Empagliflozin and sacubitril/valsartan reverse methotrexate cardiotoxicity by repressing oxidative stress and hypoxia in heart embryonic H9c2 cardiomyocytes - the role of morphology of mitochondria observed on electron microscopy.

OBJECTIVE: Oxidative stress and hypoxia play an important role in the pathogenesis of various cardiovascular diseases. We aimed to evaluate the effectiveness of sacubitril/valsartan (S/V) and Empagliflozin (EMPA) on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 rat embryonic cardiomyocyte cells. MATERIALS AND METHODS: BH9c2 cardiomyocyte cells were treated with methotrexate (MTX) (10-0.156 µM), empagliflozin (EMPA; 10-0.153 µM) and sacubitril/valsartan (S/V; 100-1.062 µM) for 24, 48 and 72 h. The half maximum inhibitory concentration (IC50) and half maximum excitation concentration (EC50) values of MTX, EMPA and S/V were determined. The cells under investigation were exposed to 2.2 µM MTX before treatment with 2 µM EMPA and 25 µM S/V. The cell viability, lipid peroxidation, oxidation of proteins and antioxidant parameters were measured while morphological changes were also observed by transmission electron microscopy (TEM). RESULTS: The results showed that treatment with 2 µM EMPA, 25 µM S/V or their combination produced a protective effect against the reduction in cell viability caused by 2.2 µM MTX.  While HIF-1α levels plunged to their lowest with S/V treatment, oxidant parameters dipped, and antioxidant parameters soared to their highest level with S/V and EMPA combination treatment. A negative correlation was found between HIF-1α and total antioxidant capacity in the S/V treatment group. CONCLUSIONS: A significant decrease in HIF-1α and oxidant molecules together with an enhancement in antioxidant molecules and normalization of the mitochondria morphology as observed on electron microscopy in S/V and EMPA-treated cells were detected. Although S/V and EMPA have both protective effects against cardiac ischemia and oxidative damage, this effect may be increased more with S/V treatment alone compared to combined treatment.

Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells. MATERIALS AND METHODS: We have assessed the effects of increasing concentrations of methotrexate (MTX) and ranolazine on proliferation of H9c2 rat cardiomyocyte cells by MTT assay. Malondialdehyde (MDA) protein oxidation [advanced oxidation protein products (AOPPs)], lipid hydroperoxide (LOOH) and xanthine oxidase (XO) activity as oxidative stress markers and HIF-1α levels increased and total thiol (T-SH), catalase (CAT) activity and total antioxidant capacity (TAC) antioxidant capacity markers decreased in MTX-treated cells compared to control cells. RESULTS: Oxidative stress markers decreased, and antioxidant capacity markers increased in cells treated with ranolazine alone compared to control cells. For all parameters, we showed that the levels of oxidant, antioxidant markers and HIF-1α in cells treated with MTX and ranolazine together reached the level of the control group, and ranolazine reversed the oxidative damage caused by MTX. CONCLUSIONS: The cell viability increased the levels of oxidant and prooxidant markers and decreased the levels of antioxidant markers decreased in H9c2 cardiomyocytes induced by oxidative stress. These results suggest that ranolazine may protect the cardiomyocytes from MTX-induced oxidative damage. The effects of ranolazine could result from its antioxidant properties.

CIRCULATING MIR-132, MIR-146A, MIR-222, AND MIR-320 EXPRESSION IN DIFFERENTIAL DIAGNOSIS OF WOMEN WITH POLYCYSTIC OVARY SYNDROME.

Purpose: The aim of the study was to investigate whether the circulating miR-132, miR-146a, miR-222, and miR-320 levels are used in the differential diagnosis of women with polycystic ovary syndrome (PCOS) and healthy women. Methods: This prospective case-control study included 50 women with PCOS and age- and body mass index- matched 50 healthy controls. The hormone and lipid profiles, levels of microRNAs (miRNAs), and parameters of carbohydrate metabolism were measured. Results: Expression levels of miRNAs were assessed using the two-step quantitative real-time polymerase chain reaction. Circulating miR-132, miR-146a and miR-222 levels were significantly downregulated in the PCOS group compared with the control group. The miR-320 levels did not differ between the two groups. Free testosterone was negatively correlated with miR-132, miR-146a and miR-222. Insulin was negatively correlated with miR-132 and miR-146a. Conclusions: The results of the study revealed that miRNA expression, may suggest a possible distinction between healthy women and PCOS patients. miR-132, miR-146a, and miR-222 may have key functions in the pathogenesis of PCOS.

Malignancy Rates of Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) Cases: A Tertiary Center Study.

AIM: To evaluate the malignancy rates of Atypia of undetermined significance /follicular lesion of undetermined significance (AUS/FLUS) cases in the light of clinical and sonographic features. MATERIAL AND METHODS: The percentage of AUS/FLUS cases, second fine needle aspiration cytology (FNAC) results, cyto-histopathological correlations and risk of malignancy were analyzed. RESULTS: 113 out of 1461 thyroid FNAC samples (7.7%) were diagnosed as AUS/FLUS and included in the study. Seventy three out of 113 cases (64.6 %) underwent repeat biopsies or surgery. From 45 cases repeat biopsies were taken and 28 had thyroidectomy or lobectomy. There was a significant relation between nodule size and underwent surgery or repeat FNAC (p=0.036). Malignancy rate was 24.6% for cases which had any managements. The malignancy rates were higher in AUS/FLUS cases with cytological atypia (28.8%). After surgery the most common malignancy was papillary thyroid carcinoma, followed by follicular carcinoma. CONCLUSION: The risk of malignancy of AUS/FLUS cases is quite high because of the heterogeneity of the group. The sub-classification of this category according to cytological or/and architecture atypia may be more useful in predicting malignancy risk. Further larger studies with ancillary techniques including molecular analysis may be more useful in determining the malignancy risk and appropriate management of this heterogeneous category.

Turkish pediatric residents' knowledge, perceptions, and practices of blood culture sampling.

INTRODUCTION: Pediatrics is one of the medical specialties in which blood cultures for bloodstream infections are performed very frequently. This study aimed to evaluate pediatric residents' knowledge and perceptions of blood culture sampling. MATERIAL AND METHODS: Between June 2019 and September 2019, a questionnaire comprising 20 questions about blood culture sampling was sent via email to participants who were pediatric residents at five different hospitals in Turkey. There were 11 true/false and nine multiple-choice questions that assessed three aspects of culture sampling: indications, sampling practice and knowledge, and contamination. The percentage of correct answers was used to calculate an overall score and subsection scores. RESULTS: A total of 132 pediatric residents [102 (77%) female] with a mean age of 28.3±2.8 years completed the questionnaire. Forty-five (35%) were in their 1st year of residency. Sixty (46%) participants reported that they had not performed blood culture sampling in the last week. There was a negative relationship between years in training and the number of cultures performed (Kendal's tau-b=-0.297, p<0.001). The overall median score was 65 (range, 35-90) and it seemed to increase with years of training. The lowest median score was in the contamination subscale and only one (0.76%) participant correctly answered all questions concerning contamination. CONCLUSION: Residents who obtained the majority of blood cultures had the lowest knowledge levels. Therefore, it is evident that the knowledge levels of pediatric residents must be increased in order to improve blood culture sampling practices in centers where they perform blood culture sampling.

ABC transporters Mdr1a/1b, Bcrp1, Mrp2 and Mrp3 determine the sensitivity to PhIP/DSS-induced colon carcinogenesis and inflammation.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is an abundant dietary carcinogen, formed during high-temperature cooking of meat. In this study, we investigated whether clinically relevant ATP-binding cassette (ABC) efflux transporters can modulate PhIP-induced colorectal carcinogenesis in vivo using wild-type (WT), Bcrp1-/-; Mrp2-/-; Mrp3-/- and Bcrp1-/-; Mdr1a/b-/-; Mrp2-/- mice. We used a physiological mouse model of colorectal cancer; a combination of a single high-dose oral PhIP administration (200 mg/kg), followed by administering a colonic inflammatory agent, dextran sodium sulfate (DSS), in drinking water for 7 days. Pilot experiments showed that both knockout strains were more sensitive to DSS-induced colitis compared to WT mice. Lack of these transporters in mice also led to clearly altered disposition of activated PhIP metabolites after a high-dose oral PhIP administration. The results suggest that Mdr1a/1b, Bcrp1 and Mrp2 contributed to biliary excretion and Mrp3 to sinusoidal secretion of the pre-carcinogenic metabolite N2-OH-PhIP. The levels of a genotoxicity marker, PhIP-5-sulphate, were at least 4- and 17-fold reduced in the intestinal tissue and intestinal content of both knockout strains compared to WT mice. In line with these findings, the level of colon carcinogenesis was reduced by two- to four-fold in both knockout strains compared to WT mice when PhIP and DSS treatments were combined. Thus, perhaps counterintuitively, reduced activity of these ABC transporters may in part protect from PhIP-induced colon carcinogenesis. Collectively, these data suggest that ABC transporters are important in protecting the body from inflammatory agents such as DSS, in the disposition of carcinogenic metabolites, and in determining the sensitivity to dietary PhIP-induced carcinogenesis.

The level of collaboration amongst nurses in Turkey.

AIM: This study was conducted to determine the level of collaboration amongst nurses in Turkey. BACKGROUND: Collaboration amongst nurses is thought to increase nurse-physician collaboration and decrease medical mistakes. It has been connected with positive patient outcomes and increased job satisfaction for nurses. There are some studies on nurse-physician collaboration in Turkey, but nurse-nurse collaboration has not been measured before in this context. There are limited studies in the literature on nurse-nurse collaboration. METHODS: The sample of this study consisted of 859 nurses who work at one public hospital, one university hospital and four private hospitals in Turkey. The study was designed as descriptive and cross-sectional research. The data were collected using the nurse-nurse collaboration scale and a socio-demographic questionnaire. The nurse-nurse collaboration scale comprises five subdimensions: problem-solving, shared process, communication, coordination and professionalism. The cut-off value of the scale for minimum expected collaboration degree was determined as 2.5. RESULTS: It was found that the total nurse-nurse collaboration level in the sample was 3.09, which is above minimum expected degree of collaboration (2.5). In regard to the subdimensions of the scale, the lowest mean score (2.97) was for problem-solving and the highest (3.20) was for professionalism. Graduate nurses' problem-solving, coordination, professionalism and cooperation skills were found to be higher than those of undergraduate nurses. Nurses employed under continuous employment contracts presented higher collaboration scores than those employed with annual, temporary contracts. CONCLUSIONS: Regarding the results obtained in the study, although the Turkish nurses were collaborating at the minimum expected level, they can collaborate more. Improved collaboration between nurses will increase patient satisfaction and thus will have a favourable impact on patient safety. IMPLICATIONS FOR NURSING POLICY AND HEALTH POLICY: Nurses who have a bachelor's or higher level degree should be hired, and nurses should be provided with job security in the form of a continuous employment contract to enhance nurse-nurse collaboration.

Pentraxin-3 levels are associated with vasculitis and disease activity in childhood-onset systemic lupus erythematosus.

Objectives Childhood-onset systemic lupus erythematosus (cSLE) is a multisystemic autoimmune disease characterized by inflammatory organ damage by means of vasculitis. Pentraxin-3 (PTX3) is expressed locally at the sites of inflammatory processes, predominantly from endothelial cells. In adult studies, PTX3 has shown to be an indicator of active vasculitis both in large-vessel and small-vessel vasculitides, as well as in SLE. Moreover, in SLE it has found to be correlated with disease activity, and with some of the clinical manifestations and laboratory parameters. We aimed to ascertain if PTX3 might be a significant mediator in cSLE and if it might indicate active vasculitis during the course of the disease. Methods Serum PTX3 levels were measured in 76 patients with cSLE and 41 healthy subjects. We have investigated its relation with disease activity, damage, clinical features, laboratory parameters and medications. Results Serum levels of PTX3 were found to be increased in cSLE compared to healthy controls (mean ± SD; 10.6 ± 8.2 ng/mL vs 2.7 ± 1.3 ng/mL, p < 0.001). PTX3 concentrations were also in correlation with SLEDAI-2K ( r = 0.57, p < 0.001). When viewed from the clinical perspective, serum PTX3 levels were significantly higher only in patients with active vasculitis ( p < 0.001), Raynaud phenomenon ( p = 0.006) and mucocutaneous manifestations ( p < 0.001). However, an association between PTX3 and age, age at disease onset, disease duration, complement levels, PedSDI score (pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), ESR, CRP, procalcitonin levels, anti-ds DNA antibody, anticardiolipin antibodies was not detected. Conclusions Patients with cSLE have increased levels of serum PTX3 compared to healthy controls. Thus, serum PTX-3 level might be a significant mediator in cSLE. Apart from these, the results support that PTX3 reflects active cutaneous vasculitis in cSLE and correlates with disease activity.

The intestinal helminth community of the spiny-tailed lizard Darevskia rudis (Squamata, Lacertidae) from northern Turkey.

Populations of the lizard Darevskia rudis (Bedriaga, 1886) from northern Anatolia were examined for intestinal parasites in adult specimens. One cestode, Nematotaenia tarentolae López-Neyra, 1944 and four nematode species, Spauligodon saxicolae Sharpilo, 1962, Skrjabinelazia hoffmanni Li, 1934, Oswaldocruzia filiformis (Goeze, 1782) and Strongyloides darevskyi Sharpilo, 1976, were found. Three of these nematodes, S. saxicolae, S. hoffmanni and S. darevskyi are suggested to be part of a module in the network of Darevskia spp. and their parasites. Only one, S. darevskyi, was identified as a Darevskia spp. specialist. The very low infection and diversity parameters are indicative of the depauperate helminth communities found in this lacertid lizard, falling among the lowest within the Palaearctic saurians. Nevertheless these values are higher than those found in parthenogenetic Darevskia spp. Interpopulation variation in the intensity of S. saxicolae and N. tarentolae is attributable to local changes in ecological conditions. On the other hand, parasite abundance and richness increased in the warmer localities, while the effect of lizard sex and size on infection was negligible. The structure of these helminth communities in D. rudis are compared with those observed in other European lacertid lizards.

P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387.

CYT387 is an orally bioavailable, small molecule inhibitor of Janus family of tyrosine kinases (JAK) 1 and 2. It is currently undergoing Phase I/II clinical trials for the treatment of myelofibrosis and myeloproliferative neoplasms. We aimed to establish whether the multidrug efflux transporters P-glycoprotein (P-gp; MDR1; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) restrict oral availability and brain penetration of CYT387. In vitro, CYT387 was efficiently transported by both human MDR1 and BCRP, and very efficiently by mouse Bcrp1 and its transport could be inhibited by specific MDR1 inhibitor, zosuquidar and/or specific BCRP inhibitor, Ko143. CYT387 (10 mg/kg) was orally administered to wild-type (WT), Bcrp1(-/-), Mdr1a/1b(-/-) and Bcrp1;Mdr1a/1b(-/-) mice and plasma and brain concentrations were analyzed. Over 8h, systemic exposure of CYT387 was similar between all the strains, indicating that these transporters do not substantially limit oral availability of CYT387. Despite the similar systemic exposure, brain accumulation of CYT387 was increased 10.5- and 56-fold in the Bcrp1;Mdr1a/1b(-/-) mice compared to the WT strain at 2 and 8h after CYT387 administration, respectively. In single Bcrp1(-/-) mice, brain accumulation of CYT387 was more substantially increased than in Mdr1a/1b(-/-) mice, suggesting that CYT387 is a slightly better substrate of Bcrp1 than of Mdr1a at the blood-brain barrier. These results indicate a marked and additive role of Bcrp1 and Mdr1a/1b in restricting brain penetration of CYT387, potentially limiting efficacy of this compound against brain (micro) metastases positioned behind a functional blood-brain barrier.

Electrochemical behaviour of 3,8-difluorobenzo[c]cinnoline at mercury electrode.

Voltametric and coulometric methods have been used to study the electroanalytical behaviour of 3,8-difluorobenzo[c]cinnoline. The number of electrons transferred, the wave characteristics, diffusion coefficient and reversibility of the reactions have been investigated in ethyl alcohol-BR. Adsorption of the molecule on the surface of the mercury drop electrode was analyzed and this phenomena was exploited to calculate the diffusion coefficient of 3,8-difluorobenzo[c]cinnoline. A mechanism for the electrode reaction was proposed.

[Distribution and typing in salmonellosis in children 1978-1983]. / 1978-1983 yillari arasinda cocuklarda görülen salmonellozislerin dagilimi ve tiplendirilmesi.

329 infants with salmonellosis were evaluated in Pediatric and Microbiology Department of Anadolu University Teaching and Training Hospital. It was established 127 (38.6%) S. typhimurium, 42 (12.8%) S. typhosa and 6 (1.8%) S. paratyphi A and B in our series. Besides these serotypes, 154 (46.8%) patients could not be typed. S. typhimurium was importantly noticed than other types (p less than 0.001) and this feature makes the distribution of typing of salmonellosis in children as characteristic. This infection was encountered especially between December (8.5%), it made peak in January (20.3%) and April (9.73%) period. Then, between April-December, this infections was established quite lower (p less than 0.001). This distribution is specific for Eskisehir district, and it was gradually decreased year by year (p less than 0.05).