Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G‐2, Hep‐2, and Caco‐2). Compounds 18b, 19b, 23, 25b , and 26 showed strong potencies against all tested cell lines with IC₅₀ values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC₅₀ values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC₅₀ = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC₅₀ value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell‐cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G‐2 cells. It has revealed cell‐cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl‐2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.     

Mitigation of acetamiprid – induced renotoxicity by natural antioxidants via the regulation of ICAM,NF-kB and TLR 4 pathways

BackgroundAcetamiprid (ACMP) is a member of the neonicotinoid group of insecticides. It is extensively used worldwide. The misuse of ACMP creates danger hazards to human and animal.MethodsACMP induced renal damage evidenced by an increase in kidney injury biomarkers. So the goal of this work is to clarify the reno protective effect of Quercetin (Qrctn) and/or Nano-glutathione (N-Gluta) solely or in combination to counterbalance the danger effect of ACMP. All treatments with the previous agents were coadministered orally with ACMP for one month.ResultsACMP ingestion caused a significant rise in serum creatinin, urea, and uric acid, TNF α along with renal cystatin C, lipid peroxidation and nitric oxide with the concomitant decline in the levels of reduced glutathione and IL-10 levels. Protein expression of ICAM was upregulated as well as mRNA expression of NF-κB while mRNA expression of Nrf2 was down-regulated. Immune histochemistry of TLR 4 revealed strong immune reaction. The administration of Qrctn or N-Gluta either individually or together modulated all the preceding aforementioned parameters.ConclusionFascinatingly Qrctn and N-Gluta combination was the most powerful regimen to frustrate ACMP reno-toxicity and may be deliberate as a hopeful applicant for renal therapy.     

The associations between noise annoyance and psychological distress with blood pressure in children and adolescents: The CASPIAN‐V Study

Although blood pressure (BP) tracks from childhood to adulthood, and the prevalence of pediatric primary hypertension is increasing, related determinants are not well understood. The role of noise pollution and psychological distress in increasing BP is well documented in adults, but it remains elusive in children. This study aims to investigate the association of noise annoyance and psychological distress with BP in a pediatric population. This national cross‐sectional study was conducted in 2015 on a sample of 14400 Iranian students, aged 7‐18 years. Information regarding noise annoyance and psychological distress were assessed using questionnaires, and BP values were measured. Levels of noise annoyance and psychological distress were classified based on tertiles to no/low, moderate, and high. Data of 14274 students were completed. The mean age of participants was 12.28 (0.05), with 51% boys and 71.4% urban inhabitant. Diastolic BP and mean arterial BP (MAP) had positive correlations with noise annoyance (regression coefficient: 0.028, 95 % CI: 0.005 ‐ 0.05 and 0.025, 95 % CI: 0.002 – 0.04, respectively). Participants with higher psychological distress were 15 % more likely to experience abnormally high BP compared to those with normal psychological status or mild distresses (OR: 1.15, 95 % CI: 1.003 – 1.34). Here, we found significant positive relationships between the level of noise annoyance and values of diastolic BP and MAP. Moreover, high psychological distress showed to increase the chance of abnormally high BP. The clinical impact of these findings should be assessed in further longitudinal studies.     

Occult Hepatitis C Virus Infection in Patients With Autoimmune Hepatitis

Background:

Occult hepatitis C virus infection (OCI) is recognized by finding hepatitis C virus (HCV) RNA in hepatocytes without detectable anti-HCV antibodies and viral RNA in plasma. Autoimmune hepatitis (AIH) is a chronic and generally progressive disease without exactly-identified etiology.

Objectives:

This study aimed to determine the prevalence of OCI among patients with AIH and to evaluate the tests used to rule out HCV infection in diagnosing AIH.

Patients and Methods:

Between July 2012 to February 2013, 35 Iranian patients with AIH who attended Tehran Hepatitis Center were investigated. For identifying OCI, detection of HCV RNA in both ultracentrifuged serum samples and peripheral blood mononuclear cells (PBMCs) was used. Data analysis was performed using SPSS.

Results:

Six males and 29 females with mean disease duration of 77.1 ± 39.5 month and mean age of 43.62 ± 12.67 years were investigated. All cases were negative for anti-HCV antibody and we could not find any HCV RNA in ultracentrifuged serum samples and PBMCs.

Conclusions:

With our laboratory diagnostic method, it seems that there are no cases of OCI in patients with AIH. However, we recommend further studies with more samples and more precise laboratory method.     

Early postnatal development of the mandibular permanent first molar in infants with isolated cleft palate

International Journal of Paediatric Dentistry 2012; 22: 280–285 Background. Based on measurements on dental casts, smaller permanent teeth in children with cleft palate have previously been reported in the literature; however, the early maturation of teeth and the size of the follicles and crowns have not been investigated. Hypothesis. The maturation of the mandibular permanent first molar (M1_inf) is delayed, and the mesiodistal diameters of the follicle and crown of M1_inf, respectively, are reduced in children with isolated cleft palate (ICP). Design. Retrospective, longitudinal. Cephalometric X‐rays were available for 2 and 22 months old children with clefts (64 children with ICP, and a control group of 38 children with unilateral incomplete cleft lip). The width of the follicle and the crown of M1_inf, and the maturation of M1_inf were assessed. Intra‐observer error was acceptable. Results. M1_inf maturation was delayed in children with ICP at both 2 and 22 months of age. The mesiodistal diameter of the crown of M1_inf in the ICP group was reduced. Thus, the two hypotheses could not be refuted. Conclusions. Children with ICP showed smaller dimensions of the M1_inf, and in addition, the maturation of M1_inf was delayed.     

Detection of Chikungunya virus in Aedes aegypti during 2011 outbreak in Al Hodayda, Yemen

In October 2010, the Ministry of Public Health and Population reported an outbreak of dengue-like acute febrile illness in Al Hodayda governorate. By January 2011, a total of 1542 cases had been recorded from 19 of the 26 districts in the governorate with 104 purportedly associated deaths. In response this event, in January 2011 entomological investigations aimed at identifying the primary vector and the epidemic associated etiological agent were carried out. Based on the reported cases and the progress of the outbreak in the governorate, mosquito collection was undertaken in two of the most recent outbreak areas; Al Khokha district (130 km south of Al Hodayda) and Al Muneera district (100 km north). Mosquito adults were collected from houses using BG-sentinel? traps, aspiration of resting mosquitoes and knock-down spraying. Indoor and outdoor containers adjacent to the houses were inspected for larvae. Subsequently mosquito pools were analyzed by RT-PCR for detection of the four dengue virus serotypes (DENV-1, DENV-2, DENV-3, DENV-4), and for Chikungunya virus (CHIKV). Aedes aegypti was the dominant mosquito species collected. Four pools represent 40% of the tested pools, all containing adult female Ae. aegypti, were positive for CHIKV. Three CHIKV isolates were obtained from the RNA positive mosquito pools and identified by rRT-PCR. This finding marks the first record of CHIKV isolated from Ae. aegypti in Yemen. The larval container and Breteau indices in the visited localities surveyed were estimated at 53.8 and 100, respectively. The emergence of this unprecedented CHIKV epidemic in Al Hodayda is adding up another arboviral burden to the already existing vector-borne diseases. Considering the governorate as one focal port in the Red Sea region, the spread of the disease to other areas in Yemen and in neighboring countries is anticipated. Public health education and simple measures to detect and prevent mosquito breeding in water storage containers could prevent and reduce the spread of mosquito-borne viruses like CHIKV and DENV in Yemen.     

Autograft and pulmonary allograft performance in the second post-operative decade after the Ross procedure: insights from the Rotterdam Prospective Cohort Study

Aims The objective of the present study was to report our ongoing prospective cohort of autograft recipients with up to 21 years of follow-up. Methods and results All consecutive patients (n = 161), operated between 1988 and 2010, were analysed. Mixed-effects models were used to assess changes in echocardiographic measurements (n = 1023) over time in both the autograft and the pulmonary allograft. The mean patient age was 20.9 years (range 0.05-52.7)-66.5% were male. Early mortality was 2.5% (n = 4), and eight additional patients died during a mean follow-up of 11.6 ± 5.7 years (range 0-21.5). Patient survival was 90% [95% confidence interval (CI), 78-95] up to 18 years. During the follow-up, 57 patients required a re-intervention related to the Ross operation. Freedom from autograft reoperation and allograft re-intervention was 51% (95% CI 38-63) and 82% (95% CI 71-89) after 18 years, respectively. No major changes were observed over time in autograft gradient, and allograft gradient and regurgitation. An initial increase of sinotubular junction and aortic anulus diameter was observed in the first 5 years after surgery. The only factor associated with an increased autograft reoperation rate was pre-operative pure aortic regurgitation (AR) (hazard ratio 1.88; 95% CI 1.04-3.39; P= 0.037). Conclusion We observed good late survival in patients undergoing autograft procedure without reinforcement techniques. However, over half of the autografts failed prior to the end of the second decade. The reoperation rate and the results of echocardiographic measurements over time underline the importance of careful monitoring especially in the second decade after the initial autograft operation and in particular in patients with pre-operative AR.