ABSTRACT
PURPOSE: No known UK empirical research has investigated prospective associations between ambient air pollutants and conduct problems in adolescence. Ethnic minority children are disproportionately exposed to structural factors that could moderate any observed relationships. This prospective study examined whether exposure to PM2.5 and NO2 concentrations is associated with conduct problems in adolescence, and whether racism or ethnicity moderate such associations. METHODS: Longitudinal associations between annual mean estimated PM2.5 and NO2 concentrations at the residential address and trajectories of conduct problems, and the potential influence of racism and ethnicity were examined school-based sample of 4775 participants (2002-2003 to 2005-2006) in London, using growth curve models. RESULTS: Overall, in the fully adjusted model, exposure to lower concentrations of PM2.5 and NO2 was associated with a decrease in conduct problems during adolescence, while exposure to higher concentrations was associated with a flattened trajectory of conduct symptoms. Racism amplified the effect of PM2.5 (ß = 0.05 (95% CI 0.01 to 0.10, p < 0.01)) on adolescent trajectories of conduct problems over time. At higher concentrations of PM2.5, there was a divergence of trajectories of adolescent conduct problems between ethnic minority groups, with White British and Black Caribbean adolescents experiencing an increase in conduct problems over time. CONCLUSION: These findings suggest that the intersections between air pollution, ethnicity, and racism are important influences on the development of conduct problems in adolescence.
Subject(s)
Air Pollution , Racism , Adolescent , Air Pollution/adverse effects , Child , Ethnicity , Humans , Longitudinal Studies , Minority Groups , Prospective StudiesABSTRACT
The present study describes the synthesis of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines starting from 4-chloro derivative VI via the reaction with either phenolic compounds to obtain VIIa-f, IXa-d, 2-amino-6-(un)substituted benzothiazole to produce VIIIa-c or hydrazine hydrate to give X. Reaction of the hydrazino functionality of X with appropriate acid anhydride, acid chloride or aldehyde affords XIa-c, XIIa-c and XIVa-i, respectively. The target compounds were screened for their efficacy as EGFR inhibitors compared to gefitinib. Compounds eliciting superior EGFR inhibitory activity were further screened for their in vitro cytotoxicity against two human cancer cell lines namely: MCF7 (breast) and A549 (lung), in addition to normal fibroblast cell WI38 relative to gefitinib as a reference. Furthermore, compounds that showed potent inhibitory activity on wild-type EGFR were screened against mutant EGFR and assayed for their cytotoxicity against mutant EGFR-expressing cell lines PC9 and HCC827. The unsubstituted benzothiazol-2-amine VIIa showing superior EGFR inhibition (IC50 = 0.096 µM) and anticancer activity against MCF-7 cell line (IC50 = 2.49 µM) was subjected to cell cycle analysis and apoptotic assay. Moreover, a molecular docking study was performed to investigate the interaction of some representive compounds with the active site of EGFR- TK.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Various pyridopyridazinone derivatives were designed as Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. The pyridopyridazinone scaffold was used as an isostere of the phthalazine nucleus of the lead compound Olaparib in addition to some modifications in the tail part of the molecule. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to Olaparib in nanomolar level. The best PARP-1 inhibitory activity was observed for compound 8a with (IC50â¯=â¯36â¯nM) compared to Olaparib as a reference drug (IC50â¯=â¯34â¯nM). Molecular modeling simulation revealed that, the designed compounds docked well into PARP-1 active site and their complexes are stabilized by three key hydrogen bond interactions with both Gly863 and Ser904 as well as other favorable π-π and hydrogen-π stacking interactions with Tyr907 and Tyr896, respectively. Computational ADME study predicted that the target compounds 8a and 8e have proper pharmacokinetic and drug-likeness properties. These outcomes afford a new structural framework for the design of novel inhibitors for PARP-1.
Subject(s)
Drug Design , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Pyridazines/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Pyridazines/chemical synthesis , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: Health care workers (HCW) are at risk of occupational infection with blood-borne pathogens (BBP). AIM OF THE STUDY: 1) to assess the knowledge, attitude and practice (KAP) of nurses, lab technicians and housekeepers working in nine Primary Health Care centers in Cairo and Giza governorates in Egypt concerning BBP; 2) to apply a health education intervention on BBP; 3) to assess the effectiveness of the health education intervention on the level of KAP of the study population. METHODS: A total of 130 study participants were enrolled and received the health education intervention, only 86 participants came back for the post-intervention evaluation (drop-out rate = 33.8%). RESULTS: It was found that 34% of participants were exposed to one or more needle stick injuries during the 3 months preceding the intervention, and only 13.8% received the hepatitis B immunization. Comparison of the pre- and post-intervention scores for the total study population showed a significant increase in the post-intervention cumulative KAP score, as well as the knowledge, attitude and practice scores by about 13, 12, 11 and 20% respectively (p<0.001). The housekeepers, compared to nurses and lab technicians, were the best recipients to the health education intervention with a significantly higher percent change of the KAP score (27.7, 16.9 and 9.5% respectively, p=0.005). Reasons for non-compliance to the application of preventive measures to protect against BBP were lack of resources, work overload and lack of training. CONCLUSION AND RECOMMENDATIONS: Continuous education and in-service training on prevention of BBP transmission is mandatory to protect HCW.
