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5-Aminoimidazole-4-carboxamide ribonucleoside-induced autophagy flux during differentiation of monocytic leukemia cells
Get PDFPharmacological modulators of AMP-dependent kinase (AMPK) have been suggested in treatment of cancer. The biguanide metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) have been reported to inhibit proliferation of solid tumors and hematological malignancies, but their role in differentiation is less explored. Our previous study demonstrated that AICAR alone induced AMPK-independent expression of differentiation markers in monocytic U937 leukemia cells, and no such effects were observed in response to metformin. The aim of this study was to determine the mechanism of AICAR-mediated effects and to test for the possible role of autophagy in differentiation of leukemia cells. The results showed that AICAR-mediated effects on the expression of differentiation markers were not mimicked by A769662, a more specific direct AMPK activator. Long-term incubation of U937 cells with AICAR and other differentiation agents, all-trans-retinoic acid (ATRA) and phorbol 12-myristate 13-acetate, increased the expression of the autophagy marker LC3B-II, and these effects were not observed in response to metformin. Western blot and immunofluorescence analyses of U937 cells treated with bafilomycin A1 or transfected with mRFP-GFP-LC3 proved that the increase in the expression of LC3B-II was due to an increase in autophagy flux, and not to a decrease in lysosomal degradation. 3-Methyladenine inhibited the expression of differentiation markers in response to all inducers, but had stimulatory effects on autophagy flux at dose that effectively inhibited the production of phosphatidylinositol 3-phosphate. The small inhibitory RNA-mediated down-modulation of Beclin 1 and hVPS34 had no effects on AICAR and ATRA-mediated increase in the expression of differentiation markers. These results show that AICAR and other differentiation agents induce autophagy flux in U937 cells and that the effects of AICAR and ATRA on the expression of differentiation markers do not depend on the normal levels of key proteins of the classical or canonical autophagy pathway
Warfarin should not be used for thromboprohylaxis in elective major orthopaedic surgery: a Croatian perspective
Get PDFAim: To identify modes of venous thromboembolism (VTE) prophylaxis in patients undergoing elective major orthopaedic surgery (total hip or knee arthroplasty, THA/TKA) at a single university-associated hospital in Croatia. ----- Methods: A retrospective analysis of consecutive patients subjected to THA or TKA over a two-year period (2014-2015) with a focus on anticoagulation during the first 15 post-surgical days (period of highest VTE risk). ----- Results: Of 603 identified patients three (0.5%) were not anticoagulated (haemophilia) and others received perioperative doses of low molecular weight heparins (LMWH). Overall, 228 (37.8%) patients received prophylaxis not involving warfarin, and 372 continued with short-term LMWH with switching to warfarin. They contributed a total of 1218 international normalized ratio (INR) values (median=3, range=1-8). These were consistently below the target INR range across the observed period. Between post-surgical days 6 and 15 (after the initial titration), 438 values were taken in patients treated with LMWH+warfarin and 92.7% were below, and only 6.8% within the target range; 580 values were taken in patients already switched to warfarin, 74% were below and only 25% within the range. ----- Conclusion: The prevailing mode of VTE prophylaxis was in a clear contrast to (then) actual professional guidelines, with inadequate monitoring and poor anticoagulation. There is no reason to expect a substantially different situation at other institutions across the country. The prevailing practice of VTE prophylaxis in major orthopaedic surgery in Croatia should be promptly abandoned and up-dated in agreement with the current state of the art
Uzroci smrti u bolesnika sa sistemskim eritemskim lupusom: uloga sistemske bolesti i komorbiditeta [Causes of death of patients with systemic lupus erythematosus: role of the systemic disease and comorbidities]
Get PDFCauses of death and morbidity of patients with systemic lupus erythematosus (SLE) include the systemic disease itself and a number of comorbidities, most frequently cardiovascular diseases, infections and malignancies. Given the complex relationship between SLE and comorbidities, it is not always possible to ascribe a single cause of death to deceased patients with SLE. In this review we present the most important causes of morbidity and the way they contribute to death in patients with SLE. Furthermore, we analyze the problem of (non)recording of SLE in death certificates of SLE patients. Matching data from at least two different sources – medical charts from a lupus center and a vital statistics database – may improve the recognition of SLE as a cause of death in the general population
Pseudokolinesteraza i pokazatelji oksidacijskoga stresa u djece s tumorskom bolešću u središnjem živčanom sustavu
Get PDFThe aim of the study is to determine the activity of pseudocholinesterase
(PChE) in serum and cerebrospinal fluid (CSF) and oxydative stress enzymes superoxide dismutase (SOD), catalase (CAT) and glutation peroxidase (GPx) in CSF and blood in children with solid central nervous system (CNS) tumor and to assess whether PChE activity and SOD, CAT and GPx could be a valid biomarker for solid CNS tumors in children. One of the final products of lipid peroxidation is malodialdehide (MDA) was determined too. Methods: The study and control group included 30 children each. Children in the study group had a solid CNS tumor, while those from the control group had never suffered from any tumor diseases. CSF and blood samples were collected from all participants. PChE activity was determined using the Ellman’s spectrophotometric method. GPx, SOD and CAT activity were measured spectrophotometrically; MDA with HPLC method. PChE activity in CSF was shown as a cerebrospinal fluid/serum ratio expressed in percentage, ie, PChE CSF/serum ratio. Receiver operating characteristic (ROC) curve was used to assess whether PChE activity, SOD, CAT and GPx can be used as a biomarker for identifying children with solid CNS tumors. Results: Children with solid CNS tumor had significantly higher PChE activity in CSF and serum, as well as PChE CSF/serum ratio (P= 0.001). PChE CSF/serum ratio in the study group was 2.38% (interquartile range [IQR] 1.14-3.97) and 1.09% (IQR 0.95-1.45) in the control group. ROC curve. analysis of PChE CSF/serum ratio resulted in an area under the curve (AUC) value of 0.76 (95% confidence interval [CI] 0.63-0.88) and a cut-off of 1.09. Twenty five of 29 patients with elevated PChE CSF/serum ratio had a tumor, corresponding to a sensitivity of 83% and a specificity of 53%.
SOD, CAT, GPx and MDA in CSF have high specifity and sensitivity for the solid brain tumors in children and this study provide a cutt of values for the each of them. Between antioxidants highest sensitivity in plasma has SOD 84.62%; highest specifity has GPx 75%. In CSF highest sensitivity showed GPx 89.29%, highest specifity has SOD 100%. MDA sensitivity in brain tumor children in plasma is 80% and in CSF 70%. It’s specificity for plasma is 85.19% and in CSF 78.57%. SOD in plasma resulted in AUC 0,51 and in CSF 0,91; GPx in plasma 0,85 in CSF 0,93; CAT in plasma 0,69 and in CSF 0,90; MDA in plasma 0,89 in CSF 0,78. Conclusion: PChE CSF/serum ratio and SOD, CAT and GPx in CSF resulted in AUC from 0,80 to 0,93 and may be used as a biomarkers with good sensitivity and good or excellent tests for solid CNS tumors in children
Promjer vene nakon intraoperativne dilatacije kao pretkazatelj uspjeha krvožilnoga pristupa za hemodijalizu [Vein diameter after intraoperative dilatation as a predictor of success of hemodialysis arteriovenous fistulas]
Get PDFIntroduction: Vascular access is “the life line” for patients on chronic hemodialysis. The autogenous arteriovenous fistula provides the best access to the circulation because of low complication rate, long-term use, and lower cost, compared to arteriovenous graft and central venous catheter. Vessel characteristics are the most important factors affecting success in angioaccess surgery. Vein diameter after intraoperative dilatation is a new predictor and has never been investigated.
Objectives: The primary objective of this prospective study was to investigate the predictive value of vein diameter after intraoperative dilatation with vessel probes on hemodialysis fistula maturation.
Methods: From February 1, 2006 to January 31, 2009 ninety-three fistulas were investigated. Following characteristics were included in statistical analysis: age, gender, body-mass index, diabetes, hypertension, central venous catether, first fistula construction, location of access, vein diameter, artery diameter and vein diameter after intraoperative dilatation.
Results: Early failure occurred in 20 % of fistulas and 70 % matured sufficiently for cannulation. Variables with significant impact on the failure to mature by univariate analysis were: body-mass index (P = 0,041), artery diameter (P < 0,001), vein diameter (P = 0,004), and vein diameter after dilatation (P = 0,002). However, multivariate analysis showed that only body-mass index (P = 0,038), artery diameter (P = 0.001), and the diameter of the vein after dilatation (P = 0,018) significantly affected maturation. In a group of patients with vein diameter before dilatation ≤2 mm, among vessel characteristics found by multivariate analysis, only vein diameter after dilatation (P = 0,004) significantly affected function.
Conclusion: Vein diameter after intraoperative dilatation with vessel probes and artery diameter were the main predictors of fistula function
Blood transfusion rates as a primary outcome measure: the use of predetermined triggers and display of clinical indications in providing accurate comparative transfusion rates
Get PDFMRI guidance in high-dose-rate brachytherapy for prostate cancer
Get PDFINTRODUCTION: MRI has been widely accepted as the best imaging modality for prostate cancer. However, there is lack of knowledge how MRI perform when applied in MRI-only workflow for catheter insertion and treatment planning in patients receiving standard-care high-dose-rate (HDR) brachytherapy prior to external beam radiotherapy for prostate cancer.
PATIENTS AND METHODS: Forty patients with intermediate or high-risk prostate cancer were enrolled on a prospective clinical trial approved by institution’s research ethics board. Multiparametric MR imaging with stereotactic navigation was used to guide insertion of brachytherapy catheters, followed by MRI-based treatment planning.
RESULTS: Sixty-two implants were performed. Median catheter insertion + imaging time was 100 min, and overall anaesthesia time was 4.0 hours (range 2.1-6.9 hours). MRI at the time of brachytherapy re-staged 14 patients (35%) who were found to have a higher stage of disease. In 6 patients this translated in directed insertion of brachytherapy catheters outside of the prostate boundary (extracapsular disease (n=2) or seminal vesicle invasion (n=4)). Most patients (80%) had gross tumor visible on MRI, which influenced catheter insertion and treatment planning. MRI depicted post-implant anatomic boundaries clearly, with the exception of the apical prostate which was blurred by blood after catheter insertion. Conventional dose planning objectives for PTV coverage (PTV V100>98%) and for the rectum (rectal V75<1.0 cc) were difficult to achieve, but toxicities were low (acute grade≥2 genitourinary = 20%, late grade≥2 genitourinary = 15%, late grade ≥2 gastrointestinal = 7%).Urethral trauma visualized on MRI led to 2 transient grade 3 events.
CONCLUSION: Despite a standard-care treatment, MRI acquired throughout the procedure altered catheter insertion and dose-planning strategies. An MRI-only workflow is feasible and safe, but must be streamlined for broader acceptance
Pulmonary myelolipoma containing osseous tissue: an unexpected finding at autopsy
Get PDFPulmonary myelolipoma is a very rare benign tumor composed of mature adipose tissue and hematopoietic elements such as erythroid, myeloid and megakaryocytic. It usually represents accidental finding during autopsy or chest imaging, since most cases are asymptomatic. Larger masses can lead to hemorrhage, chest pain and chest organ compression. We present a case of incidental finding of pulmonary myelolipoma during the autopsy of an 83- year old woman who died of abdominal aortic rupture. In the right lower lung lobe, solitary, well-circumscribed yellow-brown nodule which was 3 cm in its longest diameter was found. Pathohistological analysis revealed tumor composed of mature adipose tissue and hematopoietic cells (myeloid cells, megakaryocytes, erythroid cells) with fragments of mature bone tissue. Differential diagnosis of pulmonary myelolipoma includes lipoma, liposarcoma, hamartoma, phlebangioma, teratoma and extramedullary hematopoiesis. In majority of cases, tumor removal is not necessary, however, larger lesions should be surgically removed. No cases of malignant transformation or recurrence have so far been reported in the literature
Usporedba kriterija Svjetske zdravstvene organizacije i studije "HAPO" u dijagnostici gestacijskoga dijabetesa [Comparison between World Health Organization criteria and HAPO study criteria in the diagnosis of gestational diabetes mellitus]
Get PDFGestational diabetes mellitus is the most common metabolic disorder in pregnancy. Pregnancies with gestational diabetes have worse outcomes compared to pregnancies with normal glucose tolerance. The objectives of the study were to determine the incidence of GDM according to the IADPSG criteria, to compare the outcomes of pregnancies with GDM based on the WHO (1999) and IADPSG diagnostic criteria and to determine the degree of insulin resistance in a group of pregnant women with GDM according to the IADPSG criteria and their newborns.
PATIENTS AND METHODS: The study is divided into retrospective and prospective part. A retrospective part included 2 405 pregnant women who delivered in the Department of Obstetrics and Gynecology Clinical Hospital Centre Zagreb in the period from 2009 to 2010.
Based on the results of the oGTT pregnant women were divided into four groups: the first group of pregnant women with gestational diabetes according to the WHO criteria; the second group of pregnant women with normal glucose tolerance according to the WHO criteria, but according to the IADPSG criteria with gestational diabetes; the third group of pregnant women with overlapping results and the fourth group of pregnant women with normal glucose tolerance according to the both criteria. A prospective part of the study analyzed 120 pregnant women divided according to the results of oGTT in the two groups. The first group included 60 pregnant women with GDM according to the IADPSG criteria (fasting plasma glucose 5,1 - 6,9 mmol/L) and the second group included 60 pregnant women with normal glucose tolerance. We analyzed demographic data of pregnant women and their newborns, primary outcomes (LGA, macrosomia, cesarean section) and secondary outcomes (hypertensive disordes, preterm delivery, SGA). Prospectively we analyzed concentration of plasma glucose and C-peptide in maternal and umbilical blood samples. RESULTS: We found significantly higher prevalence of GDM according to the IADPSG criteria compared to the WHO criteria (6.2% vs. 21.7%; Χ² = 361; p < 0.001). Pregnant women with hyperglycemic disorders in pregnancy had worse pregnancy outcomes compared to pregnant women with normal glucose tolerance. The overall proportion of overweight and obese pregnant women was the highest in the group of untreated pregnant women with GDM according to the IADPSG criteria (44%) (group 2). In this group we found significantly higer rate of fetal macrosomia (23,2%) and LGA (25,1%). The rate of caesarean section was significantly higher in comparison to healthy controls (20.0% vs. 13.8%, p < 0,001). Prospectively, in a group of pregnant women with GDM according to the IADPSG criteria, who were treated, we found higher rate of macrosomia, LGA and cesarean section. The differencies were statistically significant (p = 0,043). The newborns of diabetic pregnant women had higher insulin resistance compared to the newborns of pregnant women with normal glucose tolerance (p < 0,001). Increased body mass index is associated with adverse pregnancy outcomes. The rate of chronic hypertension (3%), gestational hypertension (18,8%), cesarean section (31%), fetal macrosomia (24,4%) and LGA (28%) was significantly higher in obese pregnant women compared tonpregnant women with normal body weight (p < 0,001). The rate of preterm delivery (6,5%) and SGA (10,9%) was higher in underweight pregnant women.
CONCLUSION: IADPSG diagnostic criteria for GDM reveals more women with hyperglycemic disorders in pregnancy. A group of pregnant women who were normoglycemic according to the WHO criteria, but according to the IADPSG were diagnosed GDM, had adverse pregnancy outcomes. Lower values of glycemia, than those defined for diabetes in pregnancy, are associated with adverse pregnancy outcomes. Hyperglycemic disorders in pregnancy are closely related to obesity. Obese women should be educated and treated well before the pregnancy to reduce the risk of adverse pregnancy outcomes. The important focus should be on the prevention of obesity
Utjecaj morfologije druza na sloj fotoreceptora u senilnoj makularnoj degeneraciji [Influence of drusen morphology on disruption of photoreceptor layer in age-related macular degeneration]
Get PDFINTRODUCTION: Age related macular degeneration (ARMD) is progressive neurodegenerative disease and one of the major causes of irreversible vision loss in developed countries. Dry form of ARMD is characterized with presence of abnormal pigment changes and drusen in macula which may lead to decrease in vision quality. Drusen are made of extracellular material situated between Bruch membrane and retinal pigment epithelium. With their position and growth they cause disturbance in their surroundings. OCT enables insight in drusen morphology as well in morphology of surrounding structures, first of all photoreceptors and retinal pigment epithelium. Although many papers that confirm presence of outer nuclear photoreceptor layer atrophy and atrophy of ellipsoid zone above drusen have been published, so far the relation between drusen morphology and photoreceptor atrophy has not been established.
AIM OF STUDY: To determine which morphologic characteristics of drusen are related to photoreceptor atrophy as well to establish progression of photoreceptor atrophy in 2 years interval
MATERALS AND METHOD: In this prospective study we analyzed and compared OCT scans of 44 eyes patients having dry drusiform ARMD in 2 years period. We used Optopol Copernicus 6x6 milimeter 3D scan of macular area. In every OCT scan we analyzed all drusen for their: number, shape, reflectivity, homogeneity, outer nuclear layer thickness, height, width, and central retinal thickness (CRT).
RESULTS: Comparison of number of drusen related to photoreceptor atrophy on the beginning and the end of study revealed that there is statistically significant increase of drusen related to photoreceptor atrophy in 2 years period. On the other hand, decrease of drusen number not related to photoreceptor atrophy was noticed in the same period.
Analysis of drusen height to ellipsoid zone and outer nuclear layer atrophy showed that the higher are the drusen the more significant atrophy above drusen exists. Analysis of drusen width to ellipsoid zone and outer nuclear layer atrophy showed that the wider are the drusen the more significant atrophy above drusen exists.
Very interesting result occurred when we compared the eyes in which there was increase in number of drusen related to photoreceptor atrophy in to 2 years period to the eyes in which those kind of drusen were not present. The results showed, that eyes in which increase of drusen number related to photoreceptor atrophy was present, had statically higher values of CRT, average height and total drusen number.
CONCLUSION: Interpretation of OCT scans in patients having drusiform ARMD should not be limited only to confirmation of dry form of disease or excluding wet form of disease. Every patient, after being diagnosed with certain disease is interested in their prognosis. Results of this study enable individual interpretation of drusen morphologic characteristics and provide more precise evaluation of stage and progression of disease for individual patient diagnosed with dry ARMD.
With duration of dry ARMD there is increase of drusen number related to photoreceptor atrophy. The higher and wider in average the drusen are, the photoreceptor atrophy is more pronounced. Patients having higher total drusen number, higher average drusen height and higher CRT value have more chance for increase of drusen related to photoreceptor atrophy in period of 2 years and therefore probably more chance for vision deterioration