of patients (140/484) and other non-cardiac pathologies (ONCP) in 59% of patients (286/484). For cTnI assessed using the Access® analyser with the usual cut-off value (≥ 0.5 ng/mL), sensitivity was 43% and specificity was 94%, while for the proposed cut-off value (≥ 0.11 ng/mL), the values were 68% and 83%, respectively. For cTnI assessed using the Vidas® analyser with the usual cut-off value (≥ 0.11 ng/mL), sensitivity was 64% and specificity was 87%, while for the proposed cut-off value (≥ 0.06 ng/mL), the values were 75% and 79%, respectively. The sensitivity and specificity for both CK-MB were lower compared with cTnI., Conclusion: The cut-off values proposed in this study for both cTnI in patients with CRF (stage 3 to 5) to diagnose ACS are significantly different from that of the general population.

The ideal gasoline must have a high pump octane number, in the 86 to 94 range, and a low environmental impact. Alkanes, as a family, have much lower photochemical reactivities than aromatics or olefins, but only the highly branched alkanes have adequate octane numbers. The purpose of this work is to examine the possibilities of extending the technological alternative of paraffin isomerization to heavier feedstocks (i.e., n-heptane) using non-conventional catalytic systems which have been previously proposed in the literature: a Pt/sulfated zirconia catalyst and a molybdenum sub-oxide catalyst. Under the experimental conditions at which these catalysts have been evaluated, the molybdenum sub-oxide catalyst maintains a good activity and selectivity to isomerization after 24 h, while the Pt/sulfated zirconia catalyst shows a higher dimethylpentanes/methylhexanes ratio, probably due to a lower operating temperature, but also a high formation of cracking products, and presents signs of deactivation after 8 h. Though much remains to be done, the performance of these catalysts indicates that there are good perspectives for their industrial application in the isomerization of n-heptane and heavier alkanes.

β-Secretase is one of the aspartic proteases involved in the formation of amyloid plaques in Alzheimer's disease patients. Our previous results using a combination of surface plasmon resonance experiments with molecular modeling calculations suggested that the Asp dyad in β-secretase bound to hydroxylethylene containing inhibitors adopts a neutral charged state. In this work, we show that the Asp dyad diprotonated state reproduced the binding ranking of a set of these inhibitors better than alternative protonation states.

BACE-1 is one of the aspartic proteases involved in the cleavage of beta amyloid peptide, an initial step in the formation of amyloid plaques whose toxicity induces neuron death in Alzheimer's disease patients. One of the central issues in the search of novel BACE-1 inhibitors is the optimum pH for the binding of inhibitors to the enzyme. It is known that the enzyme has optimal catalytic activity at acidic pH, while cell active inhibitors may bind optimally at higher pH. In this work we determine the effect of the pH on the affinities of a set of inhibitors, with a variety of chemical motifs, for the ectodomain region of BACE-1 by a surface plasmon resonance (SPR) biosensor based assay. In order to understand the molecular interactions that underlie the diverse optimum pH for the binding of the various inhibitors as observed experimentally, we have calculated the titration curves for a set of BACE-1 ligand complexes. The results indicate that the pK(a) values of the titratable residues of the protein depend on the nature of the ligand involved, in disagreement with previous work. The enzyme-inhibitor structures with the resulting protonation states at pH values 4.5 and 7.4 served as the starting point for the prediction of the pH-dependent binding ranking. Our calculations reproduced the entire affinity ranking observed upon pH increase and most of the binding trends among inhibitors, especially at low pH. Finally, our cell-based assays indicate a possible correlation between high inhibitor affinity at both acidic and neutral pH values, with optimal cell response, a result that may open new venues for the search of potent BACE-1 inhibitors that are active at the cellular level.

The clinicopathological features currently used in breast cancer prognosis often fail to characterize the clinical heterogeneity of the disease accurately. Our study is aimed to investigate the predictive value of DNA flow cytometry in breast cancer. Previously untreated breast carcinoma samples (584) were snap frozen for flow-cytometry. Tumors were classified into three DNA index (DI) categories: i) tumors showing a DI =0.96-1.15 (diploid and near-diploid); ii) tumors with a DI >or=1.16 (hyperdiploid, tetraploid, multiploid and/or those with more than one diploid population); and iii) tumors with a DI

Unlabelled: Pruritus is a common complication of cholestatic liver diseases or liver graft dysfunction. Current medical therapies lack efficacy. The molecular adsorbent recirculating system (MARS) represents an interesting therapeutic option. Our objective was to report our experience in the management of four patients with intractable pruritus with MARS., Patients and Methods: The MARS treatment cycle included three consecutive treatments, each of 8 hours duration. The four patients with intractable pruritus who were treated had primary biliary cirrhosis/autoimmune hepatitis overlap syndrome (n = 1), ductopenic allograft rejection (n = 2), or posttransplant cholestatic HCV recurrence (n = 1). Intensity of pruritus was documented 24 hours before as well as 24 hours, 7 and 30 days after MARS therapy, and at the end of follow-up. We measured complete blood cell counts, glucose, BUN, creatinine, sodium, potassium, AST, ALT, GGT, alkaline phosphatase, bilirubin, prothrombin activity, and activated partial thromboplastin time., Results: MARS therapy was well tolerated. Patient 1 experienced temporal relief of pruritus, but needed another MARS cycle because of relapse. Patient 2 experienced partial and temporary relief of pruritus, was listed for retransplantation, and received a liver graft 2 months later. Patient 3 showed a dramatic reduction in the degree of pruritus with MARS. Pruritus in patient 4 decreased promptly with MARS therapy and conversion of immunosuppression to tacrolimus, thereby avoiding retransplantation., Conclusion: MARS therapy is a promising, safe therapeutic option to treat refractory pruritus caused by cholestatic liver disorders.

MoO3 transformations under isomerization process conditions were studied. The products obtained after different times under stream (H2/n-heptane mixture, 18.5 bar, at 370 degrees C) were characterized by X-ray diffraction, Raman spectroscopy, thermal analysis, and high-resolution transmission electron microscopy (HRTEM). Theoretical quantum calculations were carried out with the aim of understanding the paradox of the real active phase in isomerization reactions. Theoretical calculations predict the existence of a metallic-like MoO phase with a structure that matches the X-ray diffraction experimental results. From experimental and simulated HRTEM images it was possible to identify the presence of small MoO cubic crystallites inside MoOx matrix phases. These results also support the previously proposed idea that isomerization reactions take place as a result of the existence of a bifunctional catalyst. The Raman and thermo-programmed oxidation (TPO) analyses show the existence of at least two types of carbonaceous deposits which tend to increase its ordering with the increase of time under stream. The carbon K edge in electron energy loss spectroscopy (EELS) of a sample after 24 h under stream shows that these carbonaceous deposits consist of a mixture of sp2- and sp3-hybridized carbons.

For much human activity there exists a 'lateral preference', that is a tendency to use one side of the body or the other; with respect to the hands for example, the vast majority of individuals have a preference for either the right or left hand. Most experts agree that mastication is no exception in that there is a 'preferred chewing side' but the determination of this preference is somewhat complex. This research analyses the mastication of 60 healthy subjects by means of preferred chewing side or 'PCS' tests, the Kazazoglu test, and kinesiography (KGF). While some authors consider the PCS to be the side which first comes into contact with the food we prefer to define it as the side on which the majority of the cycles analysed and registered take place. The objective of this research was to analyse the relationship that might exist between the two different methods used for determining a lateral chewing preference. Although there was no statistically significant agreement between the two techniques, both reflected the fact that there was a marked preference for the right hand side.

Objective: To find out if nuclear morphometry is a useful indicator of prognosis in patients with familial adenomatous polyposis (FAP) before and after treatment with sulindac., Design: Open study., Setting: Teaching hospital, Spain., Subjects: 29 patients (17 women and 12 men) with FAP who had been treated by colectomy. There were two control groups: 17 people with healthy rectal mucosa and 10 patients with colorectal cancer., Interventions: The 29 patients with FAP were treated with sulindac 150 mg orally twice daily for 6 months., Main Outcome Measures: Results of histological examination of biopsy specimens and nuclear morphometry., Results: Before treatment, all patients with FAP had nuclei of cells in the rectal mucosa that were intermediate in size between those in healthy mucosa (small nuclei) and those in cancer (large nuclei). After 6 months' treatment with sulindac the patients with FAP no longer had any polyps and the size of the nuclei was similar to those in healthy mucosa. Only 1 patient failed to respond, and in this patient one of the polyps subsequently became malignant., Conclusions: Nuclear morphometry may be useful in identifying patients with FAP who are at high risk of malignant degeneration.

Objective: To evaluate the medium-term results of percutaneous closure of atrial septal defect., Methods: Twenty-two children (mean weight, 23 11kg; mean age, 5.7 2.4 years) underwent percutaneous atrial septal defect closure under general anesthesia. The procedure was monitored by transesophageal echocardiography. DAS-Angel Wings (n4) and the Amplatzer device (n18) were used., Results: Mean pulmonary artery pressure was 13 2.8mmHg, mean pulmonary vascular resistance was 1.50.5U/m2 and mean Qp/Qs flow ratio was 2.2 0.6. The mean diameter of the defects was 14.5 6.3mm by transesophageal echocardiography OmniPlane measurement and 15.95.3mm using balloon occlusion reference. A total of 31 devices were used: 4 Angel Wings and 27Amplatzer devices. Twelve Amplatzer devices were withdrawn through the introducer without complications, 5 due to a discrepancy in the size of the left auricle, 4 because they were too small to stabilize in the septum and 3 due to defective opening in the left auricle. In 19 patients implantation was successful. In 17 patients transthoracic color Doppler echocardiography carried out 24 hours after the procedure showed a minimal shunt which was no longer present 1 month later. The mean time of discharge was 38 12 hours after the procedure. After a mean follow up 15 6 months the patients remain asymptomatic with no clinical or technical problems., Conclusion: The success rate of percutaneous closure of atrial septal defects in well-selected patients was high and presented no complications.

Although advances in the management of acute myocardial infarction have resulted in a decline in long-term risk of sudden death, it continues to be high in certain subsets of patients. Thus, it is important to identify and treat these patients. Left ventricular ejection fraction less than 0.40, frequent premature ventricular ectopy on Holter monitoring, late potentials on signal-averaged electrocardiogram, impaired heart rate variability, abnormal baroreflex sensitivity and inducible sustained monomorphic ventricular tachycardia during electrophysiological study are predictors of sudden death and arrhythmic events. Although the negative predictive value of each factor is high, the positive predictive accuracy is low. Several tests can be combined to obtain higher positive predictive values. In fact, in some studies combined noninvasive tests have been used to select patients for ventricular stimulation study. Some preventive treatment can be applied in these patients. Available data do not justify prophylactic therapy with amiodarone in high-risk survivors of acute myocardial infarction. Sudden death and total mortality have been significantly reduced in postinfarction patients by long-term beta blockade. Hence, beta blockers should be given to all patients with acute myocardial infarction who do not have contraindications to their use. The MADIT study has shown the beneficial effect of implantable cardioverter defibrillator in reducing mortality in patients with prior myocardial infarction, an ejection fraction less than 0.36, asymptomatic nonsustained ventricular tachycardia, and inducible sustained ventricular tachycardia, unsuppressable by procainamide. Besides, several studies are under way to evaluate the prophylactic use of implantable defibrillator for improving survival in high-risk patients.

Unlabelled: In many types of cancer, certain morphometric characteristic of tumor cells correlate with patient survival. Our observations suggested that the survival of patients with colorectal carcinomas is negatively correlated with tumor-cell nucleus size., Methods: We investigated relationships between postsurgery survival and nucleus morphometric in 90 patients who had undergone resection for a colorectal tumor. The nucleus-size variables considered were maximum diameter, minimum diameter, perimeter, area, and form factor (means for 100 nuclei from each patient were used in all cases)., Results: Our results confirmed that patients with large maximum nucleus diameter (where large = greater than the first quartile) have significantly worse survival than patients with smaller maximum nucleus diameter (mean survival, 28 vs. 43 months). Similar results were obtained for the other nucleus-size variables. Stepwise Cox regression analysis was then performed, with postsurgery survival time as the dependent variable and the following candidate independent variables: age, gender. Dukes class, degree of histologic differentiation, the various nucleus-size variables, and relative frequencies of different nucleus shapes (spherical, oval, cylindrical, fusiform, and irregular). The variables selected for the prognostic model were Dukes class, relative frequency of irregular nuclei, and maximum nucleus diameter., Conclusions: These findings indicated that nucleus size and shape are useful predictors of survival. Even in Dukes class is known, consideration of nucleus size and shape significantly improves prediction of survival.

Background and Objectives: Quantitative coronary angiography can be performed in two ways: on-line during catheterism, and off-line once the procedure is finished. Consequently, several studies have been published comparing both systems. Nevertheless, none of them has compared the measurements made off-line with those acquired on-line by the hemodynamist in charge of procedure. The objective of this study was to compare the measurements made on-line by the hemodynamist involved in the procedure with a digital system (DCI) with those obtained off-line by an independent and alien observer to the procedure by using film-based system (CMS)., Material and Methods: Forty coronary lesions suitable for quantification were measured in a prospective fashion. They came from follow-up angiograms. Either balloon or stent were used in the previous angioplasty. Stenoses were assessed on-line and off-line by using the most severe view as judged by the hemodynamist., Results: No significant differences were found for obstruction diameter, reference diameter nor percent diameter stenosis. Pearson's correlation coefficient values (r), intraclass correlation coefficient (ri), regression line equation and mean of signed differences with their standard deviations are showed: a) obstruction diameter: r = 0.83, ri = 0.83, DCI = 0.42 + 0.76 x CMS, -0.01 +/- 0.42 mm; b) reference diameter: r = 0.72, ri = 0.69, DCI = 1.29 + 0.61 x CMS, 0.003 +/- 0.38 mm, y c) percent diameter stenosis: r = 0.86, ri = 0.86, DCI = 10.05 + 0.77 x CMS, 1.19 +/- 10.75%., Conclusions: We attained good concordance between both quantification systems under clinical conditions. In our opinion these results support the use of on-line quantification as a reliable tool for clinical decision making in the catheterization laboratory.

Purpose: In many types of cancer, certain morphometric characteristic of tumor cells correlate with patient survival. Our observations suggested that the survival of patients with colorectal carcinomas is negatively correlated with tumor-cell nucleus size., Methods: We investigated relationships between postsurgery survival and nucleus morphometrics in 90 patients who had undergone resection for a colorectal tumor. The nucleus-size variables considered were maximum diameter, minimum diameter, perimeter, area, and form factor (means for 100 nuclei from each patient were used in all cases)., Results: Our results confirmed that patients with large maximum nucleus diameter (where large = greater than the first quartile) have significantly worse survival than patients with smaller maximum nucleus diameter (mean survival, 28 vs. 43 months). Similar results were obtained for the other nucleus-size variables. Stepwise Cox regression analysis was then performed, with postsurgery survival time as the dependent variable and the following candidate independent variables: age, gender, Dukes class, degree of histologic differentiation, the various nucleus-size variables, and relative frequencies of different nucleus shapes (spherical, oval, cylindrical, fusiform, and irregular). The variables selected for the prognostic model were Dukes class, relative frequency of irregular nuclei, and maximum nucleus diameter., Conclusions: These findings indicated that nucleus size and shape are useful predictors of survival. Even if Dukes class is known, consideration of nucleus size and shape significantly improves prediction of survival.

Atheroma plaque rupture with liberation of tissue factor activates the coagulation cascade and plateletes, leading to the formation of intracoronary thrombi in many patients with acute coronary syndromes. In this process, tissue factor, thrombin, Factor Xa and fibrin play a major role. This review analyses the clinical efficacy of the antithrombotic drugs: fractionated heparin, low molecular or fractionated heparins, direct thrombin inhibitors, specific Xa factor inhibitors and inhibitors of the tissue factor pathway in patients with unstable angina and non-Q wave myocardial infarction. Enoxaparin, a low molecular weight fractionated heparin, has shown to be associated with a greater clinical efficacy, superior to that achieved with conventional heparin anticoagulation or treatment with aspirin, and probably should be considered as the antithrombotic of choice. Present clinical research should be aimed at the identification of patients with greater benefit, new treatment protocols with other antithrombotic drugs and the efficacy in special situations such as invasive coronary interventions or the association with other drug like, thrombolytic agents or new antiplatelet antiaggregants.

Introduction: Radiofrequency catheter ablation of atrial tachycardia guided by bipolar activation mapping has been reported in the last years. This article reports the use of radiofrequency catheter ablation for the treatment of atrial tachycardia using simultaneous bipolar and unipolar activation mapping at our institution., Methods: Nine patients (7 male and 2 female, mean age 37.2 +/- 24.1 years), were selected for radiofrequency catheter ablation of drug refractory atrial tachycardia. Mapping procedure included an investigation of the local earliest bipolar and unipolar activity and unipolar morphology analysis., Results: Atrial tachycardia was successfully ablated in 7 patients (78%) with an average number of 6.8 +/- 3.1 RF pulses. Procedure related complications and tachycardia follow-up recurrences were not observed in any patient. Bipolar local activation time was significantly shorter at successful than at unsuccessful ablation sites (-30 +/- 21.1 ms vs -18.3 +/- 20.6 ms; p = 0.01). No difference was observed in unipolar local activation time between successful and unsuccessful sites (-22.5 +/- 26.2 ms vs -19.8 +/- 21.5 ms; p = 0.56). Accurate localization of the successful ablation site by unipolar electrogram analysis was not feasible because a "QS" pattern was found at both 21 unsuccessful and 2 successful ablation sites. Finally, a fast slope of the negative deflection of the unipolar electrogram was found at 2 out of 45 unsuccessful and 3 out of 6 successful ablation sites., Conclusions: Radiofrequency catheter ablation of atrial tachycardia is feasible without complications in most patients. Bipolar activation mapping accurately localizes the successful ablation site. A "QS" pattern is not predictive of successful radiofrequency application.

Unlabelled: Thrombolytic therapy (TT) modifies the natural history of acute myocardial infarction (AMI) diminishing morbi-mortality rate. In recent studies, modification of infusion velocity, decreased the mortality 10 percentage points., Objective: Test if rt PA administration over an hour is safe and practical., Material and Methods: A prospective, cooperative trial during 3 years, included patients with AMI with less than 6 hours of the onset of symptoms that received rt-PA therapy. Initially 10 mg bolus and then 90 mg over 60 minutes period. Together with the administration of rt-PA, 5000 units of heparin was given, followed by 1000 units per hour adjusted to keep PTT at 1.5 to 2 times normal. All patients received aspirin and according of the evolution adjuvant therapy. We defined bleeding complications and/or cerebrovascular accident related to thrombolytic therapy., Results: We included 225 patients who received rt-PA. Average age was 57.1 +/- 22.2 years, 78.7% males and 21.3% females. Arrival time at hospital was 2.93 +/- 1.7 hours. 82.2% were in class I-II by NYHA. 59.2% had anterior wall location and 32.4% posterior-inferior wall 80% had reperfusion criteria. Only 7.1% required transfusion and 0.4% presented CNS bleeding. The survival rate was 95.2%. The mortality had no relation with bleeding., Conclusion: Fast infusion is an effective and safe method. Transfusion requirements are no greater, and CNS bleeding was noted in 0.4% of the cases.

A 23 year-old primigravid woman presented eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) with severe left ventricular dysfunction after having a cesarean section. In a few weeks, clinic disappeared and ventricular function normalized. The importance of differential diagnosis between ventricular dysfunction in eclampsia and peripartum myocardiopathy is discussed.