Influence of Redox-Active Chitosan-Polyaminoxyl Micelles Loaded with Daunorubicin on Activity of Nrf2 Transcription Factor.

A new system for delivery of anthracycline antibiotics based on chitosan-polyaminoxyls (CPA) was studied in a model of non-tumor (human embryonic mesenchymal stem cells) and tumor cells (human hepatocellular carcinoma) in vitro. The presence of CPA micelles considerably suppresses daunorubicin-induced ROS generation in normal cells without affecting this process in tumor cells. CPA micelles do not reduce the cytotoxic effect of daunorubicin and do not prevent its accumulation in cells. The use of CPA significantly increases accumulation of Nrf2 transcription factor in the nuclei of both normal and tumor cells in comparison with free daunorubicin. Increased nuclear translocation of Nrf2 leads to a significant increase in the expression of its target gene TXN1, but not the NQO1, GPX1, and HMOX1 genes, the increased expression of which can lead to the development of resistance to anthracycline antibiotics. Redox-active CPA micelles have great potential for the development of nanoparticles for the transport of anthracycline antibiotics in experimental tumor chemotherapy, and also as promising activators of Nrf2 transcription factor.

The Increase of Antileukemic Efficiency of Doxorubicin and Other Cytostatics Combined with Platinum(IV)-Nitroxyl Complex ВС118.

Combined treatment of murine leukemia P388 with doxorubicin and platinum(IV)-nitroxyl complex ВС118 administered in low doses improved efficiency of treatment (cure of 83% of animals) without increasing toxicity.

Influence of Tumor Suppressor p53 Functioning on the Expression of Antioxidant System Genes under the Action of Cytotoxic Compounds.

The effect of inhibition of the tumor suppressor p53 on the antioxidant system genes expression under the influence of cytotoxic compounds of the platinum group was studied. It was found that the action of platinum(II) and platinum(IV) complexes induced accumulation of p53 protein with a maximum in 12 h, which was confirmed by an increase in the expression of the P21 gene, the target gene of the p53 protein. It was shown that the action of platinum complexes activated the expression of catalase and superoxide dismutase 2 genes. Suppression of p53 protein functions with specific inhibitor α-piphitrin under the action of platinum complexes reduced the expression of catalase and superoxide dismutase 2 genes and the target gene P21, which attested to the p53-dependent regulation of these genes.

Comparison of the Effect of Platinum (IV) Complexes on Spheroids and Monolayer Culture of HeLa Cells.

We performed a comparative study of the cytotoxicity of cisplatin, JM216 complex, and aminonitroxyl platinum(IV) complexes for HeLa cells grown in monolayer and 3D culture. The growth dynamics of spheroids was studied and optimal conditions for evaluation of cytotoxicity were determined. Spheroids were less sensitive to the test compounds than cells in a monolayer. The resistance index (RI) of spheroids was determined as the ratio of IC50 for spheroids to IC50 for monolayer culture. Resistance index was 5.0±1.5 for cisplatin and ranged from 1.8 to 2.3 for platinum(IV) complexes. The observed differences are related to different physicochemical properties of the complexes and different mechanisms of their penetration into cells.

Effect of Chitosan-(Poly)Nitroxides on Normal and Tumor Cells under Conditions of Induced Oxidative Stress.

The cytotoxicity and antioxidant effects of chitosan-(poly)nitoxides of different molecular weights containing a nitroxide radical of the piperidine structure were studied on tumor (HeLa, A172, and HepG2) and normal (Vero) cell lines. The chitosan-(poly)nitroxides exhibited low cytotoxicity. Under conditions of oxidative stress induced with tert-butyl hydroperoxide, the most pronounced decrease in ROS levels in the presence of chitosan-(poly)nitroxides was observed in normal cells. In cell homogenates, the decrease in malondialdehyde levels was observed only in the presence of low-molecular-weight chitosan-(poly)nitroxide irrespective of the cell line. Our data demonstrate that the cell-specific antioxidant properties of chitosan-(poly)nitroxides are related to their penetration into cells and interaction with intracellular membranes.

Does atopy affect the course of viral pneumonia?

BACKGROUND: The presence of atopy is considered as a risk factor for severe respiratory symptoms in children. The objective of this study was to examine the effect of atopy on the course of disease in children hospitalised with viral pneumonia. METHODS: Children between the ages of 1 and 6 years hospitalised due to viral pneumonia between the years of 2013 and 2016 were included to this multicentre study. Patients were classified into two groups as mild-moderate and severe according to the course of pneumonia. Presence of atopy was evaluated with skin prick tests. Groups were compared to evaluate the risk factors associated with severe viral pneumonia. RESULTS: A total of 280 patients from nine centres were included in the study. Of these patients, 163 (58.2%) were male. Respiratory syncytial virus (29.7%), Influenza A (20.5%), rhinovirus (18.9%), adenovirus (10%), human metapneumovirus (8%), parainfluenza (5.2%), coronavirus (6%), and bocavirus (1.6%) were isolated from respiratory samples. Eighty-five (30.4%) children had severe pneumonia. Atopic sensitisation was found in 21.4% of the patients. Ever wheezing (RR: 1.6, 95% CI: 1.1-2.4), parental asthma (RR: 1.5, 95% CI: 1.1-2.2), other allergic diseases in the family (RR: 1.8, 95% CI: 1.2-2.9) and environmental tobacco smoke (RR: 1.6, 95% CI: 1.1-3.5) were more common in the severe pneumonia group. CONCLUSIONS: When patients with mild-moderate pneumonia were compared to patients with severe pneumonia, frequency of atopy was not different between the two groups. However, parental asthma, ever wheezing and environmental tobacco smoke exposure are risk factors for severe viral pneumonia in children.

Effect of Cytotoxic Compounds on Activity of Antioxidant Enzyme System in MCF-7 and H1299 Cells.

We studied the function of the antioxidant system in tumor cell lines MCF-7 and H1299 that differ by the state of tumor suppressor gene p53. Exposure to different classes of cytotoxic compounds induced several types of antioxidant system responses that depend on the type of cell line. The effects of platinum(II) and platinum(IV) complexes on activity of antioxidant enzymes vary, which can be explained by differences in their accumulation and biotransformation in tumor cells. Triazole and oxazolidinone derivatives had little effect on activity of superoxide dismutase and catalase in H1299 cells, but increased superoxide dismutase activity in MCF-7 cells.

Does the imbalance between agonistic and antagonistic IL-1 play a role in progression of febrile convulsions?

OBJECTIVE: Inflammation may play an important role in the etiopathology of febrile convulsions (FC). IL-1ß is an important mediator of inflammation and fever is also important information of FCs. It is suggested that there may be a relationship between polymorphisms of IL-1ß and FC. The aim of the present study is to investigate the polymorphic situation of promoter region of IL-1ß in two sites (-31 and -511) and assess the IL-1 RA VNTR polymorphisms in FC patients in comparison with healthy control groups. MATERIALS AND METHODS: Fifty FC patients and 50 healthy controls (HC) were included in the study. DNA extraction was performed by QIAamp DNA Mini Kit from peripheral blood lymphocytes of all subjects. IL-1ß promoter polymorphisms were analyzed by PCR-RFLP, IL-1 RA VNTR polymorphisms were analyzed by PCR-agarose gel electrophoresis. RESULTS: Genotype distribution of IL-1ß promoter region in position -31 was statistically different between FC patients and control groups. Allele I and allele II of IL-1 RA distribution were also statistically different in FC patients and healthy controls. CONCLUSIONS: We have found a significant association between IL-1 RA allele distribution and FC and a poor correlation of T/C substitution at the -31 position of IL-1ß promoter in FC. Further studies are needed to investigate the gene expression levels and polymorphic situation in same samples.

Evaluation of children with juvenile idiopathic arthritis in southeastern Turkey: a single center experience.

BACKGROUND: The aim of this study was to investigate the disease characteristics of children with juvenile idiopathic arthritis (JIA) in southeast Turkey. METHODS: The International League of Associations for Rheumatology (ILAR) criteria were used to diagnose JIA. Hospital records of the Pediatric Rheumatology Unit, of the Dicle University Hospital, were reviewed retrospectively and demographic, clinical and laboratory data were recorded. RESULTS: Totally 213 children (103 boys, 110 girls), with an age range of 1.6-18 years were enrolled. The mean age of the disease onset was 8.1 years. Polyarticular type was the most common (42.3%) presentation. The frequencies of other JIA subtypes were as follows: oligoarticular 37.1%, systemic 8.9%, enthesitis-related arthritis (ERA) 10.8% and psoriatic arthritis 0.9%. The knees (74.2%) and ankles (54.0%) were the most commonly affected joints. Uveitis was found in 4.2% of patients. Anti-nuclear antibodies were positive in 11.7% and HLA-B27 in 2.8% of patients. Active disease was seen in 57 (26.7%) patients at the last visit. CONCLUSION: In the present study, polyarticular JIA was the predominant subtype and there were fewer patients with positive ANA or uveitis compared to previous studies. Hippokratia 2015, 19 (1): 63-68.

FeNO levels in children with asthma and other diseases of the lung.

BACKGROUND: Prolonged cough in children is one of the major complaints seen in hospitals. It is difficult to make a proper diagnosis and start the appropriate treatment. Fraction of exhaled nitric oxide (FeNO) measurement is a valuable non-invasive diagnostic tool in determining the cause of prolonged cough in children. Although there are several studies on asthma and COPD, there is a lack of them on other lung diseases such as tuberculosis, bronchiectasia, bronchiolitis obliterans (BO), and pneumonia. PATIENTS AND METHODS: In this study, pre-treatment FeNO levels of patients with various lung diseases were measured and results from the sick patient groups were compared with the results from the control group. RESULTS: Pre-treatment FeNO levels in BO, asthma, and tuberculosis patient groups were higher than in the control group (p < 0.001). There was no significant difference between the acute bacterial pneumonia and bronchiectasia groups, and the control group (p > 0.05). CONCLUSIONS: FeNO measurement is a highly important guiding tool in diagnosis and treatment of various lung diseases.

Community-acquired urinary tract infections in children: pathogens, antibiotic susceptibility and seasonal changes.

AIM: Urinary tract infections (UTIs) are common infections affecting children. The aim of our study is to determine microorganisms that cause community-acquired urinary tract infections and their antibiotic susceptibility in children. MATERIALS AND METHODS: Our investigation includes 150 cases which has positive urine culture. The cases are detected at Pediatric Polyclinics of Dicle University between June 2010 and June 2011. RESULTS: The study included 118 (78.7%) female and 32 (21.3%) male children. Urinary tract infections were seen in autumn 10.7% (n = 16), summer 35.3% (n = 53), winter 30.7% (n = 46) and spring 23.3% (n = 35). The culture results indicated 75.3% (n = 113) Escherichia coli; 20.7% (n = 31) Klebsiella; 2.7% (n = 4) Proteus and % 1.3 (n = 2) Pseudomonas. The antibiotic resistance against Escherichia coli was found out is amikacin (3%), ertapenem (7%), imipenem (0%), meropenem (0%), nitrofurantoin (9%), trimethoprim/sulfamethoxazole (58%), piperacillin (83%), amoxicillin/clavulanate (50%), ampicillin/sulbactam (65%), cefazolin (54%), cefotaxime (51%), cefuroxime sodium (51% ) and tetracycline (68%). The resistance ratios of Klebsiella are amikacin (0%), imipenem (0%), levofloxacin (0%), meropenem (0%), amoxicillin/clavulanate (57%), ampicillin/sulbactam (79%), ceftriaxone (68%), cefuroxime sodium (74%) and trimethoprim/sulfamethoxazole (61%). CONCLUSIONS: The results represent the increasing antibiotic resistance against microorganisms among the community-acquired UTI patients in a developing country such as Turkey. So, the physicians should consider resistance status of the infectious agent and choose effective antibiotics which are nitrofurantoin and cefoxitin for their empirical antibiotic treatment. Furthermore, they should be trained about selection of more effective antibiotics and check the regional studies regularly.

An evaluation of cases of pneumonia that occurred secondary to hydrocarbon exposure in children.

OBJECTIVE: Hydrocarbon pneumonia is distinct among the types of childhood pneumonia in that it has a different pathogenesis and treatment and is preventable. In this study, the cases of 54 children with hydrocarbon pneumonia admitted to the Dicle University Medical Faculty Pediatric Chest Diseases Unit between the years 2006 and 2010 were analyzed retrospectively. PATIENTS AND METHODS: The medical records of 54 patients diagnosed with pneumonia after ingesting/inhaling hydrocarbons were analyzed retrospectively. Age, sex, presenting symptoms, clinical status, radiological and laboratory findings and response to treatment and prognosis were noted. RESULTS: 35 (64.8%) of the patients were male, 19 (35.2%) were female and the ages of the patients ranged from 1 to 5 with an average of 2.49 ± 0.80. The etiologies of the pneumonia were thinner (33%), naphta (3.7%) and kerosene. In 49 of the patients (90.7%), the symptoms started to occur the day the patient was exposed to hydrocarbons. The average length of hospital stay was 4.0 ± 2.3 days. Six patients were treated in the intensive care unit (ICU), and one patient with hydrocarbon pneumonia due to kerosene ingestion died. Inhaled corticosteroids were administered to 18 patients who were progressively deteriorating and inhaled salbutamol was given to 16 patients with bronchospasm. Patients with radiological findings on their chest X-rays and auscultatory findings were found to have longer hospital stays (p < 0.05). CONCLUSIONS: To prevent chemical pneumonia, precautions must be taken to stop children under 5 years of age from using/abusing chemical substances. Although some cases of chemical pneumonia lead to death, with diligent care and treatment, the outcomes are promising. The patients in this study group responded well to treatment with inhaled corticosteroids and salbutamol.

A newborn with trisomy 13 who had tetralogy of Fallot and metopic synostosis: Case report.

BACKGROUND AND AIM: Trisomy 13 (Patau syndrome) was first described by Patau et al in 1960. It is characterized by serious head, facial, and extremity anomalies, congenital heart defects, and mental abnormalities. The incidence rate of Trisomy 13 is 1/10.000 live births. Accompanying symptoms and findings vary in rate and severity among the cases. Tetralogy of Fallot and metopic synostosis are very rare abnormalities in patients with Trisomy 13. In this study, we aimed to present a newborn girl with trisomy 13 who had multiple congenital malformations accompanied by tetralogy of Fallot and metopic synostosis. Description of the case: The patient was delivered at 40 weeks of gestation, and admitted to the neonatal intensive care unit due to respiratory distress and physical abnormalities. The newborn examination revealed multiple dysmorphic features. She had boot-shaped appearance on the chest radiograph. Chromosome analysis demonstrated mosaic trisomy 13. CONCLUSION: Patients with trisomy 13 may have different type of gene variations and malformations; however, the most common type of gene variation is classic trisomy 47, XX +13, and the most common malformations are facial anomalies and congenital heart defects. In addition, tetralogy of Fallot and metopic synostosis may accompany trisomy 13.

The relationships between clinical outcome and the levels of total antioxidant capacity (TAC) and coenzyme Q (CoQ 10) in children with pandemic influenza (H 1 N1) and seasonal flu.

BACKGROUND AND AIM: This study was planned to evaluate the relationships between the levels of total antioxidant capacity (TAC) and Coenzyme Q (CoQ10) and clinical outcome in hospitalized children with pandemic influenza (H1N1). Serum copper (Cu) and zinc (Zn) levels were also determined to evaluate the changings of oxidative stress's enzyme activities depending on their cofactor concentrations. PATIENTS AND METHODS: Children with suspected H1N1 virus infection were hospitalized and nasal swabs were sent to laboratory for confirmation of H1N1 by rRT-PCR assay. Age and sex matched 31 healthy children were included as Control Group. Total antioxidant capacity and CoQ10 were determined by spectrophotometry and HPLC, respectively, and Cu and Zn were determined using atomic absorption spectrometer. RESULTS: Totally 28 children had H1N1 and 37 children had seasonal influenza (SI). TAC, CoQ10 and Zn levels were found to be significantly decreased in H1N1 patients (1.01 +/- 0.19, 752.2 +/- 163, 69 +/- 27, respectively) compared to Control Group (1.64 +/- 0.36, 934 +/- 21, 92 +/- 4, respectively). Seasonal Influenza group had significantly decreased TAC and Zn levels (1.31 +/- 0.27, 78 +/- 34 respectively) compared with control group (1.64 +/- 0.36, 92 +/-41, respectively). CoQ10 levels were also found as decreased in H1N1 compared to seasonal influenza (752.2 +/- 163 vs 1022 +/- 199, p = 0.003). There was a significant correlation between CoQ10 levels of sera and chest radiographic findings of patients with H1N1 pneumonia. No significant differences were found in serum Cu levels between patients with H1N1 and SI or control group (150 +/- 45 vs 127 +/- 37, p = 0.215). CONCLUSIONS, Pandemic influenza infection had increased oxidative stress compared to the seasonal influenza.

[Antileukemic activity and development of resistance to cisplatin (CPT) and platinum (IV)-nitroxyl complex VS118].

Treatment with low doses (1/10 of LD50) of cisplatin and platinum (IV)-nitroxyl complex VS118 [e-ammin-d-(4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl)-a,f-bi s(acetate)-b,c-dichlorplatinum (IV)] was followed by a synergistic therapeutic effect (a 100% cure of animals) as compared with monotherapy with either drug. There was no synergistic increase in toxicity. The rates of resistance development decreased in the following order: P388/cPt+VS118, P388/cPt, P388/VS118. Resistant strains P388/cPt+VS18 and P388/VS118 were highly sensitive to doxorubicin, etoposide and cyclophoshamide. Further research in cPt+VS 118 combinations should be continued.

Barriers to the uptake of cataract surgery.

In The Gambia many patients identified as blind or as having low vision are not attending for surgery. The aim of this study was to investigate the reasons for non-attendance. Three methods were used: semi-structured interviews; focus group discussions; and written questionnaires completed by staff. The most frequently identified barrier by all three methods was cost, closely followed by lack of information about services, fear, transport difficulties, and the lack of an escort. In addition to the existing measures taken by the National Eye Care Programme (NECP) to reduce these barriers, further research into both the public's knowledge and attitudes regarding surgery for cataract is needed. More contact between members of the eye care programme and the communities would aid the transfer of information about the surgery.

Binding of platinum-diaminonitroxyl complexes to animal DNA.

Reaction of PtII(DAPO)X2 complexes (where DAPO is trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl, X2 = (NO3)2, oxalato (Ox) or 1,1-cyclobutanedicarboxylato (Cbdca)) with a bovine spleen DNA in 0.01 M NaHCO3 at 37 degrees C for 24 h gives rise to formation of platinated DNA. The [bound PtII(DAPO)]/[nucleotide] ratio (r) depends on the initial ratio of the reagents and on the nature of leaving ligands X. Nitroxyl-nitroxyl distances in platinated DNA determined by the ESR suggest that at r > or = 0.1 PtII(DAPO) fragments are uniformly attached to DNA. But at lower r, the thermal characteristics of modified DNA (melting temperature Tm, melting range width delta T) and the guanine-to-adenine platination degree ratios GPt/APt imply that the nature of leaving ligands X affect the selectivity of DNA platination. At r > or = 0.1, nitroxyl groups can approach each other so close that, in an acidic medium, the electron transfer from one nitroxyl group to another becomes possible, and the nitroxyls readily disproportionate to diamagnetic products. Correlation time of nitroxyl rotation in PtII(DAPO)-DNA adducts is approximately 10(-8) s, which is related to predominantly bifunctional bonding of PtII(DAPO) with DNA. Platination-induced distortion of DNA was evidenced by changes in Tm, delta T and degree of hyperchromicity H. The major part of adducts form the intrastrand cross-links which destabilize the structure of DNA duplex. The interstrand PtII(DAPO) cross-linking (approximately 1% of the adducts) facilitates renaturation of despiralized DNA molecules upon cooling. Two types of PtII(DAPO)-DNA adducts are revealed, which differ substantially in their rates of deplatination with NaCN. ESR, electron spin resonance; r, degree of modification; cisplatin, cis-diamminedichloroplatinum(II); Tm, melting temperature; delta T, melting range width; H, degree of hyperchromicity; R, degree of renaturation; AAS, atomic absorption spectroscopy; HPLC, high performance liquid chromatography.

Synthesis and antitumor activity of platinum(II) complexes with trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl.

Platinum complexes PtII(DAPO)X2 with diaminonitroxyl radical-trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl (DAPO)-were synthesized by the direct reaction of DAPO with K2PtX4 (X = Cl, I) or by the replacement of chloro ligands in PtII(DAPO)Cl2 by bromo, nitrato, oxalato, malonato, and 1,1-cyclobutanedicarboxylato ligands. The complexes thus obtained were characterized by elemental analysis, infrared,electronic, electron paramagnetic resonance spectroscopic techniques, and high-performance liquid chromatography. The toxicity of compounds in terms of LD50 strongly depends on the nature of X-ligands, and varies between 11 mg/kg (X = NO3) and 400 mg/kg (X2 = 1,1-cyclobutanedicarboxylate). Up to 66% of mice bearing leukemia L1210 survive after the administration of these complexes. This effect is comparable to the effect of cisplatin (50% survive). An increase in the life span of the rest of the animals ranges from 158 to 383%. Complex PtII(DAPO)Cl2 appears to be more efficient than cisplatin against adenocarcinoma 755. Cisplatin, cis-diamminedichloroplatinum(II); CBDCA, 1,1-cyclobutanedicarboxylic acid; DAPO, trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl; Mal, malonic acid; Ox, oxalic acid; IR, infrared; EPR, electron paramagnetic resonance; HPLC, high-performance liquid chromatography; Ca755, adenocarcinoma 755; LD50 and LD100, dose of compounds (mg/kg), causing a death of 50 or 100% or treated animals; ILS, increase in life span of mice.