New Iron Twist to Chloroquine─Upgrading Antimalarials with Immunomodulatory and Antimicrobial Features.

Herein, upgraded chloroquine (CQ) derivatives capable of overcoming Plasmodium resistance and, at the same time, suppressing excessive immune response and risk of concurrent bacteremia were developed. Twelve new ferrocene-CQ hybrids tethered with a small azathia heterocycle (1,3-thiazolidin-4-one, 1,3-thiazinan-4-one, or 5-methyl-1,3-thiazolidin-4-one) were synthesized and fully characterized. All hybrids were evaluated for their in vitro antiplasmodial, antimicrobial, and immunomodulatory activities. Additional assays were performed on selected hybrids to gain insights into their mode of action. Although only hybrid 4a was more potent than the parent drug toward CQ-resistant Dd2 Plasmodium falciparum strain, several other hybrids (such as 6b, 6c, and 6d) manifested substantially improved antimicrobial and immunomodulatory properties. Interesting structure-activity relationship data were obtained, hinting at future research for the development of new multitarget chemotherapies for malaria and other infectious diseases complicated by drug resistance, bacterial co-infection, and immune-driven pathology issues.

Prognostic significance of symptomatic deep vein thrombosis in patients with acute symptomatic pulmonary embolism regarding the European Society of Cardiology mortality risk model.

BACKGROUND: Deep vein thrombosis (DVT) can be symptomatic or asymptomatic in patients with acute pulmonary embolism (PE). The prognostic value of the symptomatic DVT at the presentation regarding the prognosis of PE is unknown. METHODS: Data were extracted from the REgional Pulmonary Embolism Registry (REPER) which enrolled 1604 hospitalized patients after multidetector computed tomography (MDCT) diagnosed symptomatic acute PE. According to the ESC risk model, patients were classified into four subgroups. Patients who had leg edema with or without pain, and patients with leg pain and DVT confirmed by compression ultrasound were considered to have symptomatic DVT. This study aimed to compare all-cause hospital mortality between patients with symptomatic DVT and patients without symptoms or signs of DVT across the PE risk stratums. RESULTS: All-cause mortality in patients with symptomatic DVT compared to those who had no symptoms or signs of DVT were 2/196 (1.0%) vs. 11/316 (3.5%), P=0.145, 4/129 (3.1%) vs. 17/228 (7.5%), P=0.106, 14/196 (7.1%) vs. 54/290 (18.6%), P<0.001 and 16/55 (29.1%) vs. 51/139 (36.7%), P=0.402 in patients with low, intermediate-low, intermediate-high and high-risk PE, respectively. In multivariate analysis symptomatic DVT was associated with decreased in-hospital mortality only in patients with intermediate-high PE (OR 0.320, 95%CI 0.164-0.627; P=0.001). Intermediate-high risk PE patients with symptomatic DVT who were treated with thrombolysis had significantly lower hospital mortality than patients without symptoms or signs of DVT (2.2% vs. 11.4%, P=0.003). CONCLUSIONS: Intermediate-high risk PE patients with symptomatic DVT at presentation may benefit from thrombolysis and have lower hospital all-cause mortality in such circumstances.

Predictive value of admission glycemia in diabetics with pulmonary embolism compared to non-diabetic patients.

AIMS: To examine the relationship between admission glucose (AG) level and short-term in-hospital mortality and to investigate the association between hyperglycemia and major bleeding in PE patients with and without DMT2. METHODS: We evaluated 1165 patients with diagnosed acute PE with multi-detector computed tomography pulmonary angiography (MDCT-PA) enrolled in the Regional multicenter PE registry (REPER). The study population was classified to patients with diabetes mellitus type 2 (DMT2) and those without diabetes. According to quartiles of AG patients, both groups separately were categorized into four subgroups (DMT2 I: < 7.5 mmol/L; II: 7.5-10.0 mmol/L; III: 10.0-15.7 mmol/L; IV: > 15.7 mmol/L and (non-DMT2 I: < 5.5 mmol/L; II: 5.5-6.3 mmol/L; III: 6.3-7.9 mmol/L; IV: > 7.9 mmol/L). RESULTS: All-cause mortality was higher in the DMT2 group (9.5% vs. 18.2%, p < 0.001), and PE-cause mortality was 6% for the patients without DMT2 and 12.4% for DMT2 patients (p = 0.02). The patients in the fourth AG quartiles in both groups, without DMT2 and with DMT2, had significantly higher all-cause and PE-cause in-hospital mortality compared with the first quartile. Rates of major bleeding were similar between the groups. On the multivariable analysis, after adjusting for age, gender and mortality risk, the adherence in the fourth AG quartile had an independent predictive value for all-cause death (HR 2.476, 95% CI 1.017-6.027) only in DM patients. CONCLUSION: In our cohort of patients with acute PE, diabetes was associated with increased rates for all-cause and PE-cause mortality.

Predictive value of heart failure with reduced versus preserved ejection fraction for outcome in pulmonary embolism.

AIMS: This study aimed to investigate whether the risk of short-term mortality is different in pulmonary embolism (PE) patients who have heart failure with reduced ejection fraction (HFrEF) as compared with those with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Predictive value of HFrEF or HFpEF for 7-day (intrahospital) and 30-day all-cause mortality was determined in the cohort of 1055 out of 1201 consecutive acute PE patients from the Serbian multicentre PE registry. Patients were classified into either HFrEF or HFpEF group, according to guideline-proposed criteria. A 7-day (intrahospital) and 30-day all-cause mortality was 18.5% vs. 7.3% vs. 4.5% (P < 0.001) and 22.2% vs. 16.3% vs. 7.9% (P < 0.001) for patients with the history of HFrEF, HFpEF, and without HF, respectively. Multivariable analysis adjusted to age, gender, history of chronic obstructive pulmonary disease, diabetes mellitus, arterial hypertension, presence of atrial fibrillation, and mortality risk assessment at admission has shown that only HFrEF, but not HFpEF, was an independent predictor for 7-day mortality (hazard ratio 2.22, 95% confidence interval 1.25-4,38.41, P = 0.021) and neither HFrEF or HFpEF was an independent predictor for 30-day mortality. Among various admission parameters associated to PE outcome, only systolic pressure in HFrEF patients (P < 0.001), heart rate (P = 0.01), and right ventricle systolic pressure (P = 0.039) in HFpEF patients were significantly different in patients who died compared with those who survived at 7 days. CONCLUSIONS: Our study has shown that the presence of previous history of HFrEF, but not HFpEF, in acute PE is an independent risk factor for mortality at 7 days.

Biomarkers for the prediction of early pulmonary embolism related mortality in spontaneous and provoked thrombotic disease.

Factors associated with provoked PE may influence a biomarker's predictive value for the primary outcome. The aim of this study was to investigate the value of BNP, cTnI, CRP and D-Dimer measurements taken soon after hospital admission for the prediction of 30-day PE-caused death in patients with spontaneous versus provoked PE.Data were extracted from a pool of 726 consecutive PE patients enrolled in the multicenter Serbian PE registry. Blood concentrations of BNP, cTnI, CRP and D-dimer were measured during the first 24 h of hospitalization. BNP blood level had strong predictive value for the primary outcome in spontaneous PE (c-statistics 0.943, 95% CI 0.882-1.000, p = .001) and a slightly lower predictive outcome in provoked PE (c-statistics 0.824, 95% CI 0.745-0.902, p < .001). NRI and IDI showed that none of the markers, when added to BNP, could improve Cox regression prediction models for 30-day PE-related mortality in either the spontaneous or provoked PE group. Blood levels of BNP measured during the first 24 h of hospital admission had an excellent predictive value for 30-day PE-related mortality in spontaneous PE and slightly lower predictive value in provoked PE, whereas CRP, cTnI and D-Dimer did not contribute significantly to the predictive value of BNP in either group.

Co(iii) complexes of (1,3-selenazol-2-yl)hydrazones and their sulphur analogues.

The first Co(iii) complexes with (1,3-selenazol-2-yl)hydrazones as an unexplored class of ligands were prepared and characterized by NMR spectroscopy and X-ray diffraction analysis. The novel ligands act as NNN tridentate chelators forming octahedral Co(iii) complexes. The impact of structural changes on ligands' periphery as well as that of isosteric replacement of sulphur with selenium on the electrochemical and electronic absorption features of complexes are explored. To support the experimental data, density functional theory (DFT) calculations were also conducted. Theoretical NMR chemical shifts, the relative energies and natural bond orbital (NBO) analysis are calculated within the DFT approach, while the singlet excited state energies and HOMO-LUMO energy gap were calculated with time-dependent density functional theory (TD-DFT). The electrophilic f- and nucleophilic f+ Fukui functions are well adapted to find the electrophile and nucleophile centres in the molecules. Both (1,3-selenazol-2-yl)- and (1,3-thiazol-2-yl)hydrazone Co(iii) complexes showed potent antimicrobial and antioxidant activity. A significant difference among them was a smaller cytotoxicity of selenium compounds.

The Child Health Care System of Serbia.

The health care system in Serbia is based on a network of public health institutions funded by the National Health Insurance and from the state budget. Access to public health institutions is free. Preventive and curative services are provided at the local level in primary health care centers. Over the past 5-7 years, the number of pediatricians in primary health care centers decreased because of reduced number of applicants for pediatric training, which endangers the maintenance of the traditional model of pediatric care. Secondary medical care is offered in pediatric departments of local and regional general hospitals or outpatient clinics, and in specialized hospitals for children or adults. Tertiary medical care is provided by inpatient or outpatient subspecialty services in 5 major university children's clinics. The health reforms undertaken in the recent 10 years have aimed at strengthening preventive health care and reducing the overall costs for pediatric care. Current initiatives of the Ministry of Health and national pediatric associations are aimed at reestablishing and strengthening the capacity of the primary pediatric health care model by increasing the number of physicians and developing new processes of care.

Synthesis, characterization, cytotoxicity and antiangiogenic activity of copper(II) complexes with 1-adamantoyl hydrazone bearing pyridine rings.

Three novel copper complexes with tridentate N2O ligand di(2-pyridil) ketone 1-adamantoyl hydrazone (Addpy) of the formula [Cu(II)2Cu(I)2(Addpy)2Br2(µ-Br4)] (1), catena-poly[CuCl(µ-Addpy)(µ-Cl)CuCl2]n (2) and [Cu(Addpy)(NCS)2] (3) were synthesized. Complexes are characterized by X-ray crystallography, spectral (UV-Vis, FTIR), electrochemical (CV) analyses, and magnetochemical measurements. Investigation of anticancer potential of Cu(II) complexes, mode of cell death, apoptosis, and inhibition of angiogenesis were performed. All tested malignant cell lines (HeLa, LS174, A549, K562, and MDA-MB-231) showed high sensitivity to the examined Cu(II) complexes. It has been shown that the complexes induce apoptosis in the caspase 3-dependent manner, whereas the anti-angiogenic effects of 1, 2, and 3 have been confirmed in EA.hy926 cells using a tube formation assay.

Synthesis, characterization and antitumor activity of polymeric copper(II) complexes with thiosemicarbazones of 3-methyl-5-oxo-1-phenyl-3-pyrazolin-4-carboxaldehyde and 5-oxo-3-phenyl-3-pyrazolin-4-carboxaldehyde.

New polymeric copper(II) complexes with two tridentate ONS thiosemicarbazone ligands containing substituted pyrazolone moiety were synthesized and characterized by means of spectroscopic, electrochemical and crystallographic techniques. While both ligands exist as different tautomers in the solid state and DMSO-d(6) solution, Cu(II) ion coordinates the ligands from the same tautomeric form with square-pyramidal geometry around each Cu atom. In the crystal structures, the copper(II) complex cation forms polymeric chains {[Cu(L)Cl](+)}(n) with a bridging chlorine atom. One of the complexes was found to have a significantly higher cytotoxic potential in comparison with cisplatin in inhibition of several cell lines (HL60, REH, C6, L929 and B16). The results obtained on the basis of flow cytometry indicated that apoptosis could be possible mechanism of cell death.

Synthesis, spectroscopic and X-ray characterization of a copper(II) complex with the Schiff base derived from pyridoxal and aminoguanidine: NMR spectral studies of the ligand.

A copper(II) complex with the pyridoxal-aminoguanidine (PL-AG) Schiff base adduct, as an organic compound of the very potent biological activity and promising pharmacological importance in the treatment of diabetic complications, has been prepared and characterized. The X-ray structural analysis of the [CuCl2(PL-AG)] complex showed that it has a distorted pseudo-square-pyramidal (4+1) structure with the tridentate ONN Schiff base in the equatorial plane, with the Cu-O(1), Cu-N(1) and Cu-N(3) bond lengths of 1.917(2)A, 1.930(2)A and 1.984(2)A, respectively. The bond length of the equatorial Cu-Cl(1) is 2.279(1)A, while that of the apical Cu-Cl(2) is 2.792(1)A. Pyridoxal fragment is coordinated in its zwitterionic form. In addition to the X-ray structural analysis, the complex was characterized by IR spectrometric, conductometric and magnetic techniques, and the ligand itself by IR, 1H and 13C NMR spectra.