Experimental and Theoretical Study on Electron Ionization and Fragmentation of Propylene Oxide─the First Chiral Molecule Detected in the Interstellar Medium.

Propylene oxide, CH3CHOCH2, is the first chiral molecule detected in space and the third C3 oxide detected toward the Sagittarius B2 (Sgr B2 (N)) molecular cloud, the others being propanal, CH3CH2CHO, and acetone, (CH3)2CO. With homochirality being ubiquitous in the building blocks of living matter, the formation and decay paths of propylene oxide in space are of specific interest. Motivated by the significant role of photo- and secondary electrons in astrochemistry, we have studied electron ionization and fragmentation of propylene oxide. Ion appearance energies are determined and compared to threshold values for the respective processes calculated at the G4MP2 level of theory, and potential reaction pathways are computed at the DFT level of theory. Electron ionization is found to destabilize propylene oxide, leading to barrierless opening of the C1-C2 bond of the epoxy ring, hydrogen transfer, and fragmentation over the methyl vinyl ether or rupture of the C2-O bond of the epoxy ring and fragmentation of the allyl alcohol cation as an intermediate, rather than direct bond ruptures.

Food addiction symptoms are related to neuroaffective responses to preferred binge food and erotic cues.

It has been proposed that some individuals succumb to maladaptive eating behaviors because, like those with addiction, they attribute high incentive salience to food-associated cues. Here, we tested whether women that attribute high incentive salience to food-associated cues report high food addiction symptomatology. In 76 college women, we assessed self-reported food addiction symptoms using the Yale Food Addiction Scale and we recorded event-related potentials (ERPs, a direct measure of brain activity) to preferred food, erotic, unpleasant, and neutral images. We used the amplitude of the late positive potential (LPP, a component of the ERPs) as an index of the incentive salience attributed to the images. Using a multivariate classification algorithm (k-means cluster analysis), we identified two neuroaffective reactivity profiles that have been previously associated with individual differences in the tendency to attribute incentive salience to cues and with differences in vulnerability to addictive behaviors. Results showed that women with elevated LPP responses to preferred food cues relative to erotic images report higher food addiction symptoms than women with low LPP responses to preferred food cues relative to other motivationally relevant stimuli. These results support the hypothesis that individual differences in the tendency to attribute incentive salience to food cues play an important role in modulating food addiction symptomatology.

Contextual information resolves uncertainty about ambiguous facial emotions: Behavioral and magnetoencephalographic correlates.

Environmental conditions bias our perception of other peoples' facial emotions. This becomes quite relevant in potentially threatening situations, when a fellow's facial expression might indicate potential danger. The present study tested the prediction that a threatening environment biases the recognition of facial emotions. To this end, low- and medium-expressive happy and fearful faces (morphed to 10%, 20%, 30%, or 40% emotional) were presented within a context of instructed threat-of-shock or safety. Self-reported data revealed that instructed threat led to a biased recognition of fearful, but not happy facial expressions. Magnetoencephalographic correlates revealed spatio-temporal clusters of neural network activity associated with emotion recognition and contextual threat/safety in early to mid-latency time intervals in the left parietal cortex, bilateral prefrontal cortex, and the left temporal pole regions. Early parietal activity revealed a double dissociation of face-context information as a function of the expressive level of facial emotions: When facial expressions were difficult to recognize (low-expressive), contextual threat enhanced fear processing and contextual safety enhanced processing of subtle happy faces. However, for rather easily recognizable faces (medium-expressive) the left hemisphere (parietal cortex, PFC, and temporal pole) showed enhanced activity to happy faces during contextual threat and fearful faces during safety. Thus, contextual settings reduce the salience threshold and boost early face processing of low-expressive congruent facial emotions, whereas face-context incongruity or mismatch effects drive neural activity of easier recognizable facial emotions. These results elucidate how environmental settings help recognize facial emotions, and the brain mechanisms underlying the recognition of subtle nuances of fear.

Neural Processing of Food and Erotic Cues in Bulimia Nervosa.

OBJECTIVE: Event-related brain potential (ERP) studies have shown that bulimia nervosa (BN) is associated with facilitated processing of disorder-specific stimuli, visible in altered early components during presentation of food cues and bodies varying in size. Less is known about BN and late ERPs, typically less influenced by perceptual features and regarded as more reliable indices of motivational relevance. The purpose of this study was to use the late positive potential (LPP) to investigate the motivational significance of BN-relevant stimuli. METHODS: Highly salient stimuli, such as pictures of personal binge foods and images that are pleasant, neutral, and unpleasant (e.g., human attacks) were presented to 24 women with bulimia and 24 healthy women (19.7 ± 2.1 and 20.5 ± 2.6 years, respectively). Pictures of erotic couples, previously shown to prompt the greatest appetitive reactions in healthy women, were used as pleasant cues. Based on BN aversion to body cues, we hypothesized that the motivational significance of erotic cues could be increased in bulimic women. RESULTS: Consistent with the literature, the LPP was modulated by the salience of the pictures (F(2.8,130.7) = 24.6, p < .001). An additional interaction with diagnostic group (F(2.8,130.7) = 2.8, p = .047) indicated that bulimic women showed a larger LPP than healthy controls during pictures displaying binge foods (p = .037) and erotic couples (p = .031). CONCLUSIONS: The findings provide objective evidence that BN is characterized by dysregulated emotional processing that is not limited to food cues. The implications are discussed within a transdiagnostic perspective on food-related disorders.

Antimicrobial Resistance in Uropathogenic Escherichia coli Strains Isolated from Relapses from Recurrent Urinary Tract Infections.

Little is known about the characteristics of uropathogenic Escherichia coli (UPEC) associated with recurrent urinary tract infections (RUTIs). The present study aimed to analyze the phenotypic antimicrobial resistance of recurrent UPEC isolates attributable to either relapse or reinfection. A total of 140 E. coli strains were isolated from 70 outpatients with RUTIs. All isolates were analyzed by random amplified polymorphic DNA-polymerase chain reaction to evaluate genetic similarity between the first and second isolates. We found that 64.2% (45/70) of outpatients had a relapse with the primary infecting E. coli strain and 35.7% (25/70) had reinfection with a new E. coli strain. Compared with reinfecting strains, relapse UPEC isolates exhibited much higher antimicrobial resistance; 89% of these isolates were multidrug-resistant and 46.6% were extended-spectrum ß-lactamase producers. Our study provides evidence that RUTIs are mainly driven by the persistence of the original strain in the host (relapses) despite appropriate antibiotic treatments, and only RUTIs attributed to relapses seem to favor multidrug resistance in UPEC isolates.

Phase I and phase IB clinical trials for the noninvasive evaluation of intestinal lactase with 4-galactosylxylose (gaxilose).

GOALS AND BACKGROUND: Hypolactasia is widespread, yet reliable diagnostic tests are lacking. A new test based on oral administration of 4-galactosylxylose (gaxilose) and urine or serum measurement of D-xylose after cleavage by intestinal lactase is under clinical development. We investigated the optimal dose of gaxilose and calculate cutoff values of D-xylose for that dose. STUDY: In the randomized, dose-finding, phase I study, urine and serum pharmacokinetics of D-xylose were determined after oral administration of 6 ascending doses of gaxilose (and placebo) to 12 healthy adult volunteers. In the open, parallel, phase Ib study, 30 volunteers received the doses established for the urine and blood tests and D-xylose was measured. Cutoff values were calculated as 1.96 × SD below the mean value. Safety was assessed through reporting of adverse events. RESULTS: Gaxilose administration showed a progressive, dose-dependent increase in D-xylose in urine and serum. An optimal gaxilose dose of 0.45 g and urine collection periods of 4 and 5 hours were selected for further studies. For the blood test, a 2.7 g dose was selected and C max measured at 90 minutes. The calculated cutoff values of D-xylose for normal lactase activity were 27.58 and 37.87 mg for the 4- and 5-hour urine tests, respectively, and 0.97 mg/dL for the blood test. There were no treatment-related adverse events. CONCLUSIONS: The methodology described provides a simple, safe test for the evaluation of lactase activity in vivo. Further evaluation of the test as a noninvasive diagnosis of hypolactasia is ongoing in patients with lactose intolerance.

A partner's smile is not per se a safety signal: Psychophysiological response patterns to instructed threat and safety.

Recent studies on fear conditioning and pain perception suggest that pictures of loved ones (e.g., a romantic partner) may serve as a prepared safety cue that is less likely to signal aversive events. Challenging this view, we examined whether pictures of smiling or angry loved ones are better safety or threat cues. To this end, 47 healthy participants were verbally instructed that specific facial expressions (e.g., happy faces) cue threat of electric shocks and others cue safety (e.g., angry faces). When facial images served as threat cues, they elicited distinct psychophysiological defensive responses (e.g., increased threat ratings, startle reflex, and skin conductance responses) compared to viewing safety cues. Interestingly, instructed threat effects occurred regardless of the person who cued shock threat (partner vs. unknown) and their facial expression (happy vs. angry). Taken together, these results demonstrate the flexible nature of facial information (i.e., facial expression and facial identity) to be easily learned as signals for threat or safety, even when showing loved ones.

Nimotuzumab Concurrent with Gemcitabine as First-Line Treatment of Locally Advanced or Metastatic Pancreatic Adenocarcinoma.

Background: Nimotuzumab exerts its antitumor effect (mainly antiproliferative, proapoptotic, and antiangiogenic) by blocking the epidermal growth factor receptor overexpressing between 30 and 95% in pancreatic tumors cells. Methods: A prospective, nonrandomized, uncontrolled, open-label, and multicenter clinical trial was conducted to evaluate the safety and effectiveness of nimotuzumab combined with gemcitabine as first-line treatment in unresectable locally advanced or metastatic pancreatic tumors in a real-world condition. Adverse events, their intensity, severity, and causality were determined using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Median overall survival, median progression-free survival, and 1- and 2-year survival rates were determined by using the Kaplan-Meier. Results: 69 patients were included. The proportion of related serious adverse events was 1.2%. The most frequent adverse events were nausea (10%), anemia (8%), and abdominal pain (8%). Objective response was achieved in 18.5% of the patients and disease control in 43.1%. Patients with locally advanced disease achieved a median overall survival of 16.36 months (95% CI; 14.35-18.38); 1- and 2-year survival rates of 72.2 and 29.2 months, respectively; a median progression-free survival of 9.6 months (95% CI; 4.91-14.20); and a 1-year progression-free survival rate of 39%. Patients with metastatic disease achieved a median survival of 6.23 months (95% CI; 4.32-8.13); 1- and 2-year survival rates of 18.1 and 3.0 months, respectively; a median progression-free survival of 7.6 months (95% CI; 6.08-9.90); and 1- and 2-year PFS rates of 20.5 and 5.1 months, respectively. Conclusions: Nimotuzumab combined with gemcitabine represents a safe and effective first-line treatment option for patients with advanced pancreatic adenocarcinoma in real-world conditions. Survival benefits were increased in those patients who received 8 or more doses of nimotuzumab. This trial is registered with RPCEC00000245 in the Cuban Registry of Clinical Trials, part of the World Health Organization's International Clinical Trials Registry Platform (ICTRP).

Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.

BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

Supratentorial meningeal melanocytoma mimicking meningioma: case report and literature review.

Introduction: Primary melanocytic tumors originating from CNS melanocytes are rare, with a low incidence of 0.7 cases per 10 million annually. This study focuses on primary leptomeningeal melanocytomas, emphasizing their epidemiology, clinical characteristics, and diagnostic challenges. Despite their infrequency, these tumors warrant attention due to their unique features and potential for local recurrence. Case Report: A 32-year-old female presented with syncope and seizures, leading to the discovery of two left-sided supratentorial lesions initially misidentified as convexity meningiomas. Detailed imaging suggested meningioma-like features, but intraoperative findings revealed unexpected hyperpigmented lesions. Histopathological examination, supported by immunohistochemistry, confirmed primary leptomeningeal melanocytoma. The surgical approach and subsequent management are discussed. Discussion: The discussion emphasizes challenges in diagnosing primary leptomeningeal melanocytomas. Treatment debates, especially regarding adjuvant radiotherapy, are explored. Recurrence risks stress the importance of vigilant follow-up, advocating for complete surgical resection as the primary approach. The rarity of supratentorial cases adds complexity to diagnosis, necessitating a multidisciplinary approach. Insights from this case contribute to understanding and managing primary leptomeningeal melanocytomas, addressing challenges in differentiation from more common tumors and prompting ongoing research for refined diagnostics and optimized treatments. Conclusion: This study contributes insights into primary leptomeningeal melanocytomas, highlighting their rarity in supratentorial regions. The case underscores the importance of a multidisciplinary approach, incorporating clinical, radiological, and histopathological expertise for accurate diagnosis and tailored management. Ongoing research is crucial to refine treatment strategies, enhance prognostic precision, and improve outcomes for individuals with this uncommon CNS neoplasm.

Differences in lercanidipine systemic exposure when administered according to labelling: in fasting state and 15 minutes before food intake.

PURPOSE: The aim of this study was to compare the systemic exposure of lercanidipine (Zanidip) after oral administration in the fasted state and 15 min before food intake (meals) to investigate if the recommendations in the Summary of Product Characteristics (SPC) with respect to the intake of meals are adequate. METHODS: The results of three pilot bioequivalence studies performed to develop a lercanidipine generic product, where Zanidip was administered consistently as reference product in the fasted state or 15 min before a standard breakfast, were compared to estimate the drug­food interaction and the similarity of the methods of administration defined in the SPC. RESULTS: The ingestion of a standard (non-high-fat, non-high-calorie) meal 15 min after drug intake increased the area under the concentration­time curve (AUC(0-t)) of S-lercanidipine by 1.78-fold [90% confidence interval (CI) 1.48­2.15, P<0.0001] and the maximum concentration (Cmax) of Slercanidipine by 1.82-fold (90% CI 1.46­2.28, P<0.0001). These values are close to the twofold increase that has been described when Zanidip was taken immediately after a carbohydrate-rich meal. Higher levels would be expected with a high-fat, high-calorie meal. CONCLUSIONS: As intake with a carbohydrate-rich meal is not recommended in the SPC of Zanidip because a twofold difference was considered to be clinically relevant, the intake of lercanidipine only 15 min before food intake does not seem to be consistent with this recommendation. The Marketing Authorisation Holder should clarify the dosing instructions in relation to meals and identify a sufficient time-lapse to ensure an exposure similar to that obtained in phase III clinical efficacy studies.

The mere sight of loved ones does not inhibit psychophysiological defense mechanisms when threatened.

Looking at pictures of loved ones, such as one's romantic partner or good friends, has been shown to alleviate the experience of pain and reduce defensive reactions. However, little is known about such modulatory effects on threat and safety learning and the psychophysiological processes involved. Here, we explored the hypothesis that beloved faces serve as implicit safety cues and attenuate the expression of fear responses and/or accelerate extinction learning in a threatening context. Thirty-two participants viewed pictures of their loved ones (romantic partner, parents, and best friend) as well as of unknown individuals within contextual background colors indicating threat-of-shock or safety. Focusing on the extinction of non-reinforced threat associations (no shocks were given), the experiment was repeated on two more test days while the defensive startle-EMG, SCR, and threat ratings were obtained. Results confirmed pronounced defensive responding to instructed threat-of-shock relative to safety context (e.g., threat-enhanced startle reflex and SCR). Moreover, threat-potentiated startle response slowly declined across test days indicating passive extinction learning in the absence of shocks. Importantly, neither a main effect of face category (loved vs. unknown) nor a significant interaction with threat/safety instructions was observed. Thus, a long-term learning history of beneficial relations (e.g., with supportive parents) did not interfere with verbal threat learning and aversive apprehensions. These findings reflect the effects of worries and apprehensions that persist despite the repeated experience of safety and the pictorial presence of loved ones. How to counter such aversive expectations is key to changing mal-adaptive behaviors (e.g., avoidance or stockpiling), biased risk perceptions, and stereotypes.

Environmental Niche Dynamics of Blue Grama (Bouteloua gracilis) Ecotypes in Northern Mexico: Genetic Structure and Implications for Restoration Management.

Understanding the genetic structure adopted by natural populations and its relation to environmental adaptation is critical for the success of restoration programs. We evaluated the genetic structure and temporal environmental niche dynamics of blue grama (Bouteloua gracilis) in 48 populations. The genetic evaluation was performed through amplified fragment length polymorphism (AFLP) molecular markers. The maximum entropy method was used to model the past, present, and future environmental niches of the three clusters derived from the genetic analysis. The environmental niches of the three genetic clusters showed dynamic overlaps and isolations during the last interglacial and glacial maximum. The paleoclimatic events, which occurred during those periods, may have reinforced genetic exchange among populations and affected their genetic structure. Genetic clusters also presented different environmental niches in the present. Thus, they can be considered as three distinct ecotypes and restoration programs must be carried out using local germplasm from each environmental niche to increase their chance of success. Based on the environmental niches of the genetic clusters, changes are expected in the near and mid-century future. Therefore, climate change must be considered for species conservation management and future restoration programs.

Verbal threat learning does not spare loved ones.

Significant others provide individuals with a sense of safety and security. However, the mechanisms that underlie attachment-induced safety are hardly understood. Recent research has shown beneficial effects when viewing pictures of the romantic partner, leading to reduced pain experience and defensive responding. Building upon this, we examined the inhibitory capacity of loved face pictures on fear learning in an instructed threat paradigm. Pictures of loved familiar or unknown individuals served as signals for either threat of electric shocks or safety, while a broad set of psychophysiological measures was recorded. We assumed that a long-term learning history of beneficial relations interferes with social threat learning. Nevertheless, results yielded a typical pattern of physiological defense activation towards threat cues, regardless of whether threat was signaled by an unknown or a loved face. These findings call into question the notion that pictures of loved individuals are shielded against becoming threat cues, with implications for attachment and trauma research.

XIORT-MC: A real-time MC-based dose computation tool for low- energy X-rays intraoperative radiation therapy.

PURPOSE: The INTRABEAM system is a miniature accelerator for low-energy X-ray Intra-Operative Radiation Therapy (IORT), and it could benefit from a fast and accurate dose computation tool. With regards to accuracy, dose computed with Monte Carlo (MC) simulations are the gold standard, however, they require a large computational effort and consequently they are not suitable for real-time dose planning. This work presents a comparison of the implementation on Graphics Processing Unit (GPU) of two different dose calculation algorithms based on MC phase-space (PHSP) information to compute dose distributions for the INTRABEAM device within seconds and with the accuracy of realistic MC simulations. METHODS: The MC-based algorithms we present incorporate photoelectric, Compton and Rayleigh effects for the interaction of low-energy X-rays. XIORT-MC (X-ray Intra-Operative Radiation Therapy Monte Carlo) includes two dose calculation algorithms; a Woodcock-based MC algorithm (WC-MC) and a Hybrid MC algorithm (HMC), and it is implemented in CPU and in GPU. Detailed MC simulations have been generated to validate our tool in homogeneous and heterogeneous conditions with all INTRABEAM applicators, including three clinically realistic CT-based simulations. A performance study has been done to determine the acceleration reached with the code, in both CPU and GPU implementations. RESULTS: Dose distributions were obtained with the HMC and the WC-MC and compared to standard reference MC simulations with more than 95% voxels fulfilling a 7%-0.5 mm gamma evaluation in all the cases considered. The CPU-HMC is 100 times more efficient than the reference MC, and the CPU-WC-MC is about 50 times more efficient. With the GPU implementation, the particle tracking of the WC-MC is faster than the HMC, with the extraction of the particle's information from the PHSP file taking a major part of the time. However, thanks to the variance reduction techniques implemented in the HMC, up to 400 times less particles are needed in the HMC to reach the same level of noise than the WC-MC. Therefore, in our implementation for INTRABEAM energies, the HMC is about 1.3 times more efficient than the WC-MC in an NVIDIA GeForce GTX 1080 Ti card and about 5.5 times more efficient in an NVIDIA GeForce RTX 3090. Dose with noise below 5% has been obtained in realistic situations in less than 5 s with the WC-MC and in less than 0.5 s with the HMC. CONCLUSIONS: The XIORT-MC is a dose computation tool designed to take full advantage of modern GPUs, making possible to obtain MC-grade accurate dose distributions within seconds. Its high speed allows a real-time dose calculation that includes the realistic effects of the beam in voxelized geometries of patients. It can be used as a dose-planning tool in the operating room during a XIORT treatment with any INTRABEAM device.

Exploring Virome Diversity in Public Data in South America as an Approach for Detecting Viral Sources From Potentially Emerging Viruses.

The South American continent presents a great diversity of biomes, whose ecosystems are constantly threatened by the expansion of human activity. The emergence and re-emergence of viral populations with impact on the human population and ecosystem have shown increases in the last decades. In deference to the growing accumulation of genomic data, we explore the potential of South American-related public databases to detect signals that contribute to virosphere research. Therefore, our study aims to investigate public databases with emphasis on the surveillance of viruses with medical and ecological relevance. Herein, we profiled 120 "sequence read archives" metagenomes from 19 independent projects from the last decade. In a coarse view, our analyses identified only 0.38% of the total number of sequences from viruses, showing a higher proportion of RNA viruses. The metagenomes with the most important viral sequences in the analyzed environmental models were 1) aquatic samples from the Amazon River, 2) sewage from Brasilia, and 3) soil from the state of São Paulo, while the models of animal transmission were detected in mosquitoes from Rio Janeiro and Bats from Amazonia. Also, the classification of viral signals into operational taxonomic units (OTUs) (family) allowed us to infer from metadata a probable host range in the virome detected in each sample analyzed. Further, several motifs and viral sequences are related to specific viruses with emergence potential from Togaviridae, Arenaviridae, and Flaviviridae families. In this context, the exploration of public databases allowed us to evaluate the scope and informative capacity of sequences from third-party public databases and to detect signals related to viruses of clinical or environmental importance, which allowed us to infer traits associated with probable transmission routes or signals of ecological disequilibrium. The evaluation of our results showed that in most cases the size and type of the reference database, the percentage of guanine-cytosine (GC), and the length of the query sequences greatly influence the taxonomic classification of the sequences. In sum, our findings describe how the exploration of public genomic data can be exploited as an approach for epidemiological surveillance and the understanding of the virosphere.

Acceptability and characteristics of 124 human bioequivalence studies with active substances classified according to the Biopharmaceutic Classification System.

AIM: The aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes. METHODS: We evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra- and inter-subject coefficients of variation data from BE studies with generic products. RESULTS: Out of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non-bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra-subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non-BE pharmaceutical products in classes 1, 2 and 3. CONCLUSIONS: Comparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra-subject variability for C(max) or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non-BE studies.

Watch out, he's dangerous! Electrocortical indicators of selective visual attention to allegedly threatening persons.

The face of a friend indicates safety, the face of a foe can indicate threat. Here, we examine the effects of verbal instructions ('beware of this person') on the perception of unknown persons. Focusing on visual attention, face identity and facial expression information is examined during instructed threat-of-shock or safety. However, shocks never occurred. Participants quickly acquired instructed threat associations, and electrocortical processing differentiated threat- from safe-identities as well as emotional and neutral facial expressions. Importantly, face encoding varied as a joint function of identity and facial expression, as revealed by pronounced N170 amplitudes to smiling threat-identities. Moreover, instructions readily reversed previously learned affective associations leading to attention allocation and memory updating as reflected by N170, EPN and P3 amplitudes toward new threat-identities displaying angry expressions. These findings demonstrate that person perception flexibly re-adjusts according to minimal information. Intriguingly, perceptual biases occur even though the anticipated aversive consequence does not occur, with implications for research on stereotyping and anxious psychopathology.

Reversing Threat to Safety: Incongruence of Facial Emotions and Instructed Threat Modulates Conscious Perception but Not Physiological Responding.

Facial expressions inform about other peoples' emotion and motivation and thus are central for social communication. However, the meaning of facial expressions may change depending on what we have learned about the related consequences. For instance, a smile might easily become threatening when displayed by a person who is known to be dangerous. The present study examined the malleability of emotional facial valence by means of social learning. To this end, facial expressions served as cues for verbally instructed threat-of-shock or safety (e.g., "happy faces cue shocks"). Moreover, reversal instructions tested the flexibility of threat/safety associations (e.g., "now happy faces cue safety"). Throughout the experiment, happy, neutral, and angry facial expressions were presented and auditory startle probes elicited defensive reflex activity. Results show that self-reported ratings and physiological reactions to threat/safety cues dissociate. Regarding threat and valence ratings, happy facial expressions tended to be more resistant becoming a threat cue, and angry faces remain threatening even when instructed as safety cue. For physiological response systems, however, we observed threat-potentiated startle reflex and enhanced skin conductance responses for threat compared to safety cues regardless of whether threat was cued by happy or angry faces. Thus, the incongruity of visual and verbal threat/safety information modulates conscious perception, but not the activation of physiological response systems. These results show that verbal instructions can readily overwrite the intrinsic meaning of facial emotions, with clear benefits for social communication as learning and anticipation of threat and safety readjusted to accurately track environmental changes.

Positive emotional reactions to loved names.

Studies concerning personal attachment have successfully used loved familiar faces to prompt positive affective and physiological reactions. Moreover, the processing of emotional words shows similar physiological patterns to those found with affective pictures. The objective of this study was to assess whether the passive viewing of loved names would produce a pattern of subjective and physiological reactivity similar to that produced by the passive viewing of loved faces. The results showed that, compared to neutral (unknown) and famous names, loved names produced a biphasic pattern of heart rate deceleration-acceleration, heightened skin conductance and zygomaticus muscle activity, inhibition of corrugator muscle activity, and potentiation of the startle reflex response. This pattern of physiological responses was accompanied by subjective reports of higher positive affect and arousal for loved names than for neutral and famous ones. These findings highlight not only the similarity but also the differences between the affective processing of identity recognition by loved faces and names.