Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal

IS LUMBAR PUNCTURE ALWAYS NECESSARY IN THE FEBRILE CHILD WITH CONVULSION?

ObjectiveFebrile convulsion is the most common benign convulsive disorder in children. Meningitis is one of the most important causes of fever and convulsions, diagnosed by lumbar puncture (LP), a painful and invasive procedure much debated  regarding its necessity. This study evaluates the frequency of abnormal LP findings in a group of patients, to determine whether or not unnecessary LP can be prevented without missing patients with serious problems such as meningitis.Materials& MethodsThe study was a descriptive, cross sectional study, conducted on 200 children suffering from fever and convulsions. Medical files of patients were taken from the hospital records and relevant data were collected to complete the appropriate forms.ResultsOf 200 patients included in the study, 116 (58%) children were male, and 84 (42%) were female. 47 cases (23.5%) underwent LP, of whom just one (0.5%) had abnormal LP and meningitis.ConclusionRegarding Considering the low prevalence of meningitis in children with convulsion and fever, we conclude that by means of precise clinical examination and monitoring, it is possible to prevent unnecessary LP in these patients.Key Words:Fever and convulsion, Lumbar puncture, Meningitis

The multi-risk vulnerability of global coal regions in the context of mine closure

Coal mining industries face real challenges to meet legal demands on a low carbon future. The history of coal in industrial transitions seems to come to a rapid end, accompanied by widespread boom of closing active coal mining projects. This change can result in negative ramifications for coal mining regions, involving a complex interplay of multiple risks. In this paper, we aim to analyse the complexity of environmental, social, and governance factors that can cause significant difficulties in closure of coal mining operations. We identify multi-factor risk profiles for operating mines by applying spatially explicit indicators within a proposed multi-risk framework. The indicators have not been captured by conventional market, as they tend to be more long-term oriented in the context of strategy and performance. We map eight risk categories: stability, water and climate, biodiversity, vulnerability of land uses, indigenous people, social fragility, political fragility, and regulatory environment, and analyse their effect on a global dataset of active open pit coal mines. The spatial analysis reveals that a significant proportion of the projects face accumulation of multiple risk factors. A total of 552 projects out of 916 show medium to very high-risk occurrence. In this paper, we present global risk vulnerability across the coal mining projects by indicating extent to which operators of the mines face multiple risk factors when planning for closure

The Effect of Educating the Use of Developmental Positions of Premature Infants on the Clinical Performance of Neonatal Intensive Care Unit Nurses

BACKGROUND AND OBJECTIVE: One of the early interventions in neurodevelopmental disorders in neonatal intensive care units is providing proper conditions for infants. Premature infants have lost their last three months of life in the uterus, and as a result, have not reached a collapsed status, which is a developmental position that indicates brain growth in the infant. Considering the importance of the neonatal position in developmental positions and achievement of better neural evolution, this study was conducted to implement educational intervention to improve the performance of nurses in order to properly implement the developmental positions of premature infants in neonatal intensive care unit. METHODS: This interventional study was carried out among 85 neonatal intensive care unit nurses in Shahid Akbar-Abadi and Ali Asghar Hospitals in Tehran in three stages. First, the nurses' performance was evaluated regarding the supportive developmental positions of the premature infants in the neonatal intensive care unit through a neonatal assessment tool (IPAT with a maximum score of 12 and a minimum score of 3). Then, nurses were educated by slides and face to face and the performance of nurses was evaluated and compared after the first week after training and two months after the training. FINDINGS: Demographic data showed that the education level of most nurses (98.8%) was bachelor's degree and most nurses (48.2%) were older than 30 years of age. The highest work experience of nurses (42.4%) was in the range of 5–10 years. In addition, the nurses' performance score regarding the supportive developmental position of premature infants in the pre-training stage (5.84±0.03), the first week after training (8.35±1.42) and two months after training (8.71±1.16) had a significant difference (p<0.001). CONCLUSION: Based on the results of this research, educating the use of developmental positions of premature infants has positive effects on the clinical performance of neonatal intensive care unit nurses

Anti-CRISPR AcrIIA5 Potently Inhibits All Cas9 Homologs Used for Genome Editing

CRISPR-Cas9 systems provide powerful tools for genome editing. However, optimal employment of this technology will require control of Cas9 activity so that the timing, tissue specificity, and accuracy of editing may be precisely modulated. Anti-CRISPR proteins, which are small, naturally occurring inhibitors of CRISPR-Cas systems, are well suited for this purpose. A number of anti-CRISPR proteins have been shown to potently inhibit subgroups of CRISPR-Cas9 systems, but their maximal inhibitory activity is generally restricted to specific Cas9 homologs. Since Cas9 homologs vary in important properties, differing Cas9s may be optimal for particular genome-editing applications. To facilitate the practical exploitation of multiple Cas9 homologs, here we identify one anti-CRISPR, called AcrIIA5, that potently inhibits nine diverse type II-A and type II-C Cas9 homologs, including those currently used for genome editing. We show that the activity of AcrIIA5 results in partial in vivo cleavage of a single-guide RNA (sgRNA), suggesting that its mechanism involves RNA interaction

The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells. © 2013 Haas et al

Risk Factors of Cancer in Children Under 14 Years old

Background and Objectives: Recognition of the risk factors of childhood cancer has been important. However, there is little identification about these risk factors. The aim of this study was to determine the risk factors of cancer in children under14 years old.Methods: The present study has been a case-control study of 14-year-old children. 98 childhood cancer cases and 100 controls were matched on age and sex. Data were collected using a questionnaire with some of the known and suspected risk factors of cancer via the parent, and were analyzed with two independent samples t–tests, chi–square and logistic regression models.Results: In this study, low- educational status in mothers and fathers increased risk of childhood cancer (p<0.05). Children lived in low-income families (500000-1500000 Rails per month), and had a significantly higher risk of cancer (Odds ratios=3.08; 95% CI=4-6.00). Fathers smoking during pregnancy (odds ratio=3.00) and living near high voltage power lines (Odds ratios=1.5) were significantly related to an increased risk of cancer in children. In addition, there was a higher risk of cancer particularly among heavy ( 11 cigarettes per days) smokers (odds ratio= 2.7). Conclusions: The results of this study indicated that some risk factors such as living conditions, smoking fathers during pregnancy, parental educational level and financial status were associated with the risk of childhood cancer. Therefore, public health should aim at improving environmental and familial socioeconomic status for all children; efforts should be concentrated on planning preventive and educational campaigns