BACKGROUND AND PURPOSE The passage of drugs across the blood–brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is ...effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P‐glycoprotein (Pgp/ABCB1), multidrug resistance‐related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB.
EXPERIMENTAL APPROACH Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co‐cultured with human brain and epithelial tumour cells.
KEY RESULTS Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low‐density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug‐loaded nanoparticles engineered as LDLs was effective as a vehicle for non‐permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti‐tumour cytotoxicity.
CONCLUSIONS AND IMPLICATIONS We suggest that our ‘Trojan horse’ approach, based on the administration of statins plus a LDL receptor‐targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle.
Abstract Aims To evaluate and compare the association of four potential insulin resistance (IR) biomarkers (pigment-epithelium-derived factor PEDF, retinol-binding-protein-4 RBP-4, chitinase-3-like ...protein 1 YKL-40 and brain-derived neurotrophic factor BDNF) with objective measures of IR. Methods We studied 81 subjects with different metabolic profiles. All participants underwent a 5-point OGTT with calculation of multiple IR indexes. A subgroup of 21 participants additionally underwent a hyperinsulinemic-euglycemic clamp. IR was defined as belonging to the highest quartile of incremental area under the insulin curve (iAUCins), or to the lowest quartile of the insulin sensitivity index (ISI). Results PEDF was associated with adiposity variables. PEDF and RBP4 increased linearly across quartiles of iAUCins (for PEDF p-trend = 0.029; for RBP-4 p-trend = 0.053). YKL-40 and BDNF were not associated with any adiposity or IR variable. PEDF and RBP-4 levels identified individuals with IR by the iAUCins definition: A PEDF cutoff of 11.9 ng/mL had 60% sensitivity and 68% specificity, while a RBP-4 cutoff of 71.6 ng/mL had 70% sensitivity and 57% specificity. In multiple regression analyses simultaneously including clinical variables and the studied biomarkers, only BMI, PEDF and RBP-4 remained significant predictors of IR. Conclusions Plasma PEDF and RBP4 identified IR in subjects with no prior diagnosis of diabetes.
Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCB), they have contributed to the exposure of women to persistent organic pollutants (POPs). These compounds can cross the placental ...barrier and interfere with the hormonal system of newborns.
To determine concentrations of OCPs and PCBs and their xenoestrogenic activity in placentas of women from the PA-MAMI cohort of Panama.
Thirty-nine placenta samples from women in the Azuero peninsula (Panama) were analyzed. Five OCPs p-p'-dichlorodiphenyldichloroethylene (p-p'-DDE), beta-hexachlorohexane (β-HCH), γ-hexachlorohexane (lindane), hexachlorobenzene (HCB) and mirex and three PCB congeners (PCB-138, PCB-153 and PCB-180) were quantified in placenta extracts. The xenoestrogenic activity of extracts was assessed with the E-Screen bioassay to estimate the total effective xenoestrogen burden (TEXB).
All placental samples were positive for at least three POP residues and >70% for at least six. The frequencies of quantified OCPs ranged from 100% for p,p'-DDE and HCB to 30.8% for β-HCH. The highest median concentration was for lindane (380.0 pg/g placenta), followed by p,p'-DDE (280.0 pg/g placenta), and HCB (90.0 pg/g placenta). Exposure to p,p'-DDE was associated with greater meat consumption, suggesting that animal fat is a major source of exposure to DDT metabolites. The frequency of detected PCBs ranged between 70 and 90%; the highest median concentration was for PCB 138 (17.0 pg/g placenta), followed by PCB 153 (16.0 pg/g placenta). All placentas were positive in the estrogenicity bioassay with a median TEXB-α of 0.91 pM Eeq/g of placenta. Exposure to lindane was positively associated with the xenoestrogenicity of TEXB- α, whereas this association was negative in the case of exposure to PCB 153.
To our best knowledge, this study contributes the first evidence on the presence of POPs and xenoestrogenic burden in placentas from Latin-American women. Given concerns about the consequences of prenatal exposure to these compounds on children's health, preventive measures are highly recommended to eliminate or minimize the risk of OCP exposure during pregnancy.
Construction is one of the largest production sectors in the world and its development impact on employment generation, dynamism of materials and development of essential infrastructure. This is ...consistent with the growing demands and diversifications in the supply chain, supported by knowledge economies, related to organizational learning and project management, together with the acquisition of new methodologies, within the framework of current technological development, deregulation and liberalization of markets. Therefore, it is necessary to include a marketing approach in purchasing management, supported by production, distribution and consumption processes in the growing competition for better service conditions in the supply chain of construction materials, especially cement, considered the most consumed manufactured material in the world and the increase of chemical additives, as support in new technological formulations in construction processes. Consequently, the present research provides an understanding of the markets related to procurement management and supply chain in the commercialization of chemical additives in the Colombian construction sector, through the use of statistical tools of perception like set analysis and multidimensional scaling to determine patterns of preferences in the valuation of brands, prices and applicability. This last one, considered the most required attribute by users in the supply chain of additives, which is related to the degree of preference and behavior of the construction processes. Hence, the use of statistical perception tools facilitates procurement and development management in the supply chain for additives or other market segments and the reduction of risk uncertainty in the formulation of construction projects.
The Advanced Learning Methodology (AdLM) is presented as an improvement of the collaborative work assisted by the teacher, in order to strengthen the competences in the development of teamwork and ...close gaps in the Action Research (AR) process. To implement the methodology, a short course on High Performance Computing (HPC) is presented as a learning object. This short course is oriented to a group of Systems Engineering students of the University of Pamplona (Colombia). In order to validate the progress of knowledge appropriation through AdLM, an evaluation or test is applied at three different times: at the beginning, in the intermediate and at the short course's ending. The difference between each test represents a knowledge gap as a quantitative measure of knowledge appropriation. The results show that AdLM provides an alternative in the active and collaborative participation of the students, and additionally proposes a quantitative measurement of the appropriation of knowledges progress.
Background There is increasing evidence that the built environment has an influence on physical activity; however, little is known about this relationship in developing countries. Purpose This study ...examined the associations between attributes of the built environment and walking patterns among the elderly. Methods A multilevel cross-sectional study was conducted in 2007. Fifty neighborhoods were selected and 1966 participants aged ≥60 years were surveyed. Objective built environment measures were obtained in a buffer of 500 m using GIS. Environmental perceptions were assessed via questionnaire. Results People who lived in areas with middle park area (4.53%–7.98% of land) were more likely to walk for at least 60 minutes during a usual week (prevalence OR POR=1.42, 95% CI=1.02, 1.98). Those who lived in areas with the highest connectivity index (1.81–1.99) were less likely to report walking for at least 60 minutes (POR=0.64, 95% CI=0.44, 0.93). Participants who reported feeling safe or very safe from traffic were more likely to report walking for at least 60 minutes (POR=1.50, 95% CI=1.11, 2.03). The presence of Ciclovía (recreational program) was marginally associated with having walked at least 150 minutes in a usual week (POR=1.29, 95% CI=0.97, 1.73). Conclusions This study showed that certain built and perceived environment characteristics were associated with walking among older adults living in Bogotá. Further studies should be conducted to better understand the potential influence of the built environment on physical activity among the elderly population in the context of Latin American cities.
The use of osteosynthesis materials when complex fractures are presented is well known. However, the use of these materials has not achieved a correct fixation and reduction of all bone fragments. ...Therefore, an adhesive for bones would provide a simple and quick method to fix this kind of fractures. The aim of this work is to propose and to evaluate an adhesive based on chitosan hydrogels that could have a potential use as a bone adhesive underwater and will not develop cytotoxic effects. Ionically and covalently crosslinked hydrogels based on chitosan were used in this study. Butt joint test with bovine cancellous bone specimens were used in order to measure the tensile bond strength (TBS) in ideal (completely dry) and physiological (immersed in water at 37 °C) conditions. Additionally, TBS was estimated as a function of time of bone specimens immersed in water at 37 °C. Cell viability was studied using MTT assay and cell morphology on the adhesive surface was examined by scanning electron microscope. Mechanical studies revealed that only covalently crosslinked hydrogels maintain their TBS at physiological condition with respect to the dry environment. In addition, it was observed that the TBS, using only covalently crosslinked hydrogels adhesives, dramatically changes as a function of time and its behavior increases as calcium carbonate and hydroxyapatite is added. Finally, in vitro cell testing of covalently crosslinked hydrogel with calcium carbonate and hydroxyapatite exhibited excellent biocompatibility. Therefore, this formulation is proposed as a potential candidate for clinical use in orthopedic surgery.
Introduction
The Coronavirus Disease 2019 (COVID-19) can affect mental health in different ways. There is little research about psychiatric complications in hospitalized patients with COVID-19.
...Objectives
The aim of the study was to describe the psychiatric clinical profile and pharmacological interactions in COVID-19 inpatients referred to a Consultation-Liaison Psychiatry (CLP) unit.
Methods
This is a cross-sectional retrospective study, carried out at a tertiary hospital in Spain, in inpatients admitted because of COVID-19 and referred to our CLP Unit from March 17,2020 to April 28,2020. Clinical data were extracted from electronic medical records. The patients were divided in three groups depending on psychiatric diagnosis: delirium, severe mental illness (SMI) and non-severe mental illness (NSMI).
Results
Of 71 patients included (median ICR age 64 54-73 years; 70.4% male), 35.2% had a delirium, 18.3% had a SMI, and 46.5% had a NSMI. Compared to patients with delirium and NSMI, patients with SMI were younger, more likely to be institutionalized and were administered less anti-COVID19 drugs. Mortality was higher among patients with delirium (21.7%) than those with SMI (0%) or NSMI (9.45%). The rate of side effects due to interactions between anti-COVID19 and psychiatric drugs was low, mainly drowsiness (4.3%) and borderline QTc prolongation (1.5%).
Conclusions
Patients affected by SMI were more often undertreated for COVID-19. However, the rate of interactions was very low, and avoidable with a proper evaluation and drug-dose adjustment. Half of the patients with SMI were institutionalized, suggesting that living conditions in residential facilities could make them more vulnerable to infection.
Disclosure
No significant relationships.
Ivermectin is a safe and effective drug in humans and has been approved for use in numerous parasitic infections for over 50 years. In addition, many studies have already shown its antiviral ...activity. Ivermectin is generally well tolerated, with no indication of central nervous system-associated toxicity at doses up to 10 times the highest FDA-approved dose of 200 µg/kg. The in vitro results of ivermectin for reducing SARS-CoV-2 viral load are promising and show that Ivermectin kills SARS-CoV-2 within 48 hours. A hypothesized mechanism of action for this drug is a likely inhibition of IMPα/β1-mediated nuclear import of viral proteins as demonstrated for other RNA viruses. However, controlled and randomized studies are needed to prove its effectiveness in COVID-19 in humans. In a single in vivo study with published results, patients confirmed to be infected with SARS-CoV-2 received at least one dose of ivermectin at any time during hospitalization. The use of ivermectin was associated with lower mortality during treatment with COVID-19, especially in patients who required increased inspired oxygen or ventilatory support. Additionally, 81 studies with the clinical use of ivermectin in humans are being carried out worldwide according to ClinicalTrials.gov. However, none of these data has been published so far. However, private and public entities in Brazil have been adopting this drug in their protocols as prophylaxis and in the initial phase of the disease. In addition, ivermectin has been used in mass treatment to prevent onchocerciasis and lymphatic filariasis in sub-Saharan Africa for many years. Surprisingly, this region has the lowest proportional mortality rate among the continents, despite the increasing numbers of infected people released by the World Health Organization.
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