Publications by authors named "Mirjana Cvetkovic"

28 Publications

  • Page 1 of 1

Chemical Characterization and Antibacterial Activity of Essential Oil of Medicinal Plants from Eastern Serbia.

Molecules 2020 Nov 23;25(22). Epub 2020 Nov 23.

Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia.

The objective of this study was to evaluate wild growing , , , and with respect to their essential oil (EO) content, composition and antimicrobial activity. The five species were collected at Mt. Rtanj and the village of Sesalac, Eastern Serbia. The main EO constituents of Lamiaceae plants were -cymene (24.4%), geraniol (63.4%) and germacrene D (21.5%) in , and ssp. , respectively. EO had multiple constituents with major ones being camphor (9.8%), caryophyllene oxide (6.5%), terpinen-4-ol (6.3%) and 1,8-cineole (5.6%), while the main EO constituents of were 1,8-cineole (45.1%) and camphor (18.2%). Antimicrobial testing of the EO showed that (Gram-positive) was more sensitive to all of the tested EOs than (Gram-negative). EO showed the highest antimicrobial activity against both tested bacterial strains. This is the first study to characterize the EO composition and antimicrobial activity of these five medicinal species from Eastern Serbia in comparison with comprehensive literature data. The results can be utilized by the perfumery, cosmetics, food and pharmaceutical industries, but also for healing purposes in self-medication.
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http://dx.doi.org/10.3390/molecules25225482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700605PMC
November 2020

Leaf-surface guaianolides from showing protective effect on human lymphocytes DNA.

Nat Prod Res 2019 Nov 11:1-9. Epub 2019 Nov 11.

University of Belgrade - Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.

Analysis of composition of CHCl surface extract of leaves of Vis. revealed 16 sesquiterpene lactones with guaianolide skeleton, so called amphoricarpolides, typical for this genus. Four of them, -, were new derivatives and their structures were elucidated by detailed analyses of IR, NMR and MS data. Amphoricarpolide (), its 15--acetyl derivative (), and two 9-hydroxyamphoricarpolides, 3,15-di--acetyl- and 3--acetyl-15--isovaleroyl derivatives ( and , respectively) were tested for protective effect on chromosome aberrations in peripheral human lymphocytes using cytochalasin-B blocked micronucleus (CBMN) assay. The tested compound exerted a beneficial effect by decreasing DNA damage of human lymphocytes.
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http://dx.doi.org/10.1080/14786419.2019.1687470DOI Listing
November 2019

Integration of dry-column flash chromatography with NMR and FTIR metabolomics to reveal cytotoxic metabolites from Amphoricarpos autariatus.

Talanta 2020 Jan 10;206:120248. Epub 2019 Aug 10.

Institute of Chemistry, Technology and Metallurgy, National Institute, University of Belgrade, Studentskitrg12-16, 11000, Belgrade, Serbia. Electronic address:

Metabolomics generate a profile of small molecules from plant extracts, which could be directly responsible for bioactivity effects. Using dry-column flash chromatography enabled a rapid and inexpensive method for the very efficient separation of plant extract with a high resolution. This separation method coupled to NMR and FTIR-based metabolomics is applied to identify bioactive natural products. OPLS multivariate analysis method, was used for correlation the chemical composition of the plant extracts, Amphoricarpos autariatus, with the results of cytotoxic activity against Human cervical adenocarcinoma cell line (HeLa) and epithelial lung cancer cell line (A549). In this way, the highest contribution to the cytotoxic activity was recorded for the guaianolide sesquiterpene lactones named amphoricarpolides. The compounds indicated as bioactive after metabolomics analysis were tested, and their cytotoxic activity were confirmed.
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http://dx.doi.org/10.1016/j.talanta.2019.120248DOI Listing
January 2020

Association between timing of dialysis initiation and clinical outcomes in the paediatric population: an ESPN/ERA-EDTA registry study.

Nephrol Dial Transplant 2019 11;34(11):1932-1940

Department of Pediatric Nephrology, Gazi University, Ankara, Turkey.

Background: There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment.

Methods: We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ≥8 mL/min/1.73 m2 (early starters) and eGFR <8 mL/min/1.73 m2 (late starters). The primary outcomes were patient survival and access to transplantation. Secondary outcomes were growth and cardiovascular risk factors. Sensitivity analyses were performed to account for selection- and lead time-bias.

Results: The median eGFR at the start of dialysis was 6.1 for late versus 10.5 mL/min/1.73 m2 for early starters. Early starters were older [median: 11.0, interquartile range (IQR): 5.7-14.5 versus 9.4, IQR: 2.6-14.1 years]. There were no differences observed between the two groups in mortality and access to transplantation at 1, 2 and 5 years of follow-up. One-year evolution of height standard deviation scores was similar among the groups, whereas hypertension was more prevalent among late initiators. Sensitivity analyses resulted in similar findings.

Conclusions: We found no evidence for a clinically relevant benefit of early start of dialysis in children with ESKD. Presence of cardiovascular risk factors, such as high blood pressure, should be taken into account when deciding to initiate or postpone dialysis in children with ESKD, as this affects the survival.
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http://dx.doi.org/10.1093/ndt/gfz069DOI Listing
November 2019

Acute dialysis in children: results of a European survey.

J Nephrol 2019 Jun 4;32(3):445-451. Epub 2019 Apr 4.

Nephrology and Dialysis Unit, Pediatric Subspecialties Department, Institute for Scientific Research, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.

The number of children with acute kidney injury (AKI) requiring dialysis is increasing. To date, systematic analysis has been largely limited to critically ill children treated with continuous renal replacement therapy (CRRT). We conducted a survey among 35 European Pediatric Nephrology Centers to investigate dialysis practices in European children with AKI. Altogether, the centers perform dialysis in more than 900 pediatric patients with AKI per year. PD and CRRT are the most frequently used dialysis modalities, accounting for 39.4% and 38.2% of treatments, followed by intermittent HD (22.4%). In units treating more than 25 cases per year and in those with cardiothoracic surgery programs, PD is the most commonly chosen dialysis modality. Also, nearly one quarter of centers, in countries with a gross domestic product below $35,000/year, do not utilize CRRT at all. Dialysis nurses are exclusively in charge of CRRT management in 45% of the cases and pediatric intensive care nurses in 25%, while shared management is practiced in 30%. In conclusion, this survey indicates that the choice of treatment modalities for dialysis in children with AKI in Europe is affected by the underlying ethiology of the disease, organization/set-up of centers and socioeconomic conditions. PD is utilized as often as CRRT, and also intermittent HD is a commonly applied treatment option. A prospective European AKI registry is planned to provide further insights on the epidemiology, management and outcomes of dialysis in pediatric AKI.
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http://dx.doi.org/10.1007/s40620-019-00606-1DOI Listing
June 2019

Challenges in Pediatric Cardiac Anesthesia in Developing Countries.

Front Pediatr 2018 29;6:254. Epub 2018 Oct 29.

Depertment of Critical Care, Theatres, Anaesthesia, Pain and Sleep, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom.

Approximately 90% of a million children worldwide born with congenital heart defect do not have an access to adequate pediatric cardiac care. The World Society for Pediatric and Congenital Heart Surgery, established in 2006 shifted the focus from providing individual pediatric cardiac care to developing global standards for the practice of pediatric cardiac surgery and professional education of the local teams. After recognizing the challenges of the local team regarding providing safe anesthesia and functioning as a broader team, we have focused our education on simplifying anesthetic procedures and advancing structured team approach. The appropriate selection of patients and simplifying anesthetic technique should be the standard of care. We introduced structured approach to daily education using just in time teaching, case based discussions and simple skill training simulation sessions. Furthermore, we enhanced team-training approach applying tools such as WHO surgical safety checklist and implementation manual, SAFE communication, introducing KDD with SMART aim, SCAMPs, advanced protocols of care and culture change tools. Following a significant number of short missions to developing centers we have, within NGO, succeeded to support building and maintaining several local pediatric cardiac centers with structured approach to anesthesia and team building. The appropriate selection of patients is one of the most important contributing factors for decreasing morbidity and mortality rate in pediatric cardiac surgery patients. The anesthesia technique for pediatric cardiac procedures should be aimed at fast-track surgery, with early extubation as a goal. Regional blocks such as paravertebral and caudal should be considered for perioperative pain control. By introducing structured approach to daily education and by enhancing team-training approach we have contributed evolving sustainable pediatric cardiac centers in developing countries.
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http://dx.doi.org/10.3389/fped.2018.00254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215813PMC
October 2018

Comparison of Early Outcomes for Normothermic and Hypothermic Cardiopulmonary Bypass in Children Undergoing Congenital Heart Surgery.

Front Pediatr 2018 17;6:219. Epub 2018 Aug 17.

East Midlands Congenital Heart Centre, University Hospitals of Leicester, Leicester, United Kingdom.

Comparison of early outcomes of normothermic cardiopulmonary bypass (N-CPB, ≥35°C) with hypothermic cardiopulmonary bypass (H-CPB, 28-34°C) for congenital heart defects. Data from 99 patients <2 years operated with N-CPB ( = 48) or H-CPB ( = 51) were retrospectively reviewed: aortic X-clamping and CPB duration, vasoactive inotropic score (VIS), arterial lactate, pH and base excess, urine output, extubation, PICU stay, transfusion requirements, chest drain losses, costs of transfusions, and costs of PICU stay. The two groups were homogeneous for diagnosis, risk factors, surgery and demographic variables: N-CPB age 7.7 ± 6.1 months, weight 6.2 ± 2.4 kg, and H-CPB age 6.6 ± 6.5 months, weight 6.1 ± 2.4 kg. There were no hospital deaths in either group. VIS in N-CPB was lower than H-CPB on PICU arrival (9.7 ± 5.9 vs. 13.4 ± 7.9, < 0.005), after 4 h (7.0 ± 5.2 vs. 11.1 ± 7.3, < 0.001) and 24 h (2.8 ± 3.6 vs. 5.6 ± 5.6, < 0.003); arterial pH was better at PICU arrival (7.33 ± 0.09 vs. 7.30 ± 0.09, = 0.046) after 4 h (7.35 ± 0.07 vs. 7.32 ± 0.07, = 0.022) and after 24 h (7.37 ± 0.05 vs. 7.35 ± 0.05, = 0.01). Extubation was earlier in N-CPB than in H-CPB (22 ± 27 vs. 48 ± 57 h, = 0.003) as PICU discharge (61 ± 46 h vs. 87 ± 69 h, = 0.021). Transfusion requirements in operating room were lower in N-CPB vs. H-CPB for RBC, FFP, cryoprecipitate, and platelets, while during the first 24 h in PICU were lower only for cryoprecipitate and platelets. Chest drain losses (mL/kg) on PICU arrival, after 4 and 24 h were lower with N-CPB vs. H-CPB (respectively 1.5 ± 1.4 vs. 2.5 ± 2.7, = 0.013, 7.8 ± 6.0 vs. 10.9 ± 8.7, = 0.025, and 23.0 ± 12.0 vs. 27.9 ± 15.2, = 0.043). Tranexamic acid infusion was required in 7/48 (14.6%) patients with N-CPB vs. 18/51(= 35.3%) in H-CPB ( = 0.009). The average total costs/patient of blood and blood products (RBC, FFP, cryoprecipitate, platelets) were lower in N-CPB vs. H-CPB for both the first 24 h after surgery (£204 ± 169 vs. £306 ± 254, = 0.011) as well as during the total duration of PICU stay (£239 ± 193 vs. £427 ± 337, = 0.001). The average cost/patient/day of stay in PICU was lower in N-CPB than in H-CPB (£4,067 ± 3,067 vs. £5,800 ± 4,600, = 0.021). N-CPB may reduce inotropic and respiratory support, shorten PICU stay, and decrease peri-operative transfusion requirements, with subsequent costs reduction, compared to H-CPB. Future studies are needed to validate and support wider use of N-CPB.
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http://dx.doi.org/10.3389/fped.2018.00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108179PMC
August 2018

Effect of Age and Allele Variants of CYP3A5, CYP3A4, and POR Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia.

Ther Drug Monit 2017 12;39(6):589-595

*Department of Nephrology, University Children's Hospital; †Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences "VINCA," University of Belgrade; and ‡School of Medicine, University of Belgrade, Belgrade, Serbia.

Background: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR*28). The aim of this study was to assess the impact of age, CYP3A5*3, CYP3A4*22, and POR*28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients.

Methods: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5*3, CYP3A4*22, and POR*28.

Results: CYP3A5 nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 ± 12.75 versus 22.44 ± 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR*28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR*1/*1 genotype (165.54 ± 70.40 versus 210.55 ± 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 ± 4.72 versus 34.19 ± 11.89, P = 0.001) and C2/dose (106.75 ± 26.99 versus 209.20 ± 71.57, P < 0.001) compared with older children. Carriers of CYP3A5*3 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR*28 allele aged ≤6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P < 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016).

Conclusions: Younger age, POR*28 allele, and CYP3A5*3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy.
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http://dx.doi.org/10.1097/FTD.0000000000000442DOI Listing
December 2017

Brain monitoring in adult and pediatric ECMO patients: the importance of early and late assessments.

Minerva Anestesiol 2017 Oct 22;83(10):1061-1074. Epub 2017 Jun 22.

Cardiac Intensive Care and ECMO, Institute of Child Health, Great Ormond Street Hospital, London, UK.

Monitoring brain integrity and neurocognitive function is a new and important target for the management of a patient treated with extracorporeal membrane oxygenation (ECMO), in particular because of the increasing awareness of cerebral abnormalities that may potentially occur in this setting. Continuous regular monitoring, as well as repeated assessment for cerebral complications has become an essential element of the ECMO patient management. Besides well-known complications, like bleeding, ischemic stroke, seizures, and brain hypoperfusion, other less defined yet relevant injury and clinical manifestations are increasingly reported and impacting on ECMO patient prognosis at short term. Furthermore, it is becoming more evident that neurologic complication may not occur only in the early phase. Indeed, other potential adverse events related to the long-term neurocognitive function have been also recently documented either in children or adult ECMO patients. Despite increasing awareness of these aspects, generally accepted protocols and clinical management strategies in this respect are still lacking. Current means to monitor brain perfusion or detecting ongoing cerebral tissue injury are rather limited, and most techniques provide indirect or post-insult recognition of irreversible tissue injury. Continuous monitoring of brain perfusion, serial assessment of brain-derived serum biomarkers, timely neuro-imaging, and post-discharge counselling for neurocognitive dysfunction, particularly in pediatric patients, are novel pathways focusing on neurologic assessment with important implications in daily practice to assess brain function and integrity not only during the ECMO-related hospitalization, but also at long-term to re-evaluate the neuropsychological integrity, although well designed studies will be necessary to elucidate the cost-effectiveness of these management strategies.
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http://dx.doi.org/10.23736/S0375-9393.17.11911-5DOI Listing
October 2017

Chemical Composition and Antibacterial Activity of Angelica archangelica Root Essential Oil.

Nat Prod Commun 2017 Feb;12(2):205-206

Roots of wild growing Angelica archangelica L. from Mt. Ozren (Serbia) were subjected to hydrodistillation and GC-MS analysis. The roots contained 0.10% of essential oil with a-pinene (29.7%), 8-3-carene (14.2%), and a mixture of P-phellandrene and limonene (13.2%) as main compounds. The modified resazurin microtiter-plate assay was used to evaluate the antibacterial activity of the essential oil against Staphylococcus aureus and Escherichia coli. The minimum inhibitory concentration (MIC) values were 14.2 μL/mL for S. aureus and 28.4 μL/mL for E. coli, while the minimum bactericidal concentrations (MBC) were 56.8 μL/mL and 113.6 μL/mL, respectively. According to the obtained results, the angelica root essential oil can be applied as a natural preservative in food and as a natural antibiotic for the treatment of several infectious diseases caused by these two bacteria.
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February 2017

Shock Index Values and Trends in Pediatric Sepsis: Predictors or Therapeutic Targets? A Retrospective Observational Study.

Shock 2016 09;46(3):279-86

*Children's Acute Transport Service, Great Ormond Street Hospital NHS Trust, London, UK †University Hospitals of Leicester NHS Trusts, Leicester, UK ‡Addenbrookes Hospital NHS Trust, Cambridge, UK §Imperial College Healthcare NHS Trust, London, UK ¶University College London Institute of Child Health, London, UK.

Background: Shock index (SI) (heart rate [HR]/systolic blood pressure [SBP]) has been used to predict outcome in both adult and pediatric sepsis within the intensive care unit (ICU). We aimed to evaluate the utility of SI before pediatric ICU (PICU) admission.

Patients And Methods: We conducted a retrospective observational study of children referred to a pediatric intensive care transport service (PICTS) between 2005 and 2011. The predictive value of SI, HR, and blood pressure at three prespecified time points (at referral to PICTS, at PICTS arrival at the referring hospital, and at PICU admission) and changes in SI between the time points were evaluated. Death within the first 48 h of ICU admission (early death) was the primary outcome variable.

Results: Over the 7-year period, 633 children with sepsis were referred to the PICTS. Thirty-nine children died before transport to a PICU, whereas 474 were transported alive. Adjusting for age, time points, and time duration in a multilevel regression analysis, SI was significantly higher in those who died early. There was a significant improvement in SI with the transport team in survivors but not in nonsurvivors. However, the predictive value of a change in SI for mortality was no better than either a change in HR or blood pressure.

Conclusions: The absolute or change in SI does not predict early death any more than HR and SBP individually in children with sepsis.
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http://dx.doi.org/10.1097/SHK.0000000000000634DOI Listing
September 2016

Anismus as a cause of functional constipation--experience from Serbia.

Vojnosanit Pregl 2015 Jan;72(1):9-11

Unlabelled: BACKROUND/AIM: Anismus is paradoxal pressure increase or pressure decrease less than 20% of external anal sphincter during defecation straining. This study analyzed the presence of anismus as within a group of patients with the positive Rome III criteria for functional constipation. We used anorectal manometry as the determination method for anismus.

Methods: We used anorectal water-perfused manometry in 60 patients with obstructive defecation defined by the Rome III criteria for functional constipation. We also analyzed anorectal function in 30 healthy subjects.

Results: The presence of anismus is more frequent in the group of patients with obstructive defecation compared to the control group (a highly statistically significant difference, p < 0.01). Furthermore, we found that the Rome III criteria for functional constipation showed 90% accuracy in predicting obstructive defecation. We analyzed the correlation of anismus with the presence of weak external anal sphincter, rectal sensibility disorders, enlarged piles, diverticular disease and anatomic variations of colon. We found no correlation between them in any of these cases.

Conclusion: There is a significant correlation between anismus and positive Rome III criteria for functional constipation. Anorectal manometry should be performed in all patients with the positive Rome III criteria for functional constipation.
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http://dx.doi.org/10.2298/vsp1501009jDOI Listing
January 2015

Timing of death in children referred for intensive care with severe sepsis: implications for interventional studies.

Pediatr Crit Care Med 2015 Jun;16(5):410-7

1Children's Acute Transport Service, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom. 2Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom. 3Paediatric Intensive Care Unit, St Mary's Hospital Paddington, Imperial College Healthcare NHS Trust, London, United Kingdom. 4Paediatric Intensive Care Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom. 5Portex Unit of Respiratory Medicine, Critical Care and Anaesthesia, Institute of Child Health, University College London, London, United Kingdom.

Objective: Early deaths in pediatric sepsis may limit the impact of therapies that can only be provided on PICUs. By introducing selection and survivorship biases, these very early deaths may also undermine the results of trials that employ standard consent procedures. We hypothesized that: 1) the majority of deaths in children with severe sepsis occur very early, within 24 hours of referral to PICU; and 2) a significant proportion of deaths occur before PICU admission.

Design, Setting, And Patients: We studied consecutive referrals of newborns through to 16 years of age, between 2005 and 2011 to the Children's Acute Transport Service, the North Thames regional pediatric intensive care transport service, with a working diagnosis of "sepsis," "severe sepsis," "meningococcal sepsis," or "septic shock."

Interventions: The primary outcome measure was the proportion of deaths within 24 hours of referral. Survival distributions of previously healthy children were compared with those with significant comorbidities.

Measurements And Main Results: Thirteen thousand four hundred and nine referrals were made to Children's Acute Transport Service, of whom 703 (5%) met inclusion criteria. Data on survival to 1 year were available in 627 of 703 patients (89%). One hundred thirty children (130/627; 21%; 95% CI, 18-24%) died in the first year. A higher proportion of children with comorbidity cases (46/85, 54%, 44-64) died compared with previously healthy cases (84/542; 16%; 13-19; p < 0.0005, Fisher exact test). Seventy-one deaths occurred within 24 hours of PICU referral (71/130, 55%, 46-63). The timing of death differed with comorbidity. Similar proportions of children survived to 24 hours (previously healthy children 90% vs children with comorbidity 83%, p = 0.06). However, deaths after 24 hours were infrequent among previously healthy cases (28/84 deaths, 33%, 24-44%) compared with children with comorbidity cases (31/46 deaths, 66%, 53-79%) (p < 0.001, Fisher exact test).

Conclusions: This majority of deaths among children referred for pediatric intensive care with for severe sepsis occur within 24 hours. This has important implications for future clinical trials and quality improvement initiatives aimed at improving sepsis outcomes.
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http://dx.doi.org/10.1097/PCC.0000000000000385DOI Listing
June 2015

Further amphoricarpolides from the surface extracts of Amphoricarpos complex from Montenegro.

Chem Biodivers 2014 Sep;11(9):1428-37

Center for Chemistry, Institute for Chemistry, Technology and Metallurgy, University of Belgrade, Studentski trg 16, RS-11000 Belgrade.

Analysis of composition of sesquiterpene lactone fraction of leaf cuticular neutral lipids of Amphoricarpos complex from two different localities in north Montenegro, i.e., canyon of river Tara (A. autariatus ssp. autariatus) and mountain Zeletin (A. autariatus ssp. bertisceus) afforded sesquiterpene lactones with guaianolide skeletons (17 compounds), so called amphoricarpolides, typical for this genus. Nine of them, 9-17, were new compounds, and their structures were elucidated by detailed analyses of IR, NMR, and MS data.
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http://dx.doi.org/10.1002/cbdv.201400101DOI Listing
September 2014

Post-transplant lymphoproliferative disorder--case reports of three children with kidney transplant.

Srp Arh Celok Lek 2014 Jan-Feb;142(1-2):83-8

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It is a disease of the immunosuppressed state, and its occurrence is mostly associated with the use of T-cell depleting agents, and also intensification of immunosuppressive regimens. In the majority of cases, PTLD is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The 2008 World Health Organization classification for lymphoid malignancies divides PTLD into four major categories: early lesions, polymorphic PTLD, monomorphic PTLD and Hodgkin PTLD. The treatment and prognosis depend on histology. The cornerstone of PTLD therapy includes reduction/withdrawal of immunosuppression, monoclonal anti CD-20 antibody (rituximab) and chemotherapy.

Outline Of Cases: We reported here our experiences with three patients, two girls aged 7.5 and 15 and a 16-year old boy. They had different organ involvement: brain, combined spleen-liver and intestines, respectively. Even though EBV was a trigger of lymphoid proliferation as it was confirmed by histopathology or in cerebrospinal fluid, qualitative EBV-PCR was positive only in one patient at disease presentation. Reduction of immunosuppression therapy was applied in treatment of all three patients, while two of them received rituximab and ganciclovir. They had an excellent outcome besides many difficulties in diagnosis and management of disease.

Conclusion: Qualitative EBV-PCR is not useful marker in pediatric transplant recipients. Our suggestion is that patients with the risk factors like T-cell depleting agents, immunosuppressant protocol or increasing immunosuppressive therapy and EBV miss-match with donor must be more accurately monitored with quantitative EBV PCR.
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http://dx.doi.org/10.2298/sarh1402083sDOI Listing
October 2015

Achalasia--two types in the same patient: case report.

Srp Arh Celok Lek 2013 Nov-Dec;141(11-12):807-9

Clinical Hospital Center "Bezanijska kosa" Belgrade, Serbia.

Introduction: A paper presented a case of esophageal achalasia with both type 2 and type 3 achalasia found in the same patient.

Case Outline: High resolution impedance manometry of esophagus was performed. Liquid swallows induced panesophageal pressurization (achalasia type 2), whereas viscous swallows led to compartmentalized pressurization--distal two thirds of esophagus (achalasia type 3). No complete bolus transit was recorded. Patient refused any procedure.

Conclusion: The aim of this paper was to show the necessity of performing manometry using both liquid and viscous swallows in GI departments where this approach has not been routinely used in order to establish proper diagnosis since therapy approach is different between type 2 and type 3 achalasia.
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http://dx.doi.org/10.2298/sarh1312807jDOI Listing
October 2015

Bradbury-Eggleston syndrome - an unusual cause of gastroesophageal reflux disease (GERD).

Med Glas (Zenica) 2014 Feb;11(1):243-5

1Clinical Hospital Center Bežanijska kosa, 2Clinical Center of Serbia, Belgrade; Serbia.

The report presents a case of a 46-year-old male patient, previously treated because of dysphagia, pyrosis, vertigo while standing up and impotency. Manometric and pH-metric analysis showed presence of gastroesophageal reflux disease (GERD) caused by transient relaxation of lower esophageal sphincter (TRLES). Heart-rate variability showed decreased sympathetic function. Electromyoneurography showed a neurological lesion in muscles of upper extremities. The patient received midodrine and clonazepam which resolved this condition. These findings suggest that a neurological disorder can be a cause of GERD.
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February 2014

MMP-1 and -3 haplotype is associated with congenital anomalies of the kidney and urinary tract.

Pediatr Nephrol 2014 May 12;29(5):879-84. Epub 2014 Jan 12.

Institute of Nuclear Sciences Vinca, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia.

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of progressive chronic kidney disease that may lead to end-stage renal disease and renal replacement therapy in childhood. Altered expression or activity of matrix metalloproteinases (MMPs) have been found in CAKUT. The MMP-1, -3, and -8 polymorphisms studied here are located in the gene promoters and alter expression. Our aim was to investigate associations of MMP polymorphisms, solely and in haplotypes, with CAKUT in children.

Methods: A case-control study with 101 pediatric patients and 281 controls was performed. The MMP-1 (-1607 1G/2G), -3 (5A/6A), and -8 (-799 C/T) genotypes were determined by PCR-restriction fragment length polymorphism.

Results: We found statistically significant associations of MMP-3 5A/6A polymorphism (p < 0.0001) and 1G-(1607)-6A haplotype, with no preferences for MMP-8 -799C or T alleles, with CAKUT (OR = 2.93, 95 % CI 1.43-5.98, adjusted for gender, p = 0.003) and with obstructive uropathies in a subgroup of patients (OR = 4.57, 95 % CI 2.74-7.61, adjusted for gender, p < 0.0001).

Conclusions: MMP-3 genotypes and MMP-3 and -1 haplotypes encompassing either MMP-8 -799C or T alleles were associated with CAKUT and obstructive uropathies in pediatric patients. Still, functional and association studies are needed to elucidate evident roles of MMPs in CAKUT.
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http://dx.doi.org/10.1007/s00467-013-2699-xDOI Listing
May 2014

Celiac disease diagnosed after uncomplicated pregnancy in a patient with history of bulimia nervosa.

Vojnosanit Pregl 2013 Jan;70(1):77-9

Department of Gastroenterohepatology, Clinical and Hospital Center "Bezanijska kosa", Belgrade, Serbia.

Introduction: The association between celiac disease and eating disorders has been very rarely reported. This is the first report on celiac disease associated with bulimia in this part of Europe.

Case Report: An adult female patient with history of bulimia and one uncomplicated pregnancy was admitted to the Gastroenterology Department, due to long lasting dyspeptic symptoms, constipation, major weight loss and fatigue. After positive serological screening, the diagnosis of celiac disease was confirmed with histopathology examination of duodenal biopsy specimen.

Conclusion: Complicated interactions between celiac disease and bulimia can make them difficult to diagnose and treat. It is important to consider the presence of celiac disease in patients with bulimia and gastrointestinal symptoms.
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http://dx.doi.org/10.2298/vsp1301077mDOI Listing
January 2013

Dilated cardiomyopathy associated with celiac disease: case report and literature review.

Srp Arh Celok Lek 2012 Sep-Oct;140(9-10):641-3

Department of Gastroenterology, Clinical Hospital Center "Bezanijska kosa", Belgrade, Serbia.

Introduction: Celiac disease is an inflammatory condition of the small intestinal mucosa induced by gluten consumption in genetically susceptible individuals, leading to a spectrum of gastrointestinal presentation. A number of autoimmune and other disorders are highly associated with celiac disease. Cardiomyopathy associated with celiac disease has been rarely reported in the literature.

Case Outline: We present a case of a 27-year-old male with one month history of diarrhea, weight loss, fatigue, dyspeptic symptoms, peripheral edema, and cardiac palpitations. After positive serological screening with immunoglobulin A anti-tissue transglutaminase antibody test, the diagnosis of celiac disease was confirmed with histopathology examination of duodenal biopsy specimen. Echocardiographic findings were consistent with acute myocarditis. After common causes of myocarditis had been excluded, probable celiac disease-associated autoimmune myocarditis was diagnosed. The patient was recommended to undergo a strict life-long gluten-free diet. IgA anti-transglutaminase antibodies, and anti-gliadin antibodies, were both significantly elevated during the 6-, 12- and 18-month follow-up. Low compliance to gluten-free diet in our patient led to progressive worsening of the left ventricular ejective fraction and other serious cardiac complications which warranted invasive cardiac interventions.

Conclusion: Dilated cardiomyopathy associated with celiac disease is a serious condition which requires multidisciplinary approach involving gastroenterologist and cardiologist. Compliance with gluten-free diet is mandatory if patients are to avoid progression of cardiomyopathy. Screening of patients with idiopathic dilated cardiomyopathy for celiac disease is advisable.
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January 2013

In vivo susceptibility of ESBL producing Escherichia coli to ceftriaxone in children with acute pyelonephritis.

Srp Arh Celok Lek 2012 May-Jun;140(5-6):321-5

School of Medicine, University of Belgrade, Belgrade, Serbia.

Introduction: The choice of empiric therapy of acute pyelonephritis (APN) in children should be based on the knowledge of Escherichia coli (E. coli) as the most common uropathogen and its antibiotic sensitivities considering that nowadays ESBL-producing [ESBL (+)] E. coli is on the rise worldwide.

Objective: To examine in vivo susceptibility of ESBL (+) E. coli to ceftriaxone (CTX), and to evaluate the options for empiric therapy for APN in children.

Methods: Retrospective study of CTX empiric therapy of APN in children treated at the University Children's Hospital in Belgrade from January 2005 to December 2009. ESBL phenotypic confirmatory test with ceftazidime, CTX and cefotaxime was performed for all urine isolates by disc diffusion method on Mueller-Hinton agar plates. In vivo sensitivity of CTX documented by clinical response to empiric CTX therapy was compared between two groups of children: group I with ESBL (+) E. coli and group II with ESBL (-) E. coli APN.

Results: Group I with ESBL (+) APN consisted of 94 patients and group II of 120 patients with ESBL (-) APN, respectively. All patients received CTX as empiric therapy at a mean dose of 66.9 mg during 7.2 +/- 2.6 days of therapy. Clinical effect of CTX was similar in patients with ESBL (+) compared to those with ESBL (-) APN.

Conclusions: In vitro resistance of ESBL E. coli to CTX determined by standard methods is not sufficiently predictive for its in vivo sensitivity. Therefore CTX may be used as empiric therapy for acute pyelonephritis in children.
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August 2012

Antibiotic resistance of uropathogens in newborns and young children with acute pyelonephritis.

Srp Arh Celok Lek 2012 Mar-Apr;140(3-4):179-83

School of Medicine, University of Belgrade, Belgrade, Serbia.

Introduction: Urinary tract infection is common in childhood. Depending on the localization of the infection, severity of its clinical presentation and possible acute and long-term complications, it may be described as either acute cystitis or acute pyelonephritis.

Objective: The aim of this study was to assess the resistance patterns of uropathogens during the last 5 years in newborns and young children with acute pyelonephritis.

Methods: Uropathogens resistance to commonly usable anti-microbial agents (ampicillin, a combination of sulphamethoxasole and trimethoprim, cephalexin, ceftriaxone, cefotaxime, ceftazidime, gentamycin, amikacin, ciprofloxacin, imipenem and nalidixic acid) was retrospectively studied in newborns and young children treated during early (2005-2007) and late (2008-2009) study periods. Anti-bacterial susceptibility testing of the urine isolates was performed by the standard disc diffusion method.

Results: 117 newborns and 294 children aged 9.3 +/- 0.7 months were treated during early (n=136) or late (n=275) study period due to the first episode of acute pyelonephritis. Escherichia coli was the most common bacterial pathogen (85.5%). Compared to children older than one month, newborns had higher degree of antibacterial resistance to 2nd and 3rd generation cephalosporins, aminoglycosides, and nalidixic acid during early, and to ceftazidime, aminoglycosides and nalidixic acid during late study period. Also, multidrug resistance was more common in newborns during the early study period.

Conclusion: Newborns had higher rate of antibacterial resistance than young children.The progressive increase of anti-microbial resistance in children with acute pyelonephritis is of great concern.
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June 2012

Pediatric non-Hodgkin lymphoma: a retrospective 14-year experience with Berlin-Frankfurt-Münster (BFM) protocols from a tertiary care hospital in Serbia.

Pediatr Hematol Oncol 2012 Mar;29(2):109-18

Department of Hematology/Oncology, University Children's Hospital, School of Medicine, University of Belgrade, Belgrade, Serbia.

Use of current intensive chemotherapy protocols in pediatric non-Hodgkin lymphoma (NHL) in high-income countries resulted in event-free survival (EFS) rates ranging from 80 to 90%. The results are inferior in less privileged countries with limited resources for medical care. There are no reports about comprehensive data analysis in pediatric NHL in Serbia. A retrospective study was carried out at University Children's Hospital, Belgrade, in children aged less than 18 years diagnosed with non-Hodgkin lymphoma from 1997 to 2011. Fifty-seven children were eligible for analysis. Fourteen were diagnosed with lymphoblastic lymphoma, 38 with mature B-cell NHL (B-NHL), and 5 with anaplastic large-cell lymphoma. Mean age at diagnosis was 9.2 years, with male to female ratio 2.35:1. Children were treated according to Berlin-Frankfurt-Münster (BFM) protocols. With median follow-up of 59.3 months, 5-year probability of EFS was 84.1% for all patients, whereas overall survival was 93%. These results with BFM protocol administration, although inferior to leading international groups, reflect good treatment outcome in our patients. To the best of the authors' knowledge, this article presents the first results regarding treatment and survival of childhood NHL in Serbia.
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http://dx.doi.org/10.3109/08880018.2011.652342DOI Listing
March 2012

Henoch-Schönlein purpura outcome in children: a ten-year clinical study.

Srp Arh Celok Lek 2011 Mar-Apr;139(3-4):174-8

Nephrology Department, University Children's Hospital, Belgrade, Serbia.

Introduction: Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood. It is characterized by symptoms including nonthrombocytopenic purpura, abdominal pain, haematuria/proteinuria, and arthralgia/arthritis. The pleiomorphism of clinical signs in HSP could be confused with other conditions or other vasculitis forms.

Objective: Evaluation of HSP clinical presentation, the onset and severity of renal manifestation in affected children and their outcome.

Methods: A retrospective study of 49 patients diagnosed with HSP was conducted from September 1999 to September 2009. Children with severe renal manifestations (nephrotic range proteinuria, with or without nephrotic or nephritic syndrome) have undergone kidney biopsy.

Results: Twenty-five patients developed renal manifestations after onset of the disease. In our study child's older age was a risk factor for association with HSP nephritis. Six of the patients required kidney biopsy. They were successfully treated with various immunosuppressive protocols, as well as three of nine patients with nephrotic range proteinuria. Two patients developed most severe form of HSP nephritis, nephrotic-nephritic syndrome with histology grade IIIb/IVb. During the study period (average followup 6 years), all patients had a normal global renal function with mild proteinuria in only two cases. The prognosis of renal involvement was better than reports from other patient series.

Conclusion: Long-term morbidity of HSP is predominantly attributed to renal involvement. During the study period, no patient had renal insufficiency or end stage renal disease after various combinations of immunosuppressive treatment. It is recommended that patients with HSP nephritis are followed for longer periods of time with a regular measurement of renal function and proteinuria.
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http://dx.doi.org/10.2298/sarh1104174sDOI Listing
June 2011

[Recombinant human growth hormone treatment in short children with renal disease--our first experience].

Srp Arh Celok Lek 2010 Mar-Apr;138(3-4):197-203

Introduction: Growth retardation is a hallmark of chronic illnesses such as chronic kidney disease in children, and it is associated with increased morbidity and mortality. The growth hormone (GH) resistance observed in uraemia can be overcome by supraphysiological doses of exogenous GH.

Objective: We would like to present our first results of recombinant human growth hormone (rhGH) treatment, mainly in children on haemodialysis.

Methods: Sixteen children, aged 4.5-17.1 years (mean age 11.25 +/- 3.57) with height below -2.0 standard deviation score (SDS) for age or height velocity below -2.0 SDS for age, were selected to receive rhGH therapy at our Nephrology and Haemodialysis Department. Most of them were on haemodialysis (14 children) with mean spent time 2.88 +/- 2.68 years (0-9 years) before the initiation of rhGH therapy. One half of patients were prepubertal (8 children) and the second half were in early puberty (testicular volume between 4 and 8 ml for boys and breast development B2 or B3 in girls). All patients received 28-30 IU/m2 rhGH per week by daily subcutaneous injection. The year before rhGH therapy served as a control period.

Results: During the first year of treatment, mean height velocity in haemodialysis patients increased from 2.25 cm/year to 6.59 cm/year (p < 0.0001) and in the second year it was 5.25 cm/ year (p = 0.004). The mean height SDS in haemodialysis children did not improve significantly during the first year of rhGH treatment (from -3.01 SDS to -2.77 SDS, p = 0.063). Neither weight nor the body mass index varied compared with the pretreatment period. Two patients developed worsened secondary hyperparathyroidism and were excluded from the study, but the relationship with rhGH remains uncertain.

Conclusion: Mean height velocity significantly improved during rhGH therapy in haemodialysis patients. No significant side-effects were observed in children during three-year treatment with GH.
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http://dx.doi.org/10.2298/sarh1004197sDOI Listing
June 2010

Comparison of two nutritional assessment methods in gastroenterology patients.

World J Gastroenterol 2010 Apr;16(16):1999-2004

Department of Gastroenterohepatology, Clinical and Hospital Center Bezanijska Kosa, Autoput s/n, Belgrade, Serbia.

Aim: To investigate and compare efficacy and differences in the nutritional status evaluation of gastroenterology patients by application of two methods: subjective global assessment (SGA) and nutritional risk index (NRI).

Methods: The investigation was performed on 299 hospitalized patients, aged 18-84 years (average life span 55.57 +/- 12.84), with different gastrointestinal pathology, admitted to the Department of Gastroenterohepatology, Clinical and Hospital Center "Bezanijska Kosa" during a period of 180 d. All the patients, after being informed in detail about the study and signing a written consent, underwent nutritional status analysis, which included two different nutritional indices: SGA and NRI, anthropometric parameters, bioelectrical impedance analysis, and biochemical markers, within 24 h of admission.

Results: In our sample of 299 hospitalized patients, global malnutrition prevalence upon admission varied from 45.7% as assessed by the SGA to 63.9% by NRI. Two applied methods required different parameters for an adequate approach: glucose level (5.68 +/- 1.06 mmol/L vs 4.83 +/- 1.14 mmol/L, F = 10.63, P = 0.001); body mass index (26.03 +/- 4.53 kg/m(2) vs 18.17 +/- 1.52 kg/m(2), F = 58.36, P < 0.001); total body water (42.62 +/- 7.98 kg vs 36.22 +/- 9.32 kg, F = 7.95, P = 0.005); basal metabolic rate (1625.14 +/- 304.91 kcal vs 1344.62 +/- 219.08 kcal, F = 9.06, P = 0.003) were very important for SGA, and lymphocyte count was relevant for NRI: 25.56% +/- 8.94% vs 21.77% +/- 10.08%, F = 11.55, P = 0.001. The number of malnourished patients rose with the length of hospital stay according to both nutritional indices. The discriminative function analysis (DFA) delineated the following parameters as important for prediction of nutritional status according to SGA assessment: concentration of albumins, level of proteins, SGA score and body weight. The DFA extracted MAMC, glucose level and NRI scores were variables of importance for the prediction of whether admitted patients would be classified as well or malnourished.

Conclusion: SGA showed higher sensitivity to predictor factors. Assessment of nutritional status requires a multidimensional approach, which includes different clinical indices and various nutritional parameters.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860077PMC
http://dx.doi.org/10.3748/wjg.v16.i16.1999DOI Listing
April 2010