Benefits of VCE-003.2, a cannabigerol quinone derivative, against inflammation-driven neuronal deterioration in experimental Parkinson's disease: possible involvement of different binding sites at the PPARγ receptor.

BACKGROUND: Neuroprotection with cannabinoids in Parkinson's disease (PD) has been afforded predominantly with antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatory and neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoid cannabigerol (CBG), which may derive its activity at the peroxisome proliferator-activated receptor-γ (PPARγ). The compound is also an antioxidant. METHODS: We evaluated VCE-003.2 in an in vivo [mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS)] model of PD, as well as in in vitro (LPS-exposed BV2 cells and M-213 cells treated with conditioned media generated from LPS-exposed BV2 cells) cellular models. The type of interaction of VCE-003.2 at the PPARγ receptor was furtherly investigated in bone marrow-derived human mesenchymal stem cells (MSCs) and sustained with transcriptional assays and in silico docking studies. RESULTS: VCE-003.2 has no activity at the cannabinoid receptors, a fact that we confirmed in this study using competition studies. The administration of VCE-003.2 to LPS-lesioned mice attenuated the loss of tyrosine hydroxylase (TH)-containing nigrostriatal neurons and, in particular, the intense microgliosis provoked by LPS in the substantia nigra, measured by Iba-1/Cd68 immunostaining. The analysis by qPCR of proinflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and inducible nitric oxide synthase (iNOS) in the striatum showed they were markedly elevated by the LPS lesion and strongly reduced by the treatment with VCE-003.2. The effects of VCE-003.2 in LPS-lesioned mice implied the activation of PPARγ receptors, as they were attenuated when VCE-003.2 was co-administered with the PPARγ inhibitor T0070907. We then moved to some in vitro approaches, first to confirm the anti-inflammatory profile of VCE-003.2 in cultured BV2 cells exposed to LPS. VCE-003.2 was able to attenuate the synthesis and release of TNF-α and IL-1ß, as well as the induction of iNOS and cyclooxygenase-2 (COX-2) elicited by LPS in these cells. However, we found such effects were not reversed by GW9662, another classic PPARγ antagonist. Next, we investigated the neuroprotective effects of VCE-003.2 in cultured M-213 neuronal cells exposed to conditioned media generated from LPS-exposed cultured BV2 cells. VCE-003.2 reduced M-213 cell death, but again, such effects were not reversed by T0070907. Using docking analysis, we detected that VCE-003.2 binds both the canonical and the alternative binding sites in the PPARγ ligand-binding pocket (LBP). Functional assays further showed that T0070907 almost abolished PPARγ transcriptional activity induced by rosiglitazone (RGZ), but it did not affect the activity of VCE-003.2 in a Gal4-Luc system. However, T0070907 inhibited the effects of RGZ and VCE-003.2 on the expression of PPARγ-dependent genes upregulated in MSCs. CONCLUSIONS: We have demonstrated that VCE-003.2 is neuroprotective against inflammation-driven neuronal damage in an in vivo model of PD and in in vitro cellular models of neuroinflammation. Such effects might involve PPARγ receptors, although in silico and in vitro experiments strongly suggest that VCE-003.2 targets PPARγ by acting through two binding sites at the LBP, one that is sensitive to T0070907 (canonical binding site) and other that is not affected by this PPARγ antagonist (alternative binding site).

Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors.

Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.

Bioremediation of diuron contaminated soils by a novel degrading microbial consortium.

Diuron is a biologically active pollutant present in soil, water and sediments. It is persistent in soil, water and groundwater and slightly toxic to mammals and birds as well as moderately toxic to aquatic invertebrates. Its principal product of biodegradation, 3,4-dichloroaniline, exhibits a higher toxicity than diuron and is also persistent in the environment. On this basis, the objective of the study was to determine the potential capacity of a proposed novel diuron-degrading microbial consortium (DMC) for achieving not only diuron degradation, but its mineralisation both in solution as well as in soils with different properties. The consortium was tested in a soil solution where diuron was the only carbon source, and more than 98.8% of the diuron initially added was mineralised after only a few days. The consortium was composed of three diuron-degrading strains, Arthrobacter sulfonivorans, Variovorax soli and Advenella sp. JRO, the latter had been isolated in our laboratory from a highly contaminated industrial site. This work shows for the first time the potential capacity of a member of the genus Advenella to remediate pesticide-contaminated soils. However, neither of the three strains separately achieved mineralisation (ring-14C) of diuron in a mineral medium (MSM) with a trace nutrient solution (NS); combined in pairs, they mineralised 40% of diuron in solution, but the most relevant result was obtained in the presence of the three-member consortium, where complete diuron mineralisation was achieved after only a few days. In the presence of the investigated soils in suspension, the capacity of the consortium to mineralise diuron was evaluated, achieving mineralisation of a wide range of herbicides from 22.9 to 69.0%.

Effect of audiovisual distraction on children's behaviour, anxiety and pain in the dental setting.

AIM: To evaluate whether the parental perception of the patient's anxiety, children's anxiety, pain, behaviour and heart rate of paediatric patients improves when an audiovisual technique is used as a distraction method during dental treatment. MATERIALS AND METHODS: This non-randomised crossover trial was performed with 34 patients aged 6-8 years, who required a minimum of two treatment visits for restorative therapy. During the last visit, the patient was shown a cartoon film. RESULTS: There was a significant improvement in the global behaviour when children were shown a cartoon film (P < 0.001). A significant increase in heart rate was recorded in both visits (P = 0.0001) when the anaesthetic was injected. A 97% of the sample would like to continue seeing their chosen film during subsequent visits. No statistically significant differences were found (P > 0.05) between the visits in terms of parental perception of the patient's anxiety, or the patient's self-reported anxiety, pain and heart rate. CONCLUSIONS: The use of the audiovisual material used as a method of distraction produces a global improvement in patient behaviour, but not in parental perception of the patient's anxiety, self-reported anxiety, pain or heart rate according to the measurement scales used. This material is also highly accepted by paediatric patients.

Effects of PTH [1-34] on synoviopathy in an experimental model of osteoarthritis preceded by osteoporosis.

PURPOSE: Synoviopathy contributes to cartilage degradation in osteoarthritis (OA). Intermittent parathyroid hormone (PTH) [1-34] administration inhibits terminal differentiation of human chondrocytes and prevents cartilage damage. We aimed to determine whether PTH [1-34] could modify synovial changes in experimental OA preceded by osteoporosis (OP). METHODS: Twenty osteoporosis (OP) rabbits underwent knee surgery to induce OA. They were administered either saline vehicle or PTH for 10 weeks. Ten healthy rabbits were used as controls. Following sacrifice, synovial changes were assessed by Krenn synovitis score, immunohistochemistry for macrophages (RAM-11), B and T lymphocytes, type I collagen, parathyroid hormone 1 receptor (PTH1R), and anti-proliferating cell nuclear antigen (PCNA). Synovial mRNA levels of Col1A1, IL-1ß, cyclooxygenase 2 (COX-2), matrix-degrading metalloproteinases (MMP-9, MMP-13), and monocyte chemotactic protein-1 (MCP-1), as well as protein expression of PTH1R were also determined. Cartilage damage was analyzed by Mankin score. RESULTS: OPOA + vehicle rabbits showed an increase in synovitis score vs controls (P = 0.003), mainly due to synovial hyperplasia and fibrosis, while PTH reduced these changes (P = 0.017). Mankin and Krenn scores were well correlated in all groups (r = 0.629, P = 0.012). Immunostaining for RAM-11 and B lymphocytes was increased (P ≤ 0.05), whereas PTH1R protein levels tended to be higher in OPOA + vehicle animals vs controls. PTH did not modify RAM-11 staining or PTH1R levels; however, it restored PTH1R localization to the vicinity of synovial vessels. PTH also decreased type I collagen, MCP-1, and MMP-13 expression (P < 0.05), as well as PCNA staining compared to vehicle-treated OPOA rabbits. CONCLUSIONS: In our model of OA aggravated by previous OP, synoviopathy correlated well with cartilage damage. Intermittent PTH [1-34] administration ameliorated both hyperplasia and fibrosis.

Dissipation of a mix of priority PAHs in soils by using availability enhancers. Effect of aging and pollutant interactions.

A remediation strategy using three non-toxic availability enhancers (two cyclodextrins and a rhamnolipid biosurfactant) was applied to various soils artificially contaminated with a mix of Polycyclic Aromatic Hydrocarbons (PAHs) considered priority pollutants at two levels of contamination: only with 7 low molecular weight PAHs (LMW PAHs, 5 with 3-ring and 2 with 4-ring - fluoranthene and pyrene) or with 14 PAHs (from 3 to 6 rings). Natural attenuation of PAHs in all soils showed degradation capacity for the LMW PAHs, with a final content of LMW PAHs <5% of their initial concentration. Conversely, the rest of PAHs (high molecular weight PAHs, HMW) remained in the soils (61% - 83.5%), indicating abiotic dissipation of HMW PAHs due to formation of non-extractable residues in soils. The influence of the presence of HMW PAHs on the degradation of the 7 LMW PAHs was also tested, showing a general decrease in the time to obtain 50% dissipation (DT50), statistically significant for acenaphthene, acenaphthylene and fluorene. Availability enhancers showed different effects on PAHs dissipation. 2-hydroxypropyl-ß-cyclodextrin (HP) decreased DT50 of some of the lighter PAHs, whereas the rhamnolipid (RL) caused a slight DT50 increase due to its initial toxicity on native soil microorganisms, but showing later high degradation rate for LMW PAHs. On the contrary, randomly methylated-ß-cyclodextrin (RAMEB) slowed down PAHs degradation due to its high adsorption onto soil surface, blocking the desorption of PAHs from the soils. The high number of experimental factors not studied simultaneously before (soil type, co-contamination, availability enhancers and incubation time) allowed to conduct a statistical analysis which supported the conclusions reached. Principal Component Analysis separated the studied PAHs in 3 groups, in relation with their molecular weight and Kow. The first principal component was related with LMW PAHs, and separate the inefficient RAMEB from the other availability enhancers.

Novel nonylphenol-degrading bacterial strains isolated from sewage sludge: Application in bioremediation of sludge.

Nonylphenol (NP) is an anthropogenic pollutant frequently found in sewage sludge due to the insufficient degrading effectiveness of conventional WWTPs and has attracted attention as an endocrine disruptor. The aim of this study was to isolate specific NP-degrading bacteria from sewage sludge to be used in the degradation of this contaminant through bioaugmentation processes in aqueous solution and sewage sludge. Up to eight different bacterial strains were isolated, six of them not previously described as NP degraders. Bacillus safensis CN12 presented the best NP degradation in solution, and glucose used as an external carbon source increased its effect, reaching DT50 degradation values (time to decline to half the initial concentration of the pollutant) of only 0.9 days and a complete degradation in <7 days. Four NP metabolites were identified throughout the biodegradation process, showing higher toxicity than the parent contaminant. In sewage sludge suspensions, the endogenous microbiota was capable of partially degrading NP, but a part remained adsorbed as bound residue. Bioaugmentation was used for the first time to remove NP from sewage sludge to obtain more environmentally friendly biosolids. However, B. safensis CN12 was not able to degrade NP due to its high adsorption on sludge, but the use of a cyclodextrin (HPBCD) as availability enhancer allowed us to extract NP and degrade it in solution. The addition of glucose as an external carbon source gave the best results since the metabolism of the sludge microbiota was activated, and HPBCD was able to remove NP from sewage sludge to the solution to be degraded by B. safensis CN12. These results indicate that B. safensis CN12 can be used to degrade NP in water and sewage sludge, but the method must be improved using consortia of B. safensis CN12 with other bacterial strains able to degrade the toxic metabolites produced.

Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis.

PURPOSE: Impairment of subchondral bone density and quality aggravates cartilage damage in osteoarthritis (OA). Accordingly, we assessed whether improving microstructure and quality at subchondral bone by the bone-forming agent parathyroid hormone (PTH) [1-34] prevent cartilage damage progression in a rabbit model of OA preceded by osteoporosis (OP). METHODS: OP was induced in 20 female rabbits. At week 7, these rabbits underwent knee surgery to induce OA and, at week 12, they started either saline vehicle (n=10) or PTH (n=10) for 10 weeks. Ten healthy animals were used as controls. At week 22, microstructure was assessed by micro-computed tomography and bone remodelling by protein expression of alkaline phosphatase (ALP), metalloproteinase-9 (MMP9), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) at subchondral bone. Cartilage damage was evaluated using Mankin score. RESULTS: PTH reversed the decrease of bone area/tissue area, trabecular thickness, plate thickness, polar moment of inertia, ALP expression and OPG/RANKL ratio, as well as counteracted the increase of fractal dimension and MMP9 expression at subchondral bone of osteoarthritis preceded by osteoporosis (OPOA) rabbits compared to vehicle administration (P<0.05). Likewise, PTH decreased cartilage damage severity in OPOA rabbits. Good correlations were observed between subchondral bone structure or remodelling parameters, and cartilage Mankin score. CONCLUSIONS: Improvement of microstructural and remodelling parameters at subchondral bone by PTH [1-34] contributed to prevent cartilage damage progression in rabbits with early OPOA. These findings support the role of subchondral bone in OA. Further studies are warranted to establish the place of bone-forming agents as potential treatment in OA.

Reliability of INTERMED Spanish version and applicability in liver transplant patients: a cross-sectional study.

BACKGROUND: Integrated delivery methods in healthcare systems have been proposed to confront the increasing complexity in general health care. INTERMED is an empirically derived, observer-rated instrument to measure case complexity. It was intended as a visualized, action-oriented decision-support tool for the early assessment of bio-psychosocial health risks and health needs. This study aims to document the reliability and applicability of the Spanish version of INTERMED in liver transplant patients. METHODS: Cross-sectional study of patients who had been included in the liver transplant waiting list. Two nurses interviewed the patients with INTERMED, and scored the instrument blind to each other. Kappa and w-kappa, Spearman, Kendall and intraclass correlation coefficients, and Cronbach's alfa were calculated. RESULTS: No patient refused the interview. Satisfactory coefficients were documented in most INTERMED items. Kappa was = 0.858 for the categorization of patients as "complex", and 21 of them (48.8%) were classified in this category, and were considered to need integrated treatment. CONCLUSIONS: The Spanish version of INTERMED is reliable. Its applicability in liver transplant patients adds to its generalizability.

Objective and subjective measures for assessing anxiety in paediatric dental patients.

AIM: Anxiety has been defined as a nonspecific feeling of apprehension towards a concrete situation that does not necessarily involve a previous experience. Dental anxiety can prevent patients from cooperating fully during dental treatment. Given that there is a connection between dental anxiety and uncooperative behaviour, it is important for dentists to be able to assess anxiety in their patients. There are many methods for such assessment, and in children they depend on age and intellectual development. These measures can be objective or subjective, depending on the method used to quantify the degree of anxiety. The aim of this literature review was to analyse the objective and subjective scales that are used most commonly to assess the degree of anxiety of children in a dental setting. CONCLUSION: Knowing the degree of anxiety of dental children is important in order to guide them through their dental experience. Their level of cooperation will also improve and anxiety will be reduced as well.

Early-onset neonatal sepsis due to Cellulosimicrobium cellulans.

Cellulosimicrobium cellulans represents a rare human pathogen. Infections have been reported in immunocompromised hosts or in patients with an underlying disease. The authors describe a rare case of early-onset neonatal sepsis due to Cellulosimicrobium cellulans in an infant without any underlying disease. The infant was successfully treated with vancomycin.

Apical transportation created using three different patency instruments.

AIM: To evaluate root canal transportation at the major foramen through the use of stainless steel size 08 K-Flex files, size 10 reamers, and XF finger spreaders when used as patency instruments. METHODOLOGY: One hundred and two mesiobuccal canals of maxillary and mandibular first molars were randomly divided into three groups (34 canals each). Size 08 stainless steel K-Flex files, size 10 stainless steel reamers and stainless steel XF finger spreaders were used as patency instruments in groups A, B and C respectively. The major foramen was photographed before and after instrumentation. The images were superimposed and then evaluated using Photoshop to determine the frequency of apical transportation. The statistic analysis was performed using chi(2)test. RESULTS: Transportation was detected in 22% of the specimens; 9% in group A, 12% in group B and 44% in group C. Significant differences were observed between groups A and C (P = 0.0025) and between groups B and C (P = 0.0069), but not between groups A and B (P = 1.00). CONCLUSIONS: No transportation was found in the majority of the samples when size 08 K-Flex files and size 10 stainless steel reamers were used. The XF finger spreaders, when used to maintain apical patency, caused the greatest transportation of the major foramen.

Extraction of nonylphenol, pyrene and phenanthrene from sewage sludge and composted biosolids by cyclodextrins and rhamnolipids.

Sewage sludge generated by Waste Water Treatment Plants (WWTPs) are frequently used as organic amendments in agriculture, but they contain pollutants such as Potentially Toxic Elements (PTEs) and organic contaminants which contaminate the agricultural soils. The study presented here is part of a larger study based on the application of environmentally friendly chemical and biological techniques to decrease the content of organic pollutants in sewage sludge before agricultural application. The aim of this study was to evaluate the performance of biodegradable extractants, such as some cyclodextrins (CDs), ß-cyclodextrin (BCD), hydroxypropyl-ß-cyclodextrin (HPBCD) and randomly methylated-ß-cyclodextrin (RAMEB), and a biosurfactant (rhamnolipid, RL) on the removal and availability of pyrene (PYR), phenanthrene (PHE) and nonylphenol (NP) from several biosolids samples in order to improve their subsequent biodegradation. The influence of pollutants retention time on biosolids was studied, as well as the effect of each extractant on PTEs solubilization. Results obtained were pollutant and extractant-dependent. BCD extracted similar amounts of pollutants compared to water, whereas HPBCD and RAMEB actually increased the availability of the three pollutants in most of the samples and aging times. RL seems to be the best election for Polycyclic Aromatic Hydrocarbons (PAHs) extraction from biosolids, with percentages of extraction multiplied by more than 80 and 40 times for PHE and PYR, respectively, relative to water extraction. The extraction enhancement was the highest for NP, the most hydrophobic pollutant, reaching more than 500-fold higher with HPBCD and RAMEB. PTEs extractability was not affected by the different CDs used, but RL caused an increment in their soluble content what could endanger a subsequent biodegradation of the organic pollutants.

Natural and assisted dissipation of polycyclic aromatic hydrocarbons in a long-term co-contaminated soil with creosote and potentially toxic elements.

An enhanced bioremediation strategy was applied to an industrial soil co-contaminated with Polycyclic Aromatic Hydrocarbons (PAHs) and Potentially Toxic Elements (PTEs). Hydroxypropyl-ß-cyclodextrin (HPBCD) and a natural mixture of two rhamnolipids (RL) were added to increase PAHs bioavailability, and combined with a microbial consortium (MC) to biodegrade soil PAHs. Bioavailability of only six PAHs (3-, 4-ring PAHs) increased when using HPBCD, with a maximum increase about 2.8-fold higher. The highest dose of HPBCD (5%) enhanced PAH degradation, with the best results for 4-ring PAHs with treatments of HPBCD + MC (up to 48% degradation for pyrene and 43% for fluoranthene), whereas dissipation for 5-ring PAHs was very low and for 6-ring was negligible. The use of RL increased the bioavailability of 13 of the 16 PAHs studied, reaching up to 60-fold higher values for phenanthrene or 18-fold higher for acenaphtene. RL addition did not show degradation improvement in any situation, and even inhibited the scarce degradation observed in the control treatment. The high increase in availability of both PAHs and mainly PTEs when using RL as amendment could make them toxic for microorganisms. In fact, Microtox Acute Toxicity test using Aliivibrio fischeri and the absence of colony forming units (CFUs) of indigenous bacteria demonstrated the extremely high levels of toxicity in RL treated soil.

Diacerein has a weak effect on the catabolic pathway of human osteoarthritis synovial fibroblast--comparison to its effects on osteoarthritic chondrocytes.

OBJECTIVES: Synoviocytes play a crucial role in the inflammatory response leading to structural damage in OA. Our aim was to assess the effects of diacerein and NSAIDs on cellular responses of synoviocytes associated with inflammation and structural integrity of cartilage in OA. METHODS: The effects of diacerein, celecoxib, diclofenac, meloxicam and indomethacin on prostaglandin (PG) E2 production, cyclo-oxygenase-2 (COX-2) protein expression, nitrite levels, presence of MMP-1 and -13, and activation of nuclear factor-kappaB (NF-kappaB) were studied on stimulated OA synoviocytes and chondrocytes. RESULTS: Diacerein and NSAIDs inhibited IL-1beta-stimulated NF-kappaB activation in synoviocytes and chondrocytes except indomethacin in synoviocytes. Diacerein further increased COX-2 protein expression and PGE2 synthesis in synoviocytes stimulated with IL-1beta, while no effect was observed on stimulated chondrocytes. NSAIDs diminished until almost basal levels PGE2 release in both cells and, surprisingly, these drugs also diminished COX-2 protein expression both in synoviocytes and chondrocytes. With regard to structural mediators, diacerein decreased MMP-13 levels in synoviocytes but did not modify MMP-1 presence. NSAIDs induced a significant increase in MMP-1 levels in both cell types and in MMP-13 levels in chondrocytes. CONCLUSIONS: Diacerein does not seem to reduce but rather increase inflammatory mediators in synoviocytes, while it does not overall affect chondrocyte inflammatory profile.

Combined use of microbial consortia isolated from different agricultural soils and cyclodextrin as a bioremediation technique for herbicide contaminated soils.

The phenylurea herbicide diuron is persistent in soil, water and groundwater and is considered to be a highly toxic molecule. The principal product of its biodegradation, 3,4-dichloroaniline, exhibits greater toxicity than diuron and is persistent in the environment. Five diuron degrading microbial consortia (C1C5), isolated from different agricultural soils, were investigated for diuron mineralization activity. The C2 consortium was able to mineralize 81.6% of the diuron in solution, while consortium C3 was only able to mineralize 22.9%. Isolated consortia were also tested in soil slurries and in all cases, except consortium C4, DT50 (the time required for the diuron concentration to decline to half of its initial value) was drastically reduced, from 700 days (non-inoculated control) to 546, 351, and 171 days for the consortia C5, C2, and C1, respectively. In order to test the effectiveness of the isolated consortium C1 in a more realistic scenario, soil diuron mineralization assays were performed under static conditions (40% of the soil water-holding capacity). A significant enhancement of diuron mineralization was observed after C1 inoculation, with 23.2% of the herbicide being mineralized in comparison to 13.1% for the control experiment. Hydroxypropyl-ß-cyclodextrin, a biodegradable organic enhancer of pollutant bioavailability, used in combination with C1 bioaugmentation in static conditions, resulted in a significant decrease in the DT50 (214 days; 881 days, control experiment). To the best of our knowledge, this is the first report of the use of soil-isolated microbial consortia in combination with cyclodextrins proposed as a bioremediation technique for pesticide contaminated soils.

VCE-004.8, A Multitarget Cannabinoquinone, Attenuates Adipogenesis and Prevents Diet-Induced Obesity.

Over the past few years, the endocannabinoid system (ECs) has emerged as a crucial player for the regulation of food intake and energy metabolism, and its pharmacological manipulation represents a novel strategy for the management of metabolic diseases. The discovery that VCE-004.8, a dual PPARγ and CB2 receptor agonist, also inhibits prolyl-hydroxylases (PHDs) and activates the HIF pathway provided a rationale to investigate its effect in in vitro models of adipogenesis and in a murine model of metabolic syndrome, all processes critically regulated by these targets of VCE-004.8. In accordance with its different binding mode to PPARγ compared to rosiglitazone (RGZ), VCE-004.8 neither induced adipogenic differentiation, nor affected osteoblastogenesis. Daily administration of VCE-004.8 (20 mg/kg) to HFD mice for 3-wks induced a significant reduction in body weight gain, total fat mass, adipocyte volume and plasma triglycerides levels. VCE-004.8 could also significantly ameliorate glucose tolerance, reduce leptin levels (a marker of adiposity) and increase adiponectin and incretins (GLP-1 and GIP) levels. Remarkably, VCE-004.8 increased the FGF21 mRNA expression in white and brown adipose, as well as in a BAT cell line, qualifying cannabinoaminoquinones as a class of novel therapeutic candidates for the management of obesity and its common metabolic co-morbidities.

Nursing Students' Perceptions of Flipped Classroom and Continuous Assessment in the Nursing-Management Classroom

Abstract: Introduction: Although the training of nurses in administration and leadership has an important repercussion on the present and the future of the profession, teaching methods are still traditional in many cases. Flipped classroom is a widely used method in nursing education but studies about its application to Nursing Administration and Management are limited. Method: Qualitative study by means of anonymous survey (dichotomous and open questions). Results: 92 % of students were shown to be satisfied with the teaching methodology and 92.9 % with the assessment. Only 31.5 % had used it previously but 83 % would like to use it in more subjects. The students showed that the methodology used had improved their opinion about the content and had increased their perception its usefulness. Conclusion: The participating students have been shown to be satisfied with flipped method and continuous assessment. These teaching strategies can help motivate nursing students towards the subject of Nursing Administration and Management, which can encourage them to pursue postgraduate training and professional practice in this area

Resumen: Introducción: Si bien la formación de enfermeros en Administración y Gestión tiene una importante repercusión en el presente y el futuro de la profesión, los métodos de enseñanza siguen siendo tradicionales en muchos casos. El aula invertida es un método ampliamente utilizado en la educación de enfermería, pero los estudios sobre su aplicación a la administración y gestión de enfermería son limitados. Método: Estudio cualitativo mediante cuestionario anónimo (preguntas dicotómicas y abiertas). Resultados: El 92 % de los estudiantes se mostró satisfecho con la metodología de enseñanza y el 92,9 % con la evaluación. Solo el 31,5 % lo había usado anteriormente, pero al 83 % le gustaría usarlo en más sujetos. Los estudiantes demostraron que la metodología utilizada había mejorado su opinión sobre el contenido y había aumentado su percepción útil del mismo. Conclusión: Los estudiantes participantes han demostrado estar satisfechos con el método de aula invertida. Estas estrategias de enseñanza pueden ayudar a motivar a los estudiantes de enfermería hacia la asignatura de Administración y Gestión de los Servicios de Enfermería, lo que puede animarlos a realizar una formación de posgrado y una práctica profesional en esta área.

Resumo: Introdução: Embora a educação de Enfermagem em Administração e Gestão tenha um grande impacto no presente e futuro da profissão, os métodos de ensino continuam a ser tradicionais em muitos casos. A sala de aula invertida é um método amplamente utilizado na educação em Enfermagem, mas os estudos sobre a sua aplicação à Administração e Gestão de Enfermagem são limitados. Método: Estudo qualitativo utilizando um questionário anônimo (perguntas dicotômicas e abertas). Resultados: 92% dos estudantes ficaram satisfeitos com a metodologia de ensino e 92,9% com a avaliação. Apenas 31,5% já o tinha utilizado antes, mas 83% gostariam de utilizá-lo em mais assuntos. Os estudantes mostraram que a metodologia utilizada havia melhorado a sua opinião sobre o conteúdo e aumentado a sua percepção útil do conteúdo. Conclusão: Os estudantes participantes mostraram-se satisfeitos com o método invertido e com a avaliação contínua. Estas estratégias de ensino podem ajudar a motivar os estudantes de Enfermagem para a disciplina de Administração e Gestão de Enfermagem, o que pode encorajá-los a empreender uma educação de pós-graduação e prática profissional nesta área.