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Proton-pump inhibitors (PPIs) are among the most frequently prescribed drugs, but they are being overprescribed. To evaluate the applicability of a deprescription algorithm in hospitalized patients with chronic PPI use. A prospective study including consecutive gastroenterology department hospitalized patients with chronic PPI use. The prescription was reassessed and a deprescribing algorithm was applied. Follow-up was carried out at 4, 12, and 24 weeks. A total of 513 (44.22%) of 1160 had chronic PPI use; 371 met inclusion criteria and were evaluated: 285 (76.82%) with appropriate prescription and 86 (23.18%) with inappropriate, mainly (52.30%) due to polypharmacy. Seventy-five patients accepted the deprescribing process. Sixty-one (81.33%) maintained deprescription at week 4, 56 (74.66%) at week 12, and 54 (72.00%) at week 24. Eleven of 21 restarted the PPI because of symptoms. No differences were found between the successful deprescription group and the unsuccessful one, regarding sex (p = 0.877), age (p = 0.635), PPI indication (p = 0.663), or deprescription regimen (p = 0.805). No patient had any adverse event attributable to deprescription. There is a high inappropriate indication for PPIs in patients admitted to the gastroenterology department. The application of a patient-centered deprescribing algorithm is a safe and effective strategy to reduce their inappropriate consumption in the medium term.

Fear memory generalisation is a central hallmark in the broad range of anxiety and trauma-related disorders. Recent findings suggest that fear generalisation is closely related to hippocampal dependency during retrieval. In this review, we describe the current understanding about memory generalisation and its potential influence in fear attenuation through pharmacological and behavioural interventions. In light of systems consolidation framework, we propose that keeping memory precision could be a key step to enhance therapeutic outcomes.

Objective: The purpose of this study was to see if there was any referred medial scapula pain from C6 or C7 cervical spinal stenosis. Scapula pain of neurologic origin is currently thought to be primarily mediated by C5 via the dorsal scapular nerve. Dorsal root ganglion neurons with dichotomising axons are present in several species and are considered to play a role in referred pain. An interventional spine clinic observed a number of patients with medial scapula pain who did not have C5 stenosis, but many of these patients had C6 or C7 stenosis. Methods: The charts of 278 patients seen in an interventional spine clinic over an 11 year period from 2008 to 2018 who were diagnosed with cervical radiculopathy based on location of pain were reviewed. 135 of these had cervical MRI imaging. Data was collected to evaluate for a correlation of the level of cervical stenosis with the location of pain at the medial border of the scapula. Results: Patients with ipsilateral medial scapula pain had 0.0% incidence of stenosis at C4, 29.5% at C5, 64.6% at C6, 49.2% at C7, 0.0% at C8, and 80% with either C6 or C7 stenosis. Conclusion: This is the first report of referred pain to the medial scapula from cervical stenosis at the C6 or C7 levels. The mechanism of referred pain is reviewed and a plausible and testable neurologic explanation for these observed findings is presented.

In the last decade, pharmacological strategies targeting reconsolidation after memory retrieval have shown promising efforts to attenuate persistent memories and overcome fear recovery. However, most reconsolidation inhibiting agents have not been approved for human testing. While non-invasive neuromodulation can be considered an alternative approach to pharmacological treatments, there is a lack of evidence about the efficacy of these technologies when modifying memory traces via reactivation/reconsolidation mechanism.In this study, we evaluate the effect of cathodal (c-tDCS) and anodal (a-DCS) transcranial direct current stimulation applied after memory reactivation and extinction in rats.Male Wistar rats were randomly assigned into three groups: one sham group, one anodal tDCS group, and one cathodal tDCS group (500 μA, 20 min). Reconsolidation and extinction of fear memories were evaluated using a contextual fear conditioning.Our results showed that c-tDCS and a-tDCS after memory reactivation can attenuate mild fear memories. However, only c-tDCS stimulation prevented both fear expression under strong fear learning and fear recovery after a reinstatement protocol without modification of learning rate or extinction retrieval. Nevertheless, the remote memories were resistant to modification through this type of neuromodulation. Our results are discussed considering the interaction between intrinsic excitability promoted by learning and memory retrieval and the electric field applied during tDCS.These results point out some of the boundary conditions influencing the efficacy of tDCS in fear attenuation and open new ways for the development of noninvasive interventions aimed to control fear-related disorders via reconsolidation.

This work presents the evaluation of a co-processed material for high-load dose formulations and its real-time monitoring by near-infrared (NIR) spectroscopy at the tablet press feed frame. The powder and tableting properties of co-processed material blends were evaluated and compared to the blend of the individual excipients. The formulations with the co-processed material showed excellent flow properties and were superior to the physical blend of individual excipients. Two NIR spectroscopic methods were developed to monitor ibuprofen concentration between 40.0 and 60.0% w/w, one method using a co-processed material as the main excipient and the other using the blend of the individual excipients. The NIR spectra were obtained while the powder blends flowed within a three-chamber feed frame from a Fette 3090 tablet press. The NIR spectroscopic method with the co-processed material presented better performance with significantly lower prediction error. Variographic analysis demonstrated that using the co-processed material considerably reduces the sampling and analytical errors in the in-line determination of ibuprofen. The authors understand that this is the first study where the sampling errors are evaluated as a function of the excipients used in the pharmaceutical formulation. This study demonstrated that selecting a suitable excipient for the formulation helps optimize the manufacturing process, reducing the magnitude of the total measurement error.

Proton-pump inhibitors (PPIs) are among the most frequently prescribed drugs, but they are being overprescribed.To evaluate the applicability of a deprescription algorithm in hospitalized patients with chronic PPI use.A prospective study including consecutive gastroenterology department hospitalized patients with chronic PPI use. The prescription was reassessed and a deprescribing algorithm was applied. Follow-up was carried out at 4, 12, and 24 weeks.A total of 513 (44.22%) of 1160 had chronic PPI use; 371 met inclusion criteria and were evaluated: 285 (76.82%) with appropriate prescription and 86 (23.18%) with inappropriate, mainly (52.30%) due to polypharmacy. Seventy-five patients accepted the deprescribing process. Sixty-one (81.33%) maintained deprescription at week 4, 56 (74.66%) at week 12, and 54 (72.00%) at week 24. Eleven of 21 restarted the PPI because of symptoms. No differences were found between the successful deprescription group and the unsuccessful one, regarding sex (p = 0.877), age (p = 0.635), PPI indication (p = 0.663), or deprescription regimen (p = 0.805). No patient had any adverse event attributable to deprescription.There is a high inappropriate indication for PPIs in patients admitted to the gastroenterology department. The application of a patient-centered deprescribing algorithm is a safe and effective strategy to reduce their inappropriate consumption in the medium term.

A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

This study investigates the performance of a sampling interface for monitoring cohesive, flowing powder formulations with Hausner’s Ratio and Carr’s Index higher than 1.5 and 35%, respectively. The sampler device was operated in combination with near-infrared (NIR) spectroscopy to quantify ibuprofen concentrations between 1.5 and 4.5% w/w. NIR spectra also provided essential information to study the process dynamics within the sampler. The 200 spectra per blend obtained demonstrated a continuous powder flow with no evidence of agglomerates or segregation within the sampler for a blend of 6 kg. A NIR calibration model was optimized to predict independent test blends, delivering root mean square error of predictions and bias under 0.1% w/w. The test blends were within specifications according to the requirements of European Pharmacopeia. Variographic analysis demonstrated that the sampler device may determine low drug concentration in cohesive powder blends, presenting sampling errors below 0.011 (%w/w)2. This analysis also demonstrated that an increase in the blend compressibility leads to a slight rise in sampling errors within the sampler device. The sampler device offers statistical robustness in the evaluation of blend uniformity, providing greater confidence in the quality determination of the cohesive powder blends without significantly affecting its flow properties.

It is essential that orthopaedic resident physicians be highly proficient in all aspects, considering the balance between supply, demand, need and context. Fundamental to identify the capacity and quality installed for their training in Mexico.Observational Study, transverse, non-probabilistic sampling-conglomerates, in two phases. The instrument has 8 domains, 57 variables and 4,867 items. 60 graduate professors of 20 states, 50 hospital sites, 22 university programs.1,038 years of experience (collective intelligence), 17 years of experience/teacher (01 to 50 years). Identified: acute pathology 30 (2 to 90%), chronic pathology 30 (5 to 96%), patients 15 years, 10 (3 to 30%), patients between 15 and 65 years, 47 (2 to 78%), patients 65 years, 20 (2 to 60%), number of beds/seat 20 (2 to 510), number of clinics 3 (1 to 48), number of surgical procedures/headquarters per year at the national level, was 960 (50 to 24,650). The national average per resident doctor is 362 surgeries/year with 1,450 surgical times/year.The needs and resources for the training of physicians specializing in orthopedics/traumatology are highly heterogeneous, so it should be adapted to the epidemiological needs of the region of influence, in an area of epidemiological transition. 62.2% expressed not having or have bad academic and scientific infrastructure at its headquarters, more than 50% without rotation overseas and 90% without regular scientific production.Es fundamental que los médicos residentes de ortopedia (traumatología) sean altamente competentes en todos los aspectos, considerando el equilibrio entre la oferta, demanda, necesidad y contexto. Es primordial identificar la capacidad y calidad instalada para su formación en México.Estudio observacional, transversal, muestreo no probabilístico-conglomerados, en dos fases. El instrumento tiene ocho dominios, 57 variables y 4,867 ítems. Sesenta profesores de postgrado de 20 estados, 50 sedes hospitalarias, 22 programas universitarios.1,038 años de experiencia (inteligencia colectiva), 17 años de experiencia/profesor (01 a 50 años). Se identificó: patología aguda 30 (2 a 90%), patología crónica 30 (5 a 96%), pacientes 15 años, 10 (3 a 30%), pacientes entre 15 y 65 años, 47 (2 a 78%), pacientes 65 años, 20 (2 a 60%), número de camas/sede 20 (2 a 510), número de consultorios 3 (1 a 48), el número de procedimientos quirúrgicos/sede al año a nivel nacional fue de 960 (50 a 24,650). La media nacional por médico residente es de 362 cirugías/año con 1,450 momentos quirúrgicos/año.Las necesidades y recursos para la formación de médicos especialistas en ortopedia/traumatología son en alto grado heterogéneos, por lo cual se debería adaptar a las necesidades epidemiológicas de la región de influencia, en un ámbito de transición epidemiológica. Sesenta y dos punto dos por ciento expresó no tener o tener deficiente infraestructura académica y científica en su sede, más de 50% sin rotación al extranjero y 90% sin producción científica regular.

The requirement of NMDA receptor (NMDAR) activity for memory formation is well described. However, the plasticity mechanisms for memory can be modified by experience, such that a future similar learning becomes independent of NMDARs. This effect has often been reported in learning events conducted with a few days interval. In this work, we asked whether the NMDAR-independency is permanent or the brain regions and plasticity mechanisms of experience-dependent learning may change over time. Considering that contextual memories undergo a gradual reorganization over time, becoming progressively independent from the hippocampus and dependent upon cortical regions, we investigated the brain regions mediating a new related learning conducted at a remote time-point, when the first memory was already cortically established. First, we demonstrated that anterior cingulate cortex was not able to support a learning subsequent to a previous systems-level consolidated memory; it did require at least one functional subregion of the hippocampus (ventral or dorsal). Moreover, after replicating findings showing that a few days interval between trainings induces a NMDAR-independent learning, we managed to show that a learning following a longer interval once again becomes dependent on NMDARs in the hippocampus. These findings suggest that while the previous memory grows independent from the hippocampus over time, an experience-dependent learning following a systems-consolidated memory once again engages the hippocampus and a NMDAR-dependent plasticity mechanism.

This study reports the use of Raman and Near-infrared (NIR) spectroscopy to simultaneously monitor the drug concentration in flowing powder blends within a three-chamber feed frame. The Raman probe was located at the top of the dosing chamber, while the NIR probe was located at the top of the filling chamber. The Raman and NIR spectra were continuously acquired while the powder blends flowed through the feed frame. Calibration models were developed with spectra from a total of five calibration blends ranging in caffeine concentration among 3.50 and 6.50% w/w. These models were optimized to predict three test set blends of 4.00, 5.00, and 6.00% w/w caffeine. The results showed a high predictive ability of the models based on root mean square error of predictions of 0.174 and 0.235% w/w for NIR and Raman spectroscopic models, respectively. Concentration profiles with higher variability were observed for the Raman spectroscopy predictions. An estimate of the mass analyzed by each spectrum showed that a NIR spectrum analyzes approximately 4.5 times the mass analyzed by a Raman spectrum; despite these differences in the mass analyzed, blend uniformity results are equivalent between techniques. Variographic analysis demonstrated that both techniques have significantly low sampling errors for the real-time monitoring process of drug concentration within the feed frame.

Background It has been suggested that biologic therapy may increase the risk of postoperative complications in inflammatory bowel disease (IBD), but the evidence is scarce. Our aim was to evaluate whether the treatment with anti-TNF agents, ustekinumab or vedolizumab increase the risk of complications after surgery. Methods IBD patients undergoing intra-abdominal surgery between 1st January 2009 and 31st December of 2019 were retrospectively selected. Data collection included clinical characteristic of IBD, biochemical parameters and surgical aspects. Postoperative complications (PC) were defined as those occurring within 30 days after surgery. Exposed cohort (EC): Patients who received the last dose of the biologic within 3 months before surgery. Non-exposed cohort (NEC): Patients who did not receive biologic treatment within 3 moths prior to surgery. Predictive factors for PC and for infections were identified by logistic regression analyses. A genetic matching score was performed to balance the clinical characteristics of both groups. Results A total of 1,535 surgeries performed in 37 centres were included: 81% in Crohn’s disease, 18% in ulcerative colitis and 1% in unclassified-IBD patients. A total of 711 surgeries (46.3%) had been exposed to biologics (583 under anti-TNF therapy, 58 under vedolizumab and 69 under ustekinumab) and 824 surgeries (53.7%) the NEC. PC were reported in 38% (n=267) of patients in the exposed cohort and in 34% (n=280) of patients in the non-exposed one (p=0.15), including dehiscence, infection, obstruction, ileus, bleeding, thrombosis, fistula and evisceration. The most frequent complications were infections (48% of all the cases). A 30-day hospital readmission was needed in 7% (n=110) of the patients, and 2% (n=29) required a new surgery with no differences (p>0.05). Multivariate analysis for PC and infections is presented in table 1. The frequencies of PC for each biologic in the univariate analysis are represented in figure 1. No specific treatment was associated to PC or infections in multivariate analysis. Conclusion Preoperative administration of biological therapy does not seem to be a risk factor for overall PC, although it may be for postoperative infections.

Azolla filiculoides and Typha latifolia are invasive plants that detrimentally affect water and environmental quality in Andean wetlands. This study determined the aeration rate required to accelerate the composting process for biomass from these two plants using an enhanced semi-portable, closed, controlled bioreactor powered by a photovoltaic system. Such a system utilizing biomass from invasive aquatic plants could be used to produce compost in rural, remote, mountainous areas with little infrastructure. The solar powered, self-gyrating fixed bed gasifier bioreactor system measured tri-daily temperature, humidity, oxygen and pH. Aeration rate and humidity curves were also developed and could be used in other composting systems in tropical mountainous areas. The autonomous, self-powered, closed system bioreactor reduced composting time from the typical 9 weeks to just 4 and period of activation from 2.6 weeks to 1.5 days. Compost pH, humidity and C:N ratios were all within the range of reported values. Physical and chemical analyses show that the final compost material was suitable for local Andean cropping systems. The system can be used to sustainably utilize excess biomass residue material from Andean wetland restoration projects. © 2017 Elsevier Ltd

A novel sampler device for flowing powders was tested to quantify drug concentrations as low as 0.76% w/w in pharmaceutical powder blends. The sampler device was developed based on the powder flow behavior within a tablet press feed frame, following the principles laid down in the Theory of Sampling. Two Near-Infrared (NIR) spectroscopic calibration models were developed with powder blends that varied from 0.52 to 2.52% w/w and 1.51–4.52% w/w. The calibration models were able to determine caffeine concentration in test set blends with root mean square error of predictions and bias below 0.1% w/w. Samples were collected from the sampler device and analyzed by ultraviolet-visible (UV–Vis) to determine the caffeine concentration. A high agreement between the in-line NIR predictions and the sampled UV–Vis results was found. The paddle wheel speed in the sampler can be varied up to ±10% without affecting NIR predictions; however, the models did not respond adequately to a 25% increase in this speed. Variographic analysis showed that the sampler device may quantify low drug concentrations with nugget effects below 0.0050 (%w/w)2. This study demonstrate that the sampler device may handle throughputs up to 45 kg/h, without significantly affecting the physical properties of powder blends.

Systems consolidation is a time-dependent reorganization process involving neocortical and hippocampal networks underlying memory storage and retrieval. The involvement of the hippocampus during acquisition is well described; however we know much less about the concomitant contribution of cortical activity levels to the formation of stable remote memories. Here, after a reversible pharmacological inhibition of the anterior cingulate cortex (ACC) during the acquisition of a contextual fear conditioning, retrieval of both recent and remote memories were impaired, an effect that was reverted by a single memory reactivation session 48 h after training, through a destabilization-dependent mechanism interpreted as reconsolidation, that restored the normal course of systems consolidation in order to rescue a remote memory. Next we have shown that the integrity of both the anterior cingulate cortex and the thalamic nucleus reuniens (RE) were required for this reactivation-induced memory rescue. Because lidocaine infused into the RE inhibited LTP induction in the CA1-anterior cingulate cortex pathways, it seems that RE is a necessary component of the circuit underlying systems consolidation, mediating communication between dorsal hippocampus and cortical areas. To our notice, this is the first demonstration of the rescue of remote memories disrupted by ACC inhibition during acquisition, via a reconsolidation-driven mechanism. We have also shown the importance of RE to ensure the interconnection among brain areas that collectively seem to control the natural course of systems consolidation and allow the persistence of relevant emotional engrams. © 2017 Wiley Periodicals, Inc.

Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc.

A chute was designed following the principles of the Theory of Sampling to minimize the variations in powder flow and provide all particles in the flowing blends with the same opportunity of being selected as a sample. The design also reduces the thickness of the chute to allow the analysis of a higher portion of the flowing blends by a near infrared spectrometer. The blends that flowed through the chute had Carr's index values that fluctuated between 23 and 25 percent, indicating passable flowability. A powder fowling evaluation demonstrated that there was no powder accumulation at the inspection window of the chute. The mass flow rate profiles indicated that the system achieves mass steady-state in approximately 30 s and a throughput of 30 kg/h which makes it suitable for continuous manufacturing operations. An in-line NIR calibration model was developed to quantify caffeine concentrations between 1.51 and 4.52 % w/w. The spectra obtained from each experiment had minimal baseline variation. The developed NIR method was robust to throughput changes up to approximately ±7 %. The test blends in the caffeine concentration range between 2.02 % w/w and 4.02 % w/w met the dose uniformity requirements of the Ph.Eur. 9.0, chapter 2.9.47. Variographic analysis was done to estimate the analytical and sampling errors which yielded values below 0.01 (%w/w)2. The obtained results showed that this chute could also be used in a continuous manufacturing line or other applications with flowing powders.

Fear memory overgeneralization contributes to the genesis and persistence of anxiety disorders and is a central hallmark in the pathophysiology of post-traumatic stress disorder (PTSD). Recent findings suggest that fear generalization is closely related to hippocampal dependency during retrieval. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been used as a first-line treatment for PTSD; however, how it exerts its therapeutic effect remains a matter of debate. Here, using contextual fear conditioning in rats, we show that chronic fluoxetine treatment prevents fear generalization and enhances subsequent extinction. Moreover, fluoxetine treatment after extinction prevents spontaneous recovery. The mechanism through which fluoxetine affects generalization and extinction seems to be through the postponement of systems consolidation, thereby maintaining hippocampal involvement during retrieval. Such an effect relies on a remodeling of dendritic spines in the hippocampus, as well as the number of mature, mushroom-type spines promoted by fluoxetine treatment. In order to further investigate whether fear generalization is a potential predictor of extinction effectiveness, we categorized a large naive population according to their generalization rate. We found that discriminator rats showed a better extinction profile compared to generalizers, suggesting that the generalization rate predicts extinction effectiveness. Hence, we propose that the therapeutic strategy of choice should take into account the extension of memory generalization, in which therapies based on extinction could induce a better outcome in patients who present less fear overgeneralization. These results open new avenues for the development of interventions that prevent fear generalization by maintaining memory dependency of the hippocampus.

Blend uniformity was monitored throughout a continuous manufacturing (CM) process by near infrared (NIR) spectroscopic measurements of flowing blends and compared to the drug concentration in the tablets. The NIR spectra were obtained through the chute after the blender and within the feed frame, while transmission spectra were obtained for the tablets. The CM process was performed with semi-fine acetaminophen blends at 10.0% (w/w). The blender was operated at 250 RPM, for best performance, and 106 and 495 rpm where a lower mixing efficiency was expected. The variation in blender RPM increased the variation in drug concentration at the chute but not at the feed frame. Statistical results show that the drug concentration of tablets can be predicted, with great accuracy, from blends within the feed frame. This study demonstrated a mixing effect within the feed frame, which contribute to a 60% decrease in the relative standard deviation of the drug concentration, when compared to the chute. Variographic analysis showed that the minimum sampling and analytical error was five times less in the feed frame than the chute. This study demonstrates that the feed frame is an ideal location for monitoring the drug concentration of powder blends for CM processes.

In the last decade, several studies have shown that fear memories can be attenuated by interfering with reconsolidation. However, most of the pharmacological agents used in preclinical studies cannot be administered to humans. Caffeine is one of the world’s most popular psychoactive drugs and its effects on cognitive and mood states are well documented. Nevertheless, the influence of caffeine administration on fear memory processing is not as clear. We employed contextual fear conditioning in rats and acute caffeine administration under a standard memory reconsolidation protocol or periodical memory reactivation. Additionally, potential rewarding/aversion and anxiety effects induced by caffeine were evaluated by conditioning place preference or open field, respectively. Caffeine administration was able to attenuate weak fear memories in a standard memory reconsolidation protocol; however, periodical memory reactivation under caffeine effect was necessary to attenuate strong and remote memories. Moreover, caffeine promoted conditioned place preference and anxiolytic-like behavior, suggesting that caffeine weakens the initial learning during reactivation through counterconditioning mechanisms. Thus, our study shows that rewarding and anxiolytic effects of caffeine during fear reactivation can change the emotional valence of fear memory. It brings a new promising pharmacological approach based on drugs widely used such as caffeine to treat fear-related disorders.

Ankle fractures are one of the most frequent lesions of the musculoskeletal system; there are studies that report an increase in the incidence of these fractures starting in the 1970s, associated with the increased media outreach of sporting activities. Supra- and transyndesmal fractures often lead to injury of the syndesmosis, which, if not treated properly, will leave joint instability. The most common treatment is the placement of a transyndesmal screw; there is controversy on the height in which it should be located with regard to the distal tibial joint line.A descriptive, observational, retrospective and transversal study with clinical and radiographic records of patients operated on bimalleolar fractures; they were divided into two groups: those with the transyndesmal screw at 2 or 2.5 cm and those with the screw at 3.5 cm or more proximal. There was a total of 34 cases (group A: 16 patients; group B: 18), 22 male and 12 female, aged between 19 and 45 years.We applied the Olerud-Molander ankle score for the clinical evaluation and measured the radiographic medial space of the ankle to consider the degree of reduction. The results in both groups were compared.The location of the screw at 2.0 cm presented a percentage of 75% of joint stability and 25% of joint instability, the joint functionality was relatively smaller in comparison to the placement of the screw at 3.5 cm, with which we achieved a joint stability of 83.3% and 16.3% of joint instability.La fractura del tobillo es una de las lesiones más frecuentes del sistema musculoesquelético; existen estudios de población que reportan un aumento en la incidencia de estas fracturas a partir de los años 70 asociado al incremento en la difusión a través de los medios de las actividades deportivas de contacto. Las fracturas trans- y suprasindesmales afectan la sindesmosis y, de no tratarse adecuadamente, dejarán inestabilidad articular. El tratamiento más común es la colocación de un tornillo; existe controversia en la altura a la que este se debe colocar con respecto a la línea articular tibioastragalina.Estudio descriptivo, observacional, retrospectivo y transversal de expedientes clínicos y radiográficos de pacientes operados de fractura bimaleolar; se les dividió en dos grupos: aquellos con el tornillo transindesmal a 2 o 2.5 cm y aquellos con el tornillo a 3.5 cm o más proximal. Se recolectaron 34 casos en total (grupo A: 16 pacientes; grupo B: 18), 22 del sexo masculino y 12 del femenino, de edades entre 19 y 45 años.Se aplicó la escala funcional de OlerudMolander y se midió el claro medial del tobillo para considerar el grado de reducción de la sindesmosis. Se compararon los resultados de ambos grupos.El sitio de localización del tornillo de situación a 2.0 cm presentó un porcentaje de 75% de estabilidad articular y 25% de inestabilidad articular, la funcionalidad articular fue relativamente menor en comparación con la colocación del tornillo a 3.5 cm, donde se logró una estabilidad articular de 83.3% y 16.3% de inestabilidad articular.

ECRIS Network integrated in the Spanish AIDS Research Network., Exosome-derived miR-21 was independently associated with CD4 T cell decline in HIV-1-infected elite controllers (OR 0.369, 95% CI 0.137–0.994, p = 0.049). Also, a negative correlation between miR-21 expression and MCP-1 level was found (r = −0.649, p = 0.020), while no correlation between soluble biomarkers or cellular immune activation was found., This work has been partially funded by the Spanish Health Institute Carlos III (ISCIII) and European Regional Development Fund, Spanish AIDS Research Network (RIS) with grant numbers RD16/0025/0001, RD12/0017/0031, RD16/0025/0013, and RD16/0002/0002. Research Grant Project, Spanish Health Research Fund (FIS, ISCIII) number PI14/00011. Miguel Servet Research Program, Spanish Health Institute Carlos III (ISCIII) CP14/00198 to NR. Spanish Health Research Fund (FIS, ISCIII) and IIS-FJD Intramural Research Scholarship co-funded grant number CP14/00198 to MG. Spanish Health Institute Carlos III (ISCIII) grant CD13/00013 to MAJS. Grant Research, Madrid Education, Youth and Sport Counseling number PEJ15/bio/tl-0064 to MJRL.

The Geysers geothermal field is one of the most seismically active regions in northern California. Most of the events occur at shallow depths and are related to stress and hydrological perturbations due to energy production operations. To better understand the relationships between seismicity and operations, better source mechanism information is needed. Seismic moment tensors offer insight into the nature of equivalent forces causing the seismicity. Fifty-three M>3 events located at The Geysers geothermal field were selected from the University of California Berkeley Moment Tensor Catalog for analysis of seismic moment tensor solutions and associated uncertainties. Deviatoric and full moment tensor solutions were computed, and statistical tests were employed to assess solution stability, resolution, and significance. In this study, we examine several source models including double-couple (DC), pure isotropic (ISO; volumetric change), and volume-compensated linear vector dipole (CLVD) sources, as well as compound sources such as DC+CLVD, DC+ISO, and shear–tensile sources. In general, we find from a systematic approach toward characterizing uncertainties in moment tensor solutions that The Geysers earthquakes, as a population, deviate significantly from northern California seismicity in terms of apparent volumetric source terms and complexity.

Memory fades over time, becoming more schematic or abstract. The loss of contextual detail in memory may reflect a time-dependent change in the brain structures supporting memory. It has been well established that contextual fear memory relies on the hippocampus for expression shortly after learning, but it becomes hippocampus-independent at a later time point, a process called systems consolidation. This time-dependent process correlates with the loss of memory precision. Here, we investigated whether training intensity predicts the gradual decay of hippocampal dependency to retrieve memory, and the quality of the contextual memory representation over time. We have found that training intensity modulates the progressive decay of hippocampal dependency and memory precision. Strong training intensity accelerates systems consolidation and memory generalization in a remarkable timeframe match. The mechanisms underpinning such process are triggered by glucocorticoid and noradrenaline released during training. These results suggest that the stress levels during emotional learning act as a switch, determining the fate of memory quality. Moderate stress will create a detailed memory, whereas a highly stressful training will develop a generic gist-like memory.

Near infrared (NIR) spectroscopy was used to determine the drug concentration in 3% (w/w) acetaminophen blends within the complex flow regime of the tablet press feed frame just before tablet compaction. NIR spectra also provided valuable information on the powder flow behavior within the feed frame and were used to track when a process enters or leaves the steady state. A partial least squares regression calibration model was developed with powder mixtures that varied from 1.5 to 4.5% (w/w) by obtaining 135 spectra after steady state for each concentration while the feed frame and die disc operated at 30.5 revolutions per minute (rpm). The calibration model determined drug concentration in validation blends with a root mean square error of prediction and bias below 0.1% (w/w). The robustness of the NIR calibration model was evaluated by determining the effect of variation on the operating conditions (paddle wheel speed and die disc speed) on NIR predictions. This work found that the paddle wheel speed can be increased up to 30% and the die disc speed decrease 10% without affecting NIR predictions. The results demonstrated that paddle wheel speed has a significant effect on the wave powder behavior (frequency and amplitude) but does not have significant effect on the mass hold-up within feed frame. The die disc speed does not affect wave powder behavior but affects significantly the mass hold-up inside the feed frame. This information can be used to reduce the tablet weight variability and ensure that this critical attribute is met.

Long-lasting changes in dendritic spines provide a physical correlate for memory formation and persistence. LIM kinase (LIMK) plays a critical role in orchestrating dendritic actin dynamics during memory processing, since it is the convergent downstream target of both the Rac1/PAK and RhoA/ROCK pathways that in turn induce cofilin phosphorylation and prevent depolymerization of actin filaments. Here, using a potent LIMK inhibitor (BMS-5), we investigated the role of LIMK activity in the dorsal hippocampus during contextual fear memory in rats. We first found that post-training administration of BMS-5 impaired memory consolidation in a dose-dependent manner. Inhibiting LIMK before training also disrupted memory acquisition. We then demonstrated that hippocampal LIMK activity seems to be critical for memory retrieval and reconsolidation, since both processes were impaired by BMS-5 treatment. Contextual fear memory extinction, however, was not sensitive to the same treatment. In conclusion, our findings demonstrate that hippocampal LIMK activity plays an important role in memory acquisition, consolidation, retrieval, and reconsolidation during contextual fear conditioning. Fil: Lunardi, Paula Santana. Universidade Federal do Rio Grande do Sul; Brasil Fil: Sachser, Ricardo Marcelo. Universidade Federal do Rio Grande do Sul; Brasil Fil: Sierra, Rodrigo Ordoñez. Universidade Federal do Rio Grande do Sul; Brasil Fil: Pedraza, Lizeth Katherine. Universidade Federal do Rio Grande do Sul; Brasil Fil: Medina, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: de la Fuente, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Romano, Arturo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Quillfeldt, Jorge Alberto. Universidade Federal do Rio Grande do Sul; Brasil Fil: de Oliveira Alvares, Lucas. Universidade Federal do Rio Grande do Sul; Brasil

Extinction is a process that involves new learning that inhibits the expression of previously acquired memories. Although temporarily effective, extinction does not erase an original fear association. Since the extinction trace tends to fade over time, the original memory can resurge. On the other hand, strengthening effects have been described in several reconsolidation studies using different behavioral and pharmacological manipulations. In order to know whether an extinction memory can be strengthened by reactivation-based interventions in the contextual fear conditioning task, we began by replicating the classic phenomenon of spontaneous recovery to show that brief reexposure sessions can prevent the decay of the extinction trace over time in a long-lasting way. This fear attenuation was shown to depend both on L-type calcium channels and protein synthesis, which suggests a reconsolidation process behind the reactivation-induced strengthening effect. The extinction trace was also susceptible to enhancement by a post-reactivation infusion of a memory-enhancing drug (NaB), which was also able to prevent rapid fear reacquisition (savings). These findings point to new reactivation-based approaches able to strengthen an extinction memory to promote its persistence. The constructive interactions between extinction and reconsolidation may represent a promising novel approach in the realm of fear-related disorder treatments.

An innovative chute and stream sampler system for flowing powders has been developed and tested. The system is designed for representative sampling based on the principles of the Theory of Sampling (TOS). The sampling system was used in combination with near infrared (NIR) spectroscopy to determine the drug concentration of flowing powders. The system is comprised of three parts: a chute, a stream sampler and a sample collection port. The NIR spectra were obtained at the chute, before entering the sampler, and as the powder flowed through the stream sampler. Samples were also collected from the sample collection port to be analyzed using an ultraviolet-visible (UV–Vis) reference method to determine drug content. A total of eight pharmaceutical powder blends, ranging in concentration from 10.5(%w/w) to 19.5(%w/w) of caffeine, were used to test the sampling system. Materials were characterized before blends were made to provide information on flow properties. The throughput of the system was between 30 and 35 kg/h based on the flow properties of the blend. Drug concentration was effectively determined at the chute and stream sampler. The NIR calibration models showed low root mean squared errors of prediction, 0.65(%w/w) and 0.51(%w/w), for the chute and stream sampler respectively. The NIR calibration models also showed low bias values −0.36(%w/w) at the chute and 0.057(%w/w) at the stream sampler. Significant agreement was obtained between the results from the nondestructive NIR versus the destructive UV–Vis method. Variographic analysis was performed to estimate the analytical and sampling errors when determining the drug concentration at the chute and stream sampler respectively. The variographic analysis showed low analytical errors, 0.103(%w/w)2 and 0.181(%w/w)2 at the chute and stream sampler respectively. The analysis also showed that the minimum practical error (MPE) was around 0.2(%w/w)2 at both chute and stream sampler.

The feed frame is a force-feeding device used in the die filling process. The die filling process is crucial within pharmaceutical manufacturing to guarantee the critical quality attributes of the tablets. In recent years, interest in this unit has increased because it can affect the properties of the powder blend and tablets, and because of the success in real time monitoring of powder blend uniformity potential for Process Analytical Technology as described in this review. The review focuses on the recent advances in understanding the powder flow behavior inside the feed frame and how the residence time distribution of the powder within the feed frame is affected by the operating conditions and design parameters. Furthermore, this review also highlights the effect of the paddle wheel design and feed frame process parameters on the tablet weight, the principal variable for measuring die filling performance.

Motivated by the synaptic tagging and capture (STC) hypothesis, it was recently shown that a weak learning, only able to produce short-term memory (STM), can succeed in establishing long- term memory (LTM) with a concomitant, stronger experience. This is consistent with the capture, by the first-tagged event, of the so-called plasticity-related proteins (PRPs) provided by the second one. Here, we describe how a concomitant session of reactivation/reconsolidation of a stronger, contextual fear conditioning (CFC) memory, allowed LTM to result from a weak spatial object recognition (wSOR) training. Consist- ent with an STC process, the effect was observed only during a critical time window and was dependent on the CFC reconsolidation-related protein synthesis. Retrieval by itself (without reconsolidation) did not have the same promoting effect. We also found that the inactivation of the NMDA receptor by AP5 prevented wSOR training to receive this support of CFC reconsolidation (supposedly through the production of PRPs), which may be the equivalent of blocking the setting of a learning tag in the dorsal CA1 region for that task. Furthermore, either a Water Maze reconsolidation, or a CFC extinction session, allowed the forma- tion of wSOR-LTM. These results suggest for the first time that a recon- solidation session can promote the consolidation of a concomitant weak learning through a probable STC mechanism. These findings allow new insights concerning the influence of reconsolidation in the acquisition of memories of otherwise unrelated events during daily life situations. V C 2013 Wiley Periodicals, Inc.

Some memories enter into a labile state after retrieval, requiring reconsolidation in order to persist. One functional role of memory reconsolidation is the updating of existing memories. There are reports suggesting that reconsolidation can be modulated by a particular endogenous process taking place concomitantly to its natural course, such as water or sleep deprivation. Here, we investigated whether an endogenous process activated during a natural/physiological experience, or a pharmacological intervention, can also contribute to memory content updating. Using the contextual fear conditioning paradigm in rats, we found that the endogenous content of an aversive memory can be updated during its reconsolidation incorporating consequences of natural events such as water deprivation, transforming a previously stored memory into a state-dependent one. This updating seems to be mediated by the activation of angiotensin AT1 receptors in the dorsal hippocampus and local infusion of human angiotensin II (ANGII) was shown to mimic the water deprivation effects on memory reconsolidation. Systemic morphine injection was also able to turn a previously acquired experience into a state-dependent memory, reproducing the very same effects obtained by water deprivation or local angiotensin II infusion, and suggesting that other state-dependent-inducing protocols would also be able to contribute to memory updating. These findings trigger new insights about the influence of ordinary daily life events upon memory in its continuing reconstruction, adding the realm of reconsolidation to the classical view of endogenous modulation of consolidation.

Systems consolidation is a time-dependent reorganization process involving neocortical and hippocampal networks underlying memory storage and retrieval. The involvement of the hippocampus during acquisition is well described; however we know much less about the concomitant contribution of cortical activity levels to the formation of stable remote memories. Here, after a reversible pharmacological inhibition of the anterior cingulate cortex (ACC) during the acquisition of a contextual fear conditioning, retrieval of both recent and remote memories were impaired, an effect that was reverted by a single memory reactivation session 48 h after training, through a destabilization-dependent mechanism interpreted as reconsolidation, that restored the normal course of systems consolidation in order to rescue a remote memory. Next we have shown that the integrity of both the anterior cingulate cortex and the thalamic nucleus reuniens (RE) were required for this reactivation-induced memory rescue. Because lidocaine infused into the RE inhibited LTP induction in the CA1-anterior cingulate cortex pathways, it seems that RE is a necessary component of the circuit underlying systems consolidation, mediating communication between dorsal hippocampus and cortical areas. To our notice, this is the first demonstration of the rescue of remote memories disrupted by ACC inhibition during acquisition, via a reconsolidation-driven mechanism. We have also shown the importance of RE to ensure the interconnection among brain areas that collectively seem to control the natural course of systems consolidation and allow the persistence of relevant emotional engrams. © 2017 Wiley Periodicals, Inc.

Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc.

In the last decade, several studies have shown that fear memories can be attenuated by interfering with reconsolidation. However, most of the pharmacological agents used in preclinical studies cannot be administered to humans. Caffeine is one of the world's most popular psychoactive drugs and its effects on cognitive and mood states are well documented. Nevertheless, the influence of caffeine administration on fear memory processing is not as clear. We employed contextual fear conditioning in rats and acute caffeine administration under a standard memory reconsolidation protocol or periodical memory reactivation. Additionally, potential rewarding/aversion and anxiety effects induced by caffeine were evaluated by conditioning place preference or open field, respectively. Caffeine administration was able to attenuate weak fear memories in a standard memory reconsolidation protocol; however, periodical memory reactivation under caffeine effect was necessary to attenuate strong and remote memories. Moreover, caffeine promoted conditioned place preference and anxiolytic-like behavior, suggesting that caffeine weakens the initial learning during reactivation through counterconditioning mechanisms. Thus, our study shows that rewarding and anxiolytic effects of caffeine during fear reactivation can change the emotional valence of fear memory. It brings a new promising pharmacological approach based on drugs widely used such as caffeine to treat fear-related disorders.

This paper presents the progress made by the Neutron Activation Analysis (NAA) laboratory at the Colombian Geological Survey (SGC in its Spanish acronym), towards the characterization of its gamma spectrometric systems for Instrumental Neutron Activation Analysis (INAA), with the aim of introducing corrections to the measurements by variations in sample geometry. Characterization includes the empirical determination of the interaction point of gamma radiation inside the Germanium crystal, through the application of a linear model and the use of a fast Monte Carlo N-Particle (MCNP) software to estimate correction factors for differences in counting efficiency that arise from variations in sample density between samples and standards.

The Neutron Activation Analysis (NAA) laboratory at the Colombian Geological Survey has developed a technique for multi-elemental analysis of soil and plant matrices, based on Instrumental Neutron Activation Analysis (INAA) using the comparator method. In order to evaluate the analytical capabilities of the technique, the laboratory has been participating in inter-comparison tests organized by Wepal (Wageningen Evaluating Programs for Analytical Laboratories). In this work, the experimental procedure and results for the multi-elemental analysis of four soil and four plant samples during participation in the first round on 2015 of Wepal proficiency test are presented. Only elements with radioactive isotopes with medium and long half-lives have been evaluated, 15 elements for soils (As, Ce, Co, Cr, Cs, Fe, K, La, Na, Rb, Sb, Sc, Th, U and Zn) and 7 elements for plants (Br, Co, Cr, Fe, K, Na and Zn). The performance assessment by Wepal based on Z-score distributions showed that most results obtained |Z-score...

Memories can be destabilized by the reexposure to the training context and may reconsolidate into a modified engram. Reconsolidation relies on some particular molecular mechanisms involving LVGCCs and GluN2B-containing NMDARs. In this study we investigate the interference caused by the presence of a distractor - a brief, unanticipated stimulus that impair a fear memory expression - during the reactivation session and tested the hypothesis that this disruptive effect relies on a reconsolidation process. Rats previously trained in the contextual fear conditioning (CFC) were reactivated in the presence or absence of a distractor stimulus. In the test, groups reactivated in the original context with distractor displayed a reduction of the freezing response lasting up to 20 days. To check for the involvement of destabilization / reconsolidation mechanisms, we studied the effect of systemic nimodipine (a L-VGCC blocker) or intra-CA1 ifenprodil (a selective GluN2B/NMDAR antagonist) infused right before the reactivation session. Both treatments were able to prevent the disruptive effect of distraction. Ifenprodil results also bolstered the case for hippocampus as the putative brain structure hosting this phenomenon. Our results provide some evidence in support of a behavioral, non-invasive procedure that was able to disrupt an aversive memory in a long-lasting way.