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Abstract Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Abstract Mammary gland development occurs primarily in adulthood, undergoing extensive expansion during puberty followed by cycles of functional specialization and regression with every round of pregnancy/lactation/involution. This process is ultimately driven by the coordinated proliferation and differentiation of mammary epithelial cells. However, the endogenous molecular factors regulating these developmental dynamics are still poorly defined. Endocannabinoid signaling is known to determine cell fate-related events during the development of different organs in the central nervous system and the periphery. Here, we report that the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) plays a pivotal role in adult mammary gland development. Specifically, it is required for luminal lineage specification in the mammary gland, and it promotes hormone-driven secretory differentiation of mammary epithelial cells by controlling the endogenous levels of anandamide and the subsequent activation of cannabinoid CB1 receptors. Together, our findings shed light on the role of the endocannabinoid system in breast development and point to FAAH as a therapeutic target in milk-production deficits.

The avocado cv. Hass requires a suitable rootstock for optimal development under water stress. This study evaluated the performance of two avocado rootstocks (ANRR88 and ANGI52) grafted onto cv. Hass under four water stress conditions, 50% and 25% deficit, and 50% and 25% excess during the nursery stage. Plant height, leaf area (LA), dry matter (DM), and Carbon (OC) content in the roots, stems, and leaves were measured. Root traits were evaluated using digital imaging, and three vegetation indices (NDVI, CIRE, and MTCI) were used to quantify stress. The results showed that genotype significantly influenced the response to water stress. ANRR88 exhibited adaptation to moderate to high water deficits. ANGI52 adapted better to both water deficit and excess, and showed greater root exploration. LA and DM reductions of up to 60% were observed in ANRR88, suggesting a higher sensitivity to extreme changes in water availability. More than 90% of the total OC accumulation was observed in the stem and roots. The NDVI and the MTCI quantified the presence and levels of stress applied, and the 720 nm band provided high precision and speed for detecting stress. These insights are crucial for selecting rootstocks that ensure optimal performance under varying water availability, enhancing productivity and sustainability.

Recent research on maize root architecture has made significant progress, but further research is needed to optimize methods for efficient and accurate acquisition of root architecture data. This study aimed to assess the effectiveness of digital imaging for root phenotyping of Zea mays L. Field experiments were carried out at two locations in the province of Antioquia, Colombia, in 2019 and 2020 to analyze root architecture variables of 12 genotypes of maize. Two methodologies were used: manual phenotyping and digital image analysis. Pearson’s correlation coefficients among variables were estimated. Principal Component Analysis (PCA) was used to summarize and uncover clustering patterns in the multivariate data set. The results indicated correlations between diameter (r = 0.94) and manually measured root diameter. The manually measured right and left root angles correlated with image-derived root angle at r = 0.92 and 0.88, respectively, and root length at r = 0.62. The PCA highlighted that the digital method explained the highest proportion of variation in root areas and diameters, while the manual method dominated in root angle variables. These results corroborate a feasible method to optimize root architecture phenotyping for research questions. This protocol can be adopted under the automatic analysis with REST software for acquiring images of variables associated with roots’ angle, length, and diameter.

Abstract Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.

Abstract The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.

Excitotoxicity has been linked to the pathogenesis of several serious degenerative ocular diseases. Long-term overactivation of the NMDA receptor by glutamate in retinal ganglion cells (RGCs) results in degeneration, apoptosis and loss of function leading to blindness. NMDA receptor antagonists have been proposed as a pharmacological blockage of glutamate excitotoxicity. However, an inhibition of the pathway activated by glutamate receptors has intolerable side effects. An interesting pharmacological alternative would be the use of antiapoptotic compounds as RGCs’ neuroprotective active substances. Several mechanisms have been proposed to explain neuroprotection, including anti-inflammatory and scavenging activities. Here, the role of dexamethasone in neuroprotection was studied. For this purpose, original controlled release systems composed of microparticles containing dexamethasone with or without vitamin E and human serum albumin (HSA) were designed. The particles were prepared by the solid-in-oil-in-water (S/O/W) emulsion–evaporation technique. After properly characterization of the particles, they were intravitreally injected into an rat model of acute ocular excitotoxicity injury. The functionality of the retina was determined by electroretinography and RGCs were counted after cell immunohistochemistry. These microparticulate systems showed the ability to maintain normal electroretinal activity and promoted significant protection of RGCs. Through this proof of concept, we demonstrated that dexamethasone could be a useful anti-inflammatory agent to avoid the progression of degenerative ocular diseases. Furthermore, when administered in controlled release systems that provide low concentrations during prolonged periods of time, not only can the patient’s comfort be increased but the cytotoxicity of the drugs can also be avoided.

Objetivos. Determinar los cambios en las características clínicas y desenlaces intrahospitalarios de los pacientes hospitalizados por COVID-19 en un hospital privado de Caracas durante dos años de pandemia. Materiales y métodos. Estudio retrospectivo, observacional, de pacientes hospitalizados por COVID-19. Se investigó la correspondencia entre las olas de ingresos hospitalarios con las variantes circulantes del SARS-CoV-2 en la población general del Distrito Capital y estado Miranda. Resultados. Se incluyeron 1025 pacientes (569 hombres y 456 mujeres), con edad promedio de 62,9 DE: 16,2 años. Cuatro olas de ingresos hospitalarios fueron identificadas: primera (marzo-noviembre 2020) 150/1025 (14,6%) casos; segunda (diciembre-2020 a mayo-2021) 415/1025 (40,5%) casos; tercera (junio-diciembre 2021) 344/1025 (33,6%) casos; cuarta (enero-febrero 2022) 116/1025 (11,3%) casos. La edad promedio fue mayor en la cuarta ola (primera 64,0±15,7, segunda 61,4±15,8, tercera 62,1±16,5, y cuarta ola 68,5±16,4), mientras que la proporción de pacientes masculinos (primera 66,7%, segunda 58,8%, tercera 50,3%, y cuarta 44,8%), los pacientes con enfermedad grave-crítica (primera 65,3%, segunda 57%, tercera 51,7% y cuarta 44,8%), la estadía intrahospitalaria (primera 9,1±6,0, segunda 9,0±7,3, tercera 8,8±7,7, y cuarta 6,9±5,0 días), los ingresos a la UCI (primera 23,3%, segunda 15,7%, tercera 14,0%, y cuarta 11,2%; p=0,027) y la mortalidad (primera 21.8%, segunda 10,7%, tercera 9,1%, y cuarta 7,1%; p

Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of misfolded proteins in the endoplasmic reticulum (ER stress). Particularly, in Huntington's disease (HD) mutant huntingtin (mHtt) toxicity involves disruption of the ER-associated degradation pathway and loss of the ER protein homeostasis leading to neuronal dysfunction and degeneration. Besides the role of the UPR in regulating cell survival and death, studies that demonstrate the contribution of sustained UPR activation, particularly of PERK signaling, in memory disturbances and synaptic plasticity deficiencies are emerging. Given the contribution of hippocampal dysfunction to emotional and cognitive deficits seen in HD, we have analyzed the involvement of ER stress in HD memory alterations. We have demonstrated that at early disease stages, ER stress activation manifested as an increase in GRP78 and CHOP is observed in the hippocampus of R6/1 mice. Genetic reduction of GRP78 expression resulted in preventing hippocampal-dependent memory alterations but no motor deficits. Accordingly, hippocampal neuropathology namely, dendritic spine loss and accumulation of mHtt aggregates was ameliorated by GRP78 reduction. To elucidate the signaling pathways, we found that the inactivation of PERK by GSK2606414 restored spatial and recognition memories in R6/1 mice and rescued dendritic spine density in CA1 pyramidal neurons and protein levels of some specific immediate early genes. Our study unveils the critical role of the GRP78/PERK axis in memory impairment in HD mice and suggests the modulation of PERK activation as a novel therapeutic target for HD intervention.

Abstract Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptor-deficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cell-autonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.

El trabajo que se presenta tiene el objetivo de explicar los alcances de la herramienta de georreferenciación de cuencas (SIATL), que proporciona el Instituto Nacional de Estadística y Geografía (INEGI) .

Abstract Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB1 receptor signaling, through inhibition of the eCB‐degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM‐KO neurons. Oral treatment of ASM‐KO mice with a FAAH inhibitor prevented SM buildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also found CB1 receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann–Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient‐derived cells and in the brain of a NPC mouse model. Our findings reveal a pathophysiological crosstalk between neuronal SM and the eCB system and offer a new treatment for ASMD and other sphingolipidoses.

Seed uniformity and stability testing, and multiplication, are key steps in the seed supply chain of the common bean (Phaseolus vulgaris L.) and other crops. Optimizing agronomical practices in these phases can ultimately ensure seed quality and availability, and germplasm prospective utilization. However, farmers have rarely standardized seed testing and propagation protocols in local common bean landraces conserved in situ. An example of this is the Liborino variety (var.), a promising yellow Andean common bean known for its presumably high digestibility and adaptation to the local conditions of the Cauca river canyon (northwest Andes of Colombia), but likely experiencing genetic erosion after decades of suboptimal propagation. Therefore, this work intended to evaluate and select locally adapted genotypes of common bean var. Liborino for commercial use, to be later multiplied, evaluated by participatory breeding, and eventually shared with farmers. Specifically, we evaluated 44 accessions of var. Liborino common bean in six adaption and yield field trials in the Cauca river canyon at 1100 and 1400 m a.s.l, and in AGROSAVIA’s “La Selva” research station at 2100 m a.s.l. In parallel, we carried out standardized seed multiplication of a Liborino genotype using best practices to guarantee uniformity and stability. From the 44 accessions, nine were well adapted to the tested local conditions. Four of these accessions exhibited a bush type growth habit, while the remaining five were climbers. The trials revealed maximum average extrapolated yields of up to 1169.4 ± 228.4 kg ha−1 for the bush types (G8152) and up to 1720.0 ± 588.4 kg ha−1 for the climbers (G51018), both at 2100 m a.s.l. Three climbing accessions matched farmers’ expectations for seed coat color and shape, according to a participatory selection exercise. Uniform and stable seed of the selected genotype was delivered in 2022 to 39 farmers, ~6.5 kg of seeds per farmer. Our results will allow implementing bean genetic improvement pipelines, promoting var. Liborino commercialization, and boosting the economic and sustainable development of the rural communities in the Cauca river canyon. Seed uniformity testing and multiplication pipelines must be extended to other bean landraces conserved in situ.

Abstract Background The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids. Methods We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro. Results Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis. Conclusions The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.

Choosing a suitable prosthesis to restore the functionality of the hip joint is a complex problem. The stem geometries, materials, and type of hip damage are critical factors for avoiding potential issues (aseptic loosening, fracture, and natural wear and tear). Comparing the available stems to select the best option is not straightforward because of the various loads and boundary conditions used in the tests, making the process difficult to compare the advantages and disadvantages among them. This work proposes stem assessment using a standardized base (generated from a literature review and ISO standards) to compare the stem geometries and present a new hybrid design to improve performance using the best qualities of the implants reported in the literature review. Sixteen hip prostheses were evaluated with the finite element method (FEM) using the same boundary and loading conditions through multi-objective analysis (von Mises stress and strain). Consequently, a hybrid geometry proposal was obtained by assessing specific points through the stem length (medial and lateral region) to define the cross-section (trapezoidal) and the new profile. The new hybrid implant proposal presented a stress reduction of 9.6% when compared to the reference implant P2-T (the implant with the best behavior) in the most critical activity (activity 4) using a titanium alloy. A similar stress reduction of 9.98% was obtained using ASTM F2996-13 and ISO 7206–4:2010(E) standards.

Glaucoma is a group of chronic irreversible neuropathies that affect the retina and the optic nerve. It is considered one of the leading causes of blindness in the world. Although it can be due to various causes, the most important modifiable risk factor is the elevated intraocular pressure (IOP). In this case, the treatment of choice consists of instilling antihypertensive formulations on the ocular surface. The chronicity of the pathology, together with the low bioavailability of the drugs that are applied on the ocular surface, make it necessary to instill the formulations very frequently, which is associated, in many cases, with the appearance of dry eye disease (DED). The objective of this work is the design of topical ocular formulations capable of treating glaucoma and, at the same time, preventing DED. For this, two liposome formulations, loaded with brimonidine or with travoprost, were Tadeveloped using synthetic phospholipids and enriched by the addition of compounds with osmoprotective activity. The proposed formulations not only presented physicochemical characteristics (size, pH, osmolarity, surface tension, and viscosity) and encapsulation efficiency values (EE% of 24.78% and ≥99.01% for brimonidine and travoprost, respectively) suitable for ocular surface administration, but also showed good tolerance in human corneal and conjunctival cell cultures, as well as an in vitro osmoprotective activity. The hypotensive effect of both liposomal formulations was evaluated in normotensive albino New Zealand rabbits, showing a faster and longer lasting reduction of intraocular pressure in comparison to the corresponding commercialized products used as control. According to these results, the hypotensive liposomal formulations combined with osmoprotective agents would result in a very promising platform for the treatment of glaucoma and the simultaneous protection of the ocular surface.

The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ9-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ9-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.

Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

In this work, the effect of the proportion of a hyperbranched polyester polyol (HBP) of fourth generation on the structural, thermal, rheological, morphological and mechanical properties of tapioca starch/HBP blends (TPS) was evaluated. For this purpose, the ratios of starch:HBP employed to prepare the TPS were: 30:70 (TPS30), 40:60 (TPS40) and 50:50 (TPS50). Using infrared (IR) analysis, it was observed that the presence of HBP produced a displacement at the absorptions of the C-OH, C-O and C-O-C bonds of the TPS. The X-ray diffraction (DRX) analysis showed that the starch crystallinity is A and B type, which increased with the HBP amount. The glass transition temperature (Tg) of the TPS, increased with the HBP content, but the thermal stability and viscosity (at an angular frequency of 1 Hz) presented an opposite behavior. The scanning electronic microscopy analysis (SEM) revealed that the granular structure of the starch was not completely destructured.

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.

Alterations of the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are causally involved in a subset of malformations of cortical development (MCDs) ranging from focal cortical dysplasia (FCD) to hemimegalencephaly and megalencephaly. These MCDs represent a frequent cause of refractory pediatric epilepsy. The endocannabinoid system -especially cannabinoid CB1 receptor- exerts a neurodevelopmental regulatory role at least in part via activation of mTORC1 signaling. Therefore, we sought to characterize the possible contribution of endocannabinoid system signaling to FCD. Confocal microscopy characterization of the CB1 receptor expression and mTORC1 activation was conducted in FCD Type II resection samples. FCD samples were subjected to single nucleotide polymorphism screening for endocannabinoid system elements, as well as CB1 receptor gene sequencing. Cannabinoid CB1 receptor levels were increased in FCD with overactive mTORC1 signaling. CB1 receptors were enriched in phospho-S6-positive cells including balloon cells (BCs) that co-express aberrant markers of undifferentiated cells and dysplastic neurons. Pharmacological regulation of CB1 receptors and the mTORC1 pathway was performed in fresh FCD-derived organotypic cultures. HU-210-evoked activation of CB1 receptors was unable to further activate mTORC1 signaling, whereas CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation. Alterations of the endocannabinoid system may thus contribute to FCD pathological features, and blockade of cannabinoid signaling might be a new therapeutic intervention in FCD.

Se realizó un estudio descriptivo, prospectivo, de corte transversal, con el objetivo de establecer la frecuencia y el manejo de hematuria y proteinuria en pacientes atendidos en la emergencia de pediatría del Hospital Materno Infantil San Lorenzo de Los Mina, durante el mes de abril de 2016. Unos 54 pacientes cursaron con proteinuria o hematuria, lo que representa un 3.29% de los niños y adolescentes atendidos durante ese período. Los pacientes masculinos (67%) y los de edad entre 2-5 años (46.29%) fueron los más afectados. Los signos y síntomas agregados más frecuentes fueron vómitos, con un 42.59%, y fiebre, con un 40.74%. De los pacientes estudiados, el 40.74% cursó con amigdalitis como antecedente personal patológico; el 48.14% de sus familiares padece de hipertensión arterial. El método empleado para el diagnóstico fue la tira reactiva, dando como resultado un 77.77% con proteinuria, y un 14.81% para hematuria; el 7.40% de ellos presentó ambos hallazgos. En conclusión, se debe dar seguimiento a los pacientes que diagnostiquemos con proteinuria o hematuria para evitar complicaciones renales crónicas.

Partimos de la hipótesis de que la política ambiental en general y los instrumentos de que dispone (la Norma Oficial Mexicana, el análisis costo/beneficio, la manifestación de impacto ambiental, las declaraciones de áreas naturales protegidas, etc.) han sido diseñados para el aprovechamiento de los recursos naturales y no para conservar o desarrollar las reservas ecológicas ni los ciclos que garantizan su existencia. Lo anterior se deriva del fundamento teórico que sustenta tanto a la ciencia económica dominante, como a su componente ambiental: la creencia de que los equilibrios naturales son una consecuencia del funcionamiento de las libres fuerzas del mercado. De esta manera, la filosofía oficial de la sustentabilidad se basa en el imperativo del crecimiento. Bajo este precepto, la necesidad que tiene el sistema capitalista de incrementar el producto interno bruto, existe una contradicción irresolub le entre el desarrollo y la salud del medio ambiente. La producción implica destrucción.

To review the epidemiology of nosocomial extended spectrum β-lactamase-producing Enterobacteriaceae in Latin America, a systematic search of the biomedical literature (PubMed) was performed for articles published since 2005. Rates of nosocomial infections caused by extended spectrum β-lactamase-producing Enterobacteriaceae in Latin America have increased since 2005. Up to 32% of Escherichia coli and up to 58% of Klebsiella pneumoniae isolates are extended spectrum β-lactamase-positive, rates that are higher than in other world regions. From a region-wide perspective, 11–25% of E. coli isolates and 45–53% of K. pneumoniae isolates were nonsusceptible to third-generation cephalosporins. At the country level, there was a wide range in Enterobacteriaceae resistance rates to third-generation cephalosporins, with especially high rates of resistance to E. coli in Guatemala, Honduras, and Mexico, and high resistance rates to Klebsiella spp. in Argentina, Brazil, Chile, Guatemala, Honduras, and Paraguay. Susceptibility of extended spectrum β-lactamase-producing Enterobacteriaceae to cefepime, fluoroquinolones, ampicillin/sulbactam, aminoglycosides, and piperacillin/tazobactam has also been compromised, leaving the carbapenems, tigecycline, and colistin as the only antibiotics with >90% susceptibility rates. There is a steady increase in the prevalence and types of extended spectrum β-lactamases produced by Enterobacteriaceae isolates in Latin American hospitals (particularly CTX-Ms), suggesting endemic conditions overlaid by clonal outbreaks. Appropriate treatment decisions and infection control strategies informed by surveillance of regional and local susceptibilities and mechanisms of resistance are required to mitigate this major public health concern. Keywords: Escherichia coli, Klebsiella, Latin America, Bacterial resistance

En este estudio, polietileno de baja densidad (PEBD) fue modificado con anhídrido maleico (AM) en estado fundido usando concentraciones diferentes de peróxido de dicumilo (DCP) (0.25, 0.50, 0.75 y 1.0 %). Los materiales obtenidos fueron caracterizados por contenido de gel, titulaciones ácido-base, análisis infrarrojo (IR), calorimetría de barrido diferencial (DSC), análisis termogravimétrico (TGA), análisis reológico, propiedades mecánicas, dureza y permeabilidad al oxígeno. El análisis reométrico indicó que el tiempo óptimo para obtener las mezclas es alrededor de 7.5 minutos. El análisis IR mostró que el AM fue injertado en el esqueleto del PEBD, el grado de injerto incrementó con el contenido de DCP y el más alto grado de injerto (1.12 ± 0.015 %), fue exhibido por la muestra obtenida empleando la mayor cantidad de DCP (1 %). La estabilidad térmica de las muestras funcionalizadas fue ligeramente mayor que la del PEBD. La cristalinidad de las muestras funcionalizadas fue diferente a la exhibida por el PEBD. El comportamiento reológico presentado por las muestras fue seudoplástico. Las propiedades mecánicas, dureza y la permeabilidad al oxigeno fueron dependientes de la cantidad de DCP y AM injertado en el PEBD.

INTRODUCTION:Infections caused by carbapenem-resistant Enterobacteriaceae are a public health problem associated with higher mortality rates, longer hospitalization and increased healthcare costs. We carried out a study to describe the characteristics of patients with carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE bloodstream infection (BSI) from Latin American hospitals and to determine the clinical impact in terms of mortality and antibiotic therapy. METHODS:Between July 2013 and November 2014, we conducted a multicenter observational study in 11 hospitals from 7 Latin American countries (Argentina, Colombia, Ecuador, Guatemala, Mexico, Peru, Venezuela). Patients with BSI caused by Enterobacteriaceae were included and classified either as CPE or non-CPE based on detection of blaKPC, blaVIM, blaIMP, blaNDM and blaOXA-48 by polymerase chain reaction. Enrolled subjects were followed until discharge or death. Demographic, microbiological and clinical characteristics were collected from medical records. Both descriptive and inferential statistics were used to analyze the information. RESULTS:A total of 255 patients with Enterobacteriaceae BSI were included; CPE were identified in 53 of them. In vitro non-susceptibility to all screened antibiotics was higher in the patients with CPE BSI, remaining colistin, tigecycline and amikacin as the most active drugs. Combination therapy was significantly more frequent in the CPE BSI group (p < 0.001). The most common regimen was carbapenem + colistin or polymyxin B. The overall mortality was 37% (94/255). Overall and attributable mortality were significantly higher in patients with CPE BSI (p < 0.001); however, we found that patients with CPE BSI who received combination therapy and those who received monotherapy had similar mortality. After multivariate adjustment, CPE BSI (adjusted odds ratio [aOR] 4; 95% confidence interval [CI] 1.7-9.5; p = 0.002) and critical illness (aOR 6.5; 95% CI 3.1-13.7; p < 0.001) were independently associated with in-hospital mortality. CONCLUSIONS:This study provides valuable data on the clinical characteristics and mortality risk factors in patients with CPE BSI. We determined that CPE infection is an independent mortality predictor and thus Latin American hospitals should perform campaigns on prevention and control of CPE BSI.

El trabajo que se presenta tiene el objetivo de explicar los alcances de la herramienta de georreferenciación de cuencas (siatl), que proporciona el Instituto Nacional de Estadística y Geografía (inegi).

This article presents the hypothesis of formation of a new tendency: the auto-organization of the symbolic global system of the climate change. It identifies some auto-organizative signs in the present society, and gives to the climate change generation (those who will control the societies between 2020 and 2050) the responsibility of the acceleration of this tendency to arrive at a gradual transformation from the dominant behavior and to collectively approach mankind to the construction of a society with less carbon emissions. The author refers to some ideas exposed by the Chaos Theory and the auto-organization of the emergent systems, like Murray Gell Man and J. Doyne Farmer; and looks for support in the works of other thinkers like Jeremy Rifkin, James Lovelock and Taichi Sakaiya. The article finally concludes that to accelerate the tendency of the auto-organization of the symbolic global system of the climate change, understood as a cultural symbolic system, it is necessary to undertake a global educative effort, resulting in the gradual transformation of the present belief system that supports the dominant progress and development models.

Objectives: This analysis of the Study for Monitoring Antimicrobial Resistance Trends (SMART) evaluated the susceptibility patterns of Enterobacteriaceae in Latin America in 2008, with emphasis on susceptibility trends of E. coli and K. pneumoniae. Methods: Clinical isolates were recovered from intra-abdominal infections (IAI) from 23 centers in 10 Latin American countries. Isolates were sent to a central laboratory for confirmation of identification, antimicrobial susceptibility and ESBL testing, following the Clinical Laboratory Standards Institute (CLSI) guidelines. Results: Of 1,003 Gram-negative bacilli collected from intra-abdominal infections, E. coli and K. pneumoniae were the most commonly isolated organisms, and 26.8% of E. coli and 37.7% of K. pneumoniae were ESBL positive. Ertapenem and imipenem were the most consistently active agents tested; 99% of ESBL-positive E. coli isolates were susceptible to ertapenem and 100% to imipenem as well, and 91% of ESBL-positive K. pneumoniae were susceptible to ertapenem and 98% to imipenem. Quinolones and cephalosporins were less active, achieving 1.5% to 76% inhibition against ESBL-producing E. coli and 3.5% to 61% inhibition against K. pneumoniae. Conclusions: Local and unit-specific surveillance data is particularly important for selection of empiric therapy and in community-acquired infections as they can help the clinician with antibiotic selection by providing guidance regarding the likely pathogens and their resistance profiles. Our data also confirm the increasing frequency with which ESBL-producing organisms are found in the community setting, with 31.4% of communityacquired and 24.9% of hospital-acquired infections found to produce ESBLs. Imipenem and ertapenem are the most active agents tested for ESBL-positive E. coli and K. pneumoniae. Keywords: carbapenems, beta-lactamases, Gram-negative bacteria, drug resistance, ESBL

Dry eye is commonly treated with artificial tears; however, developing artificial tears similar to natural tears is difficult due to the complex nature of tears. We characterized and evaluated a novel artificial tear formulation with components similar to the lipid and aqueous constituents of natural tears. Nano-liposomes, composed in part of phosphatidylcholine, were dispersed in an aqueous solution of bioadhesive sodium hyaluronate. Liposome size, zeta potential, and physicochemical properties of the fresh and stored (4 °C) liposomal formulation were analyzed. In vitro tolerance was tested using human corneal and conjunctival cell lines by exposures of 15 min to 4 h. The tolerance of the liposomal formulation was evaluated in animals (rabbits). The average liposome size was 186.3 ± 7.0 nm, and the zeta potential was negative. The osmolarity of the formulation was 198.6 ± 1.7 mOsm, with a surface tension of 36.5 ± 0.4 mN/m and viscosity of 3.05 ± 0.02 mPa·s. Viability values in the human corneal and conjunctival cell lines were always >80%, even after liposomal formulation storage for 8 weeks. Discomfort and clinical signs after instillation in rabbit eyes were absent. The new formulation, based on phosphatidylcholine-liposomes dispersed in sodium hyaluronate has suitable components and characteristics, including high in vitro cell viability and good in vivo tolerance, to serve as a tear substitute.

Background: It is recognized the importance of malnutrition as a cause of morbidity and mortality in medical and surgical affections. The nutritional assessment of the patient should be based on a correct evaluation of different aspects. Objective: To assess the nutritional state of patients affected by cerebrovascular diseases in its ischemic form and the incidence of complications and deaths. Methods: A randomized simple and open clinical trial which is also prospective and longitudinal, not controlled by placebos that included 80 patients with a tomographed-clinical diagnosis of cerebral infarction admitted at the Higher Institute of Military Medicine during 2005. Clinical and dietary record, weight, size, daily assessments of the immunological performance by means of peripheral count of lymphocytes were analyzed. Results: Out of the total, 90 per cent of the patients had a weight loss lesser than 10 % of the ideal weight and, the 10% made evident a discrete increasing of weight. Patients with complications presented higher per cent of loss of weight and higher figures of urinary nitrogen. The higher per cent of loss of weight and the lowest lymphocytes count were found in patients with septic complications. An abbaissement in adequate nutritional parameters was found in deceased patients. Significant differences in the report of the initial malnourished patient’s complication existed. Conclusions: It was evident the relationship between the evolution of the cerebrovascular disease and the nutritional state which is conditioned by the appearance of complications with emphasis on sepsis. That’s why it is necessary to pay special attention to the nutrition of patients with neuroictus.

En el presente trabajo se obtienen cuantitativamente algunas de las características de la población del "langostino de rio" M. americanum Bate, obtenida durante meses de septiembre de 1977 hasta enero de 1979, mediante colectas tomadas de las capturas comerciales en el vaso de la presa "La Villita" Mich. Para mas información, favor de conunicarse al correo era@ujat.mx

This review summarizes recent epidemiology of Gram-negative infections in selected countries from Latin American and Caribbean adult intensive care units (ICUs). A systematic search of the biomedical literature (PubMed) was performed to identify articles published over the last decade. Where appropriate, data also were collected from the reference list of published articles, health departments of specific countries, and registries. Independent cohort data from all countries (Argentina, Brazil, Chile, Colombia, Cuba, Mexico, Trinidad and Tobago, and Venezuela) signified a high rate of ICU infections (prevalence: Argentina, 24%; Brazil, 57%). Gram-negative pathogens, predominantly Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, accounted for >50% of ICU infections, which were often complicated by the presence of multidrug-resistant strains and clonal outbreaks. Empirical use of antimicrobial agents was identified as a strong risk factor for resistance development and excessive mortality. Infection control strategies utilizing hygiene measures and antimicrobial stewardship programs reduced the rate of device-associated infections. To mitigate the poor health outcomes associated with infections by multidrug-resistant Gram-negative bacteria, urgent focus must be placed on infection control strategies and local surveillance programs.

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.

Surveillance systems monitoring the spread and divergence of methicillin-resistant Staphylococcus aureus (MRSA) strains are critical if preventive and therapeutic measures targeting MRSA infection are to be employed optimally. Surveillance provides information on the spread of MRSA, on the emergence of new strains within hospitals and communities, on the antibiotic resistance profile and virulence of strains, and on the risk factors associated with infection. These data help clinicians to provide appropriate empiric treatment of infections circulating in their region, leading to improved patient outcomes. While information on MRSA epidemiology in Latin America is growing, significant gaps exist in the available data, especially in local areas where fewer resources are available for characterizing and reporting MRSA strains. Here, we describe current knowledge of healthcare- and community-associated MRSA epidemiology in the region, and provide recommendations for future development of surveillance systems with a view to providing robust data at regional, national and local levels

Abstract In this work, low density polyethylene (LDPE)/plasticized starch (TPS) blends were prepared. The TPS employed in this study was obtained by plasticization of tapioca starch with a hyperbranched polyester polyol. Differential scanning calorimetry analysis showed that the melting temperature increased with the TPS content. The opposite effect was exhibited in the crystallization temperature and additional changes were not observed during the heating. X-ray diffraction analysis showed a reduction in intensity of the peak at Bragg’s angle 17.5°, proving a diminution on A type crystallinity with the increasing amount of LDPE. Micrographs obtained by scanning electron microscopy exhibited starch granules without destructure. TPS acted as a filler to LDPE, since the mechanical properties (Young’s modulus and tensile strength) improved ostensibly. The Young’ modulus and tensile strength decreased with the amount of LDPE, however, the elongation at break exhibited an opposite behavior.

Strategies to monitor and control the spread of methicillin-resistant Staphylococcus aureus (MRSA) infections are dependent on accurate and timely diagnosis of MRSA in both hospital and community settings. In Latin America, significant diversity in diagnostic and susceptibility testing procedures exists at the regional, national and local levels. Various tests for S. aureus and MRSA are available in clinical settings, but the application of these techniques differs between and within countries, and quality control measures are not uniformly applied to verify diagnoses. To optimize the diagnosis of MRSA infections across Latin America, a more consistent approach is required. This may include: adoption and appropriate adaption of specific guidelines for MRSA testing, depending on local resources; establishment of a coordinated system for quality control; regional access to central reference facilities; education of medical and healthcare professionals in best practices; and development of systems to evaluate the implementation of guidelines and best practices

OBJECTIVES: This analysis of the Study for Monitoring Antimicrobial Resistance Trends (SMART) evaluated the susceptibility patterns of Enterobacteriaceae in Latin America in 2008, with emphasis on susceptibility trends of E. coli and K. pneumoniae. METHODS: Clinical isolates were recovered from intra-abdominal infections (IAI) from 23 centers in 10 Latin American countries. Isolates were sent to a central laboratory for confirmation of identification, antimicrobial susceptibility and ESBL testing, following the Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS: Of 1,003 Gram-negative bacilli collected from intra-abdominal infections, E. coli and K. pneumoniae were the most commonly isolated organisms, and 26.8% of E. coli and 37.7% of K. pneumoniae were ESBL positive. Ertapenem and imipenem were the most consistently active agents tested; 99% of ESBLpositive E. coli isolates were susceptible to ertapenem and 100% to imipenem as well, and 91% of ESBL-positive K. pneumoniae were susceptible to ertapenem and 98% to imipenem. Quinolones and cephalosporins were less active, achieving 1.5% to 76% inhibition against ESBL-producing E. coli and 3.5% to 61% inhibition against K. pneumoniae. CONCLUSIONS: Local and unit-specific surveillance data is particularly important for selection of empiric therapy and in community-acquired infections as they can help the clinician with antibiotic selection by providing guidance regarding the likely pathogens and their resistance profiles. Our data also confirm the increasing frequency with which ESBL-producing organisms are found in the community setting, with 31.4% of communityacquired and 24.9% of hospital-acquired infections found to produce ESBLs. Imipenem and ertapenem are the most active agents tested for ESBL-positive E. coli and K. pneumoniae.

Abstract Ultrasonic fatigue tests were carried out on titanium alloy Ti-6Al-4V on the base material and the pre-corroded specimen to assess the pre-corrosion effect on the fatigue life of this alloy. The pre-corrosion was obtained by immersion of specimens in an acid solution: hydrochloric acid with 1.4 of pH during 8 and 16 minutes. All ultrasonic fatigue tests were performed following a predetermined sequence to attain the nominal applied load. Infrared images were taken at the neck section of specimens during ultrasonic fatigue testing, revealing that temperature is higher for the specimens with pre-corrosion and it increases with the time of pre-corrosion. It was observed that pits generated by pre-corrosion were associated with stress concentration, temperature increase and fatigue endurance decrease. Fracture surfaces were analyzed to determine the crack initiation and propagation and the stress intensity factor range threshold (KTH was obtained for both: the pre-corroded and non pre-corroded specimens.

The coastal lagoons are system in which many factors interact in complex w ys. The objective of this study is to establish a caracterization of the Guerrero coas­tal lagoons in four variable groups: 1) Morphometrics; among others, area, total volume, perimeter, relative depth, middle depth, max, depth and development of the coastal line and volume among other variables. 2) Hidroclimate: rainfall, mean environmental temperature, weather, basin area and fluvial discharge. 3) Physico–Chemical: salinity, temperature and dissolved oxigen. 4) Biological: presence of pisces, crustacea and mollusca. To establish any relationship between the lagoon for each variable group, the data were processes by means of a multivariate analysis (Cluster). The first variable group showed two affinity blocks; Mitla and Tres Palos on the first and Potosi, Nuxco and Coyuca on the other. Chautengo displays a low affinity arrangement with Mitla, Tres Palos on one block and Potosi, Nuxco, Salinas de Apozahualco and Chautengo on the other. This type of analysis permit regionalized the lagoons of the Coastal Plain of Guerrero for a better understanding and classification.