Design,synthesis, molecular docking study,and antibacterial evaluation of some new fluoroquinolone analogues bearing a quinazolinone moiety

BackgroundIncreasing bacterial resistance to quinolones is concerning. Hence, the development of novel quinolones by chemical modifications to overcome quinolone resistance is an attractive perspective in this context.ObjectiveIn this study, it is aimed to design and synthesize a novel series of functionalized fluoroquinolones using ciprofloxacin and sarafloxacin cores by hybridization of quinazolinone derivatives. This objective was tested by a comprehensive set of in vitro antibacterial assays in addition to SAR (structure–activity relationship) characterisation studies.MethodsA nucleophilic reaction of ciprofloxacin and sarafloxacin with 2-(chloromethyl)quinazolin-4(3H)-one in the presence of NaHCO₃ in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by ¹H, ¹³C- NMR and IR spectroscopy, MS and elemental analysis. In silico pharmacokinetics prediction assays and molecular docking studies were performed to explore the binding characteristics and interactions. Antibacterial activities of the novel compounds were evaluated by Broth microdilution, well diffusion and disc diffusion assays against three gram-positive (Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus and Enterococcus faecalis) and three gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli).ResultsThe compounds exhibited moderate to good activities against gram-positive bacteria and weak to moderate activities against gram-negative bacteria. Amongst all ciprofloxacin-derivatives, compound 5d was the most potent agent with high antibacterial activity against gram-positive bacteria, including MRSA and S. aureus ((minimum inhibitory concentration (MIC) = 16 nM for both), that is 60 times more potent than ciprofloxacin as parent drug. Compound 5i from sarafloxacin-derivatives was the most potent compound against MRSA and S. aureus (MIC = 0.125 μM). Well diffusion and disk diffusion assay results demonstrated confirmatory outcomes for the quantitative broth microdilution assay. Molecular docking study results were in accordance with the results of antibacterial activity assays.ConclusionThe results of the current study demonstrated that the novel ciprofloxacin and sarafloxacin derivatives synthesized here have promising antibacterial activities. Particularly, compounds 5d and 5i have potential for wider antibacterial applications following further analysis.Graphical abstractElectronic supplementary materialThe online version of this article (10.1007/s40199-020-00373-6) contains supplementary material, which is available to authorized users.     

Perspectives of community pharmacists on conscientious objection to provide pharmacy services: A theory informed qualitative study

BackgroundIn recent years, pharmacists have been opting out of certain pharmacy services, particularly, providing contraceptives, for moral reasons. No research has been conducted on the perceptions of community pharmacists toward conscience objection in a secular state with a mostly Muslim population.ObjectiveThis study aimed to provide an in-depth understanding of the factors related to the beliefs of community pharmacists on conscientious objection to provide pharmacy services contrary to their personal beliefs based on the theory of planned behavior.MethodsSemistructured interviews were conducted with a purposive sampling of community pharmacists. A hybrid deductive and inductive qualitative analysis approach was used on the data that were recorded and transcribed verbatim. Constructs related to attitude, subjective norm, and perceived behavioral control were explored.ResultsIn total, 25 community pharmacists were interviewed. Factors affecting pharmacists’ decision to provide pharmacy services when their personal beliefs included the desire to maintain moral integrity, beliefs about consequences for health care service, profit, patient pressure, precedence of professional values, and care for religious sources.ConclusionMost of the community pharmacists were against the behavior of conscientiously objecting to provide pharmacy services in Turkey because of possible negative consequences on health care. The pharmacists who were willing to act based on their personal beliefs were expecting from various third parties to fulfill certain responsibilities to facilitate to adopt the behavior. This novel study highlights the urgent need for more research and training for community pharmacists serving patients in different socioeconomic contexts in both developed and developing countries.     

Renal Changes and Apoptosis Caused By Subacute Exposure To Aroclor 1254 in Selenium-deficient and Selenium-supplemented Rats

Aroclor 1254 (A1254), a mixture of polychlorinated biphenyls, exerts hepatic, renal, and reproductive toxicity in rodents. This study aimed to determine a protective role of selenium on histopathological changes, oxidative stress, and apoptosis caused by A1254 in rat kidney. It included a control group, which received regular diet containing 0.15 mg/kg Se (C), a Se-supplemented group (SeS) receiving 1 mg/kg Se, a Se-deficient group (SeD) receiving Se-deficient diet of ≤0.05 mg/kg Se, an A1254-treated group (A) receiving 10 mg/kg of Aroclor 1254 and regular diet, an A1254-treated group receiving Se-supplementation (ASeS), and an A1254-treated group receiving Se-deficient diet (ASeD). Treatments lasted 15 days. After 24 h of the last dose of A1254, the animals were decapitated under anaesthesia and their renal antioxidant enzyme activities, lipid peroxidation (LP), glutathione, protein oxidation, and total antioxidant capacity levels measured. Histopathological changes were evaluated by light and electron microscopy. Apoptosis was detected with the TUNEL assay. Kidney weights, CAT activities, and GSH levels decreased significantly in all A1254-treated groups. Renal atrophic changes and higher apoptotic cell counts were observed in the A and ASeD groups. Both groups also showed a significant drop in GPx1 activities (A – 34.92 % and ASeD – 86.46 %) and rise in LP (A – 30.45 % and ASeD – 20.44 %) vs control. In contrast, LP levels and apoptotic cell counts were significantly lower in the ASeS group vs the A group. Histopathological changes and renal apoptosis were particularly visible in the ASeD group. Our findings suggest that selenium supplementation provides partial protection against renal toxicity of Aroclor 1254.     

Fatigue in the mothers of children with cerebral palsy

Purpose: To evaluate fatigue in the mothers of children with cerebral palsy (CP), and to determine its associations with clinical parameters of CP, depression and quality of life (QoL). Method: Ninety children (50 girls and 40 boys) with spastic CP and their mothers were included. Control group comprised mothers of healthy children. Gross motor function classification system (GMFCS) was used for determining functional status. Spasticity was evaluated by using modified Ashworth scale. Fatigue symptom inventory (FSI) was used for assessing maternal fatigue, Nottingham health profile (NHP) for maternal QoL, and Beck Depression Scale (BDS) for maternal depression. Results: Mothers of children with CP scored significantly higher in all FSI subgroups (intensity of fatigue, duration of fatigue and interference with QoL), all NHP subgroups and BDS (p?p?< 0.01). No association was found between FSI and clinical parameters of children with CP including age, gender, type of CP, tonus and functional impairment (p?>?0.05). Conclusions: Our findings indicate that fatigue levels of mothers with CP children are higher than those with healthy children and associated with depression and deterioration in QoL in terms of physical, social and emotional functioning. This should be considered while designing a family centred rehabilitation programme for children with CP.

• Implications for Rehabilitation

• Caring for a child with cerebral palsy has psychological, social and financial impacts on familiesand is associated with increased levels of fatigue among mothers.

• The capacity of current programs and services needs to be strengthened to accommodate theneeds of children with CP and their mothers in order to reduce fatigue of mothers.

• New programs need to be developed to provide psychosocial support for the mothers andto reduce their fatigue as they continue to care for their children.

• Provision of assistive technology devices (particularly suitable wheelchairs) will be useful inreduction of fatigue levels of mothers.

     

Internalized stigma in psoriasis: A multicenter study

Internalized stigma is the adoption of negative attitudes and stereotypes of the society regarding a person's illness. It causes decreased self‐esteem and life‐satisfaction, increased depression and suicidality, and difficulty in coping with the illness. The primary aim of this study was to investigate the internalized stigma state of psoriatic patients and to identify the factors influencing internalized stigma. The secondary aim was to identify the correlation of internalized stigma with quality of life and perceived health status. This multicentre, cross‐sectional study comprised 1485 patients. There was a significant positive correlation between mean values of Psoriasis Internalized Stigma Scale (PISS) and Psoriasis Area and Severity Index, Body Surface Area, Dermatological Life Quality Index and General Health Questionnaire‐12 (P < 0.001 in all). Lower percieved health score (P = 0.001), early onset psoriasis (P = 0.016), family history of psoriasis (P = 0.0034), being illiterate (P < 0.001) and lower income level (P < 0.001) were determinants of high PISS scores. Mean PISS values were higher in erythrodermic and generalized pustular psoriasis. Involvement of scalp, face, hand, genitalia and finger nails as well as arthropathic and inverse psoriasis were also related to significantly higher PISS scores (P = 0.001). Our findings imply that psoriatic patients experience high levels of internalized stigma which are associated with psoriasis severity, involvement of visible body parts, genital area, folds or joints, poorer quality of life, negative perceptions of general health and psychological illnesses. Therefore, internalized stigma may be one of the major factors responsible from psychosocial burden of the disease.     

Large Area Emission in p-Type Polymer-Based Light-Emitting Field-Effect Transistors by Incorporating Charge Injection Interlayers

Organic light-emitting field-effect transistors (LEFETs) provide the possibility of simplifying the display pixilation design as they integrate the drive-transistor and the light emission in a single architecture. However, in p-type LEFETs, simultaneously achieving higher external quantum efficiency (EQE) at higher brightness, larger and stable emission area, and high switching speed are the limiting factors for to realise their applications. Herein, we present a p-type polymer heterostructure-based LEFET architecture with electron and hole injection interlayers to improve the charge injection into the light-emitting layer, which leads to better recombination. This device structure provides access to hole mobility of ~2.1 cm² V⁻¹ s⁻¹ and EQE of 1.6% at a luminance of 2600 cd m⁻². Most importantly, we observed a large area emission under the entire drain electrode, which was spatially stable (emission area is not dependent on the gate voltage and current density). These results show an important advancement in polymer-based LEFET technology toward realizing new digital display applications.     

Native valve endocarditis due to Candida albicans in two children: Two new case reports

Candida endocarditis (CE) is a rare and serious complication of candidemia. Using current diagnostic tools a confirmed diagnosis is often delayed and outcomes remain poor. The majority of new cases occur following cardiac valvular surgery, and/or in patients with the following risk factors: intravenous drug use, cancer chemotherapy, prolonged presence of central venous catheters, and prior history of bacterial endocarditis. It is not a common complication in non‐neutropenic patients particularly with the absence of a prosthetic valve, and very few reports in the literature are available. Attempting to add to the limited data, 211 candidemia episodes from 172 nonneutropenic pediatric cases between January 2008 and December 2017 were evaluated. All patients were considered asymptomatic for underlying heart disease. However, 2 (0.9%) patients with a central venous catheter were determined as having endocarditis following echocardiography.     

Rotenone impairs oxidant/antioxidant balance both in brain and intestines in zebrafish

Aim of the study: Rotenone is a commonly used pesticide that inhibits complex I of the mitochondrial electron transport system. Rotenone exposed rats demonstrate many characteristics of Parkinson Disease (PD). Oxidative stress is one of the hallmarks of PD, being the major sources of ROS in the DA neurons. In recent years the strong connection between the intestinal environment and the function of the central nervous system (CNS) has gained widespread popularity. In order to explain the mechanism underlying the GI dysfunction in PD, we aimed to investigate oxidant-antioxidant status in the brain and intestine, as well as locomotor activity, in rotenone exposed zebrafish.

Materials and methods: Adult zebrafish were exposed to 2 mg/L rotenone for 30 days. At the end of the experiment, locomotor activity was determined by simple observation. Lipid peroxidation (LPO), nitric oxide (NO) levels, superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities were determined in the homogenates.

Results: Locomotor activity decreased in the rotenone exposed zebrafish. LPO increased in both brain and intestines whereas NO increased only in the brain. Decreased GST and CAT activities were found in both tissues whereas SOD activity decreased only in the intestines.

Conclusion: As a conclusion, the results of our study support the connection between gut and brain axis in rotenone exposed zebrafish by means of oxidative stress and NO for the first time in literature.