Publications by authors named "Vladimir Savic"

57 Publications

Hepatitis E Virus in Croatia in the "One-Health" Context.

Pathogens 2021 Jun 4;10(6). Epub 2021 Jun 4.

School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.

Hepatitis E virus (HEV) is the most common cause of viral hepatitis globally. The first human case of autochthonous HEV infection in Croatia was reported in 2012, with the undefined zoonotic transmission of HEV genotype 3. This narrative review comprehensively addresses the current knowledge on the HEV epidemiology in humans and animals in Croatia. Published studies showed the presence of HEV antibodies in different population groups, such as chronic patients, healthcare professionals, voluntary blood donors and professionally exposed and pregnant women. The highest seroprevalence in humans was found in patients on hemodialysis in a study conducted in 2018 (27.9%). Apart from humans, different studies have confirmed the infection in pigs, wild boars and a mouse, indicating the interspecies transmission of HEV due to direct or indirect contact or as a foodborne infection. Continued periodical surveys in humans and animals are needed to identify the possible changes in the epidemiology of HEV infections.
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http://dx.doi.org/10.3390/pathogens10060699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227679PMC
June 2021

Lymphocytic Choriomeningitis-Emerging Trends of a Neglected Virus: A Narrative Review.

Trop Med Infect Dis 2021 May 25;6(2). Epub 2021 May 25.

Department of Immunological and Molecular Diagnostics, University Hospital for Infectious Diseases "Dr Fran Mihaljevic", 10000 Zagreb, Croatia.

Lymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne zoonotic virus distributed worldwide. Since serologic assays are limited to several laboratories, the disease has been underreported, often making it difficult to determine incidence and seroprevalence rates. Although human clinical cases are rarely recorded, LCMV remains an important cause of meningitis in humans. In addition, a fatal donor-derived LCMV infection in several clusters of solid organ transplant recipients further highlighted a pathogenic potential and clinical significance of this virus. In the transplant populations, abnormalities of the central nervous system were also found, but were overshadowed by the systemic illness resembling the Lassa hemorrhagic fever. LCMV is also an emerging fetal teratogen. Hydrocephalus, periventricular calcifications and chorioretinitis are the predominant characteristics of congenital LCMV infection, occurring in 87.5% of cases. Mortality in congenitally infected children is about 35%, while 70% of them show long-term neurologic sequelae. Clinicians should be aware of the risks posed by LCMV and should consider the virus in the differential diagnosis of aseptic meningitis, especially in patients who reported contact with rodents. Furthermore, LCMV should be considered in infants and children with unexplained hydrocephalus, intracerebral calcifications and chorioretinitis. Despite intensive interdisciplinary research efforts, efficient antiviral therapy for LCMV infection is still not available.
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http://dx.doi.org/10.3390/tropicalmed6020088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163193PMC
May 2021

Prevalence and Risk Factors for Lymphocytic Choriomeningitis Virus Infection in Continental Croatian Regions.

Trop Med Infect Dis 2021 Apr 29;6(2). Epub 2021 Apr 29.

Faculty of Medicine, Institute of Microbiology and Immunology, University of Ljubljana, 1000 Ljubljana, Slovenia.

Lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen associated with aseptic meningitis, severe systemic infections in immunocompromised persons, and congenital anomalies. Data on the prevalence of LCMV infections are scarce. We analyzed the seroprevalence of LCMV in continental Croatian regions. A total of 338 serum samples of professionally exposed (forestry workers, hunters, agriculture workers in contact with rodents) and non-exposed populations (general population, pregnant women) were tested for the presence of LCMV antibodies using indirect immunofluorescence assay. No participants reported recent febrile disease. LCMV IgG antibodies were detected in 23/6.8% of participants: 9.8% exposed persons and 5.1% non-exposed persons (6.1% in the general population and 3.9% in pregnant women). No participants were LCMV IgM positive. Although higher seropositivity was found in males compared to females (8.9% vs. 4.7%), inhabitants of suburban/rural areas compared to inhabitants of urban areas (9.2% vs. 4.6%), and persons who used well as a source of water compared to those who used tap (11.4% vs. 5.6%), these differences did not reach statistical significance. Results of logistic regression showed that the presence of rodents in the house/yard and cleaning rodent nests were associated with an elevated risk for LCMV infection (OR = 2.962, 95% CI = 1.019-8.607).
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http://dx.doi.org/10.3390/tropicalmed6020067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167717PMC
April 2021

Screening of Mosquitoes for West Nile Virus and Usutu Virus in Croatia, 2015-2020.

Trop Med Infect Dis 2021 Apr 2;6(2). Epub 2021 Apr 2.

Department of Virology, Croatian Institute of Public Health, 10000 Zagreb, Croatia.

In the period from 2015 to 2020, an entomological survey for the presence of West Nile virus (WNV) and Usutu virus (USUV) in mosquitoes was performed in northwestern Croatia. A total of 20,363 mosquitoes were sampled in the City of Zagreb and Međimurje county, grouped in 899 pools and tested by real-time RT-PCR for WNV and USUV RNA. All pools were negative for WNV while one pool each from 2016 (), 2017 ( complex), 2018 ( complex), and 2019 ( complex), respectively, was positive for USUV. The 2018 and 2019 positive pools shared 99.31% nucleotide homology within the USUV NS5 gene and both clustered within USUV Europe 2 lineage. The next-generation sequencing of one mosquito pool ( complex) collected in 2018 in Zagreb confirmed the presence of USUV and revealed several dsDNA and ssRNA viruses of insect, bacterial and mammalian origin.
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http://dx.doi.org/10.3390/tropicalmed6020045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167590PMC
April 2021

Antiviral Cytokine Response in Neuroinvasive and Non-Neuroinvasive West Nile Virus Infection.

Viruses 2021 02 22;13(2). Epub 2021 Feb 22.

Department of Virology, OIE Reference Center for West Nile Disease, Istituto Zooprofilattico Sperimentale "G. Caporale", 64100 Teramo, Italy.

Data on the immune response to West Nile virus (WNV) are limited. We analyzed the antiviral cytokine response in serum and cerebrospinal fluid (CSF) samples of patients with WNV fever and WNV neuroinvasive disease using a multiplex bead-based assay for the simultaneous quantification of 13 human cytokines. The panel included cytokines associated with innate and early pro-inflammatory immune responses (TNF-α/IL-6), Th1 (IL-2/IFN-γ), Th2 (IL-4/IL-5/IL-9/IL-13), Th17 immune response (IL-17A/IL-17F/IL-21/IL-22) and the key anti-inflammatory cytokine IL-10. Elevated levels of IFN-γ were detected in 71.7% of CSF and 22.7% of serum samples ( = 0.003). Expression of IL-2/IL-4/TNF-α and Th1 17 cytokines (IL-17A/IL-17F/IL-21) was detected in the serum but not in the CSF (except one positive CSF sample for IL-17F/IL-4). While IL-6 levels were markedly higher in the CSF compared to serum (CSF median 2036.71, IQR 213.82-6190.50; serum median 24.48, IQR 11.93-49.81; < 0.001), no difference in the IL-13/IL-9/IL-10/IFN-γ/IL-22 levels in serum/CSF was found. In conclusion, increased concentrations of the key cytokines associated with innate and early acute phase responses (IL-6) and Th1 type immune responses (IFN-γ) were found in the CNS of patients with WNV infection. In contrast, expression of the key T-cell growth factor IL-2, Th17 cytokines, a Th2 cytokine IL-4 and the proinflammatory cytokine TNF-α appear to be concentrated mainly in the periphery.
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http://dx.doi.org/10.3390/v13020342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927094PMC
February 2021

Emerging and Neglected Viruses of Zoonotic Importance in Croatia.

Pathogens 2021 Jan 15;10(1). Epub 2021 Jan 15.

Poultry Center, Croatian Veterinary Institute, 10000 Zagreb, Croatia.

Several arboviruses have emerged in Croatia in recent years. Tick-borne encephalitis is endemic in continental counties; however, new natural micro-foci have been detected. Two autochthonous dengue cases were reported in 2010. West Nile virus emerged in 2012, followed by emergence of Usutu virus in 2013. Although high seroprevalence rates of Toscana virus have been detected among residents of Croatian littoral, the virus remains neglected, with only a few clinical cases of neuroinvasive infections reported. Lymphocytic choriomeningitis virus is a neglected neuroinvasive rodent-borne virus. So far, there are no reports on human clinical cases; however, the seroprevalence studies indicate the virus presence in the Croatian mainland. Puumala and Dobrava hantaviruses are widely distributing rodent-borne viruses with sporadic and epidemic occurrence. Hepatitis E virus is an emerging food-borne virus in Croatia. After the emergence in 2012, cases were regularly recorded. Seropositivity varies greatly by region and population group. Rotaviruses represent a significant healthcare burden since rotavirus vaccination is not included in the Croatian national immunization program. Additionally, rotaviruses are widely distributed in the Croatian ecosystem. A novel coronavirus, SARS-CoV-2, emerged in February 2020 and spread rapidly throughout the country. This review focuses on emerging and neglected viruses of zoonotic importance detected in Croatia.
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http://dx.doi.org/10.3390/pathogens10010073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829938PMC
January 2021

Tick-borne encephalitis outbreak following raw goat milk consumption in a new micro-location, Croatia, June 2019.

Ticks Tick Borne Dis 2020 11 16;11(6):101513. Epub 2020 Jul 16.

Croatian Institute of Public Health, Rockefellerova 7, 10000 Zagreb, Croatia; School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia.

In June 2019, the Croatian Institute of Public Health was informed of a cluster of patients with laboratory confirmed tick-borne encephalitis (TBE) from the Gorski Kotar region. Five of the six patients with TBE reported consuming raw (unpasteurized) goat milk in the two week period before symptom onset, and one reported a recent tick bite. To assess risk factors for infection, we selected six control individuals from among healthy family and community members, and conducted a case-control analysis. None of the cases or controls were vaccinated against TBE. Individuals with TBE (cases) had 25 (95 % CI 0.8-1410.2, p = 0.021) times higher odds of raw goat milk consumption compared to healthy controls. Milk samples from 12 goats from the implicated farm were tested for the TBE virus (TBEV) using RT-PCR. TBEV RNA was not detected in the milk, but serological testing of goats and other farm animals yielded evidence of exposure to the virus: Six goats from the flock had TBEV neutralizing antibodies. Our findings suggest that the vehicle for the outbreak was raw goat milk from a single farm. Following public health advice to cease consumption of raw dairy products, no further cases have been reported.
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http://dx.doi.org/10.1016/j.ttbdis.2020.101513DOI Listing
November 2020

Cauda equina arachnoiditis - a rare manifestation of West Nile virus neuroinvasive disease: A case report.

World J Clin Cases 2020 Sep;8(17):3797-3803

Department of Virology, Croatian Institute of Public Health, Zagreb 10000, Croatia.

Background: Data regarding the neuroradiology features of the West Nile virus neuroinvasive disease (WNV NID) is rather scarce. To contribute to the knowledge of the WNV NID, we present a patient with a combination of encephalitis and acute flaccid paresis, with cauda equina arachnoiditis as the main magnetic resonance (MR) finding.

Case Summary: A 72-year-old female patient was admitted due to fever, headache and gait instability. During the first several days she developed somnolence, aphasia, urinary incontinence, constipation, and asymmetric lower extremities weakness. Cerebrospinal fluid analysis indicated encephalitis. Native brain computed tomography and MR were unremarkable, while spinal MR demonstrated cauda equina enhancement without cord lesions. Virology testing revealed WNV IgM and IgG antibodies in serum and cerebrospinal fluid, which confirmed acute WNV NID. The treatment was supportive. After two months only a slight improvement was noticed but cognitive impairment, loss of sphincter control and asymmetric inferior extremities weakness remained. The patient died after a month on chronic rehabilitation.

Conclusion: Cauda equina arachnoiditis is a rare, but possible neuroradiological feature in acute flaccid paresis form of WNV NID.
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http://dx.doi.org/10.12998/wjcc.v8.i17.3797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479571PMC
September 2020

Clinical, Virological, and Immunological Findings in Patients with Toscana Neuroinvasive Disease in Croatia: Report of Three Cases.

Trop Med Infect Dis 2020 Sep 14;5(3). Epub 2020 Sep 14.

Department of Microbiology and Infectious Diseases with Clinic, Faculty of Veterinary Medicine University of Zagreb, 10000 Zagreb, Croatia.

Toscana virus (TOSV) is an arthropod-borne virus, transmitted to humans by phlebotomine sandflies. Although the majority of infections are asymptomatic, neuroinvasive disease may occur. We report three cases of neuroinvasive TOSV infection detected in Croatia. Two patients aged 21 and 54 years presented with meningitis, while a 22-year old patient presented with meningoencephalitis and right-sided brachial plexitis. Cerebrospinal fluid (CSF), serum, and urine samples were collected and tested for neuroinvasive arboviruses: tick-borne encephalitis, West Nile, Usutu, TOSV, Tahyna, and Bhanja virus. In addition, CSF and serum samples were tested for the anti-viral cytokine response. High titers of TOSV IgM (1000-3200) and IgG (3200-10,000) antibodies in serum samples confirmed TOSV infection. Antibodies to other phleboviruses (sandfly fever Sicilian/Naples/Cyprus virus) were negative. CSF samples showed high concentrations of interleukin 6 (IL-6; range 162.32-2683.90 pg/mL), interferon gamma (IFN-γ; range 110.12-1568.07 pg/mL), and IL-10 (range 28.08-858.91 pg/mL), while significantly lower cytokine production was observed in serum. Two patients recovered fully. The patient with a brachial plexitis improved significantly at discharge. The presented cases highlight the need of increasing awareness of a TOSV as a possible cause of aseptic meningitis/meningoencephalitis during summer months. Association of TOSV and brachial plexitis with long-term sequelae detected in one patient indicates the possibility of more severe disease, even in young patients.
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http://dx.doi.org/10.3390/tropicalmed5030144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557803PMC
September 2020

Epidemiology of Usutu Virus: The European Scenario.

Pathogens 2020 Aug 26;9(9). Epub 2020 Aug 26.

OIE Reference Center for West Nile Disease, Istituto Zooprofilattico Sperimentale "G. Caporale", 64100 Teramo, Italy.

Usutu virus (USUV) is an emerging arbovirus isolated in 1959 (Usutu River, Swaziland). Previously restricted to sub-Saharan Africa, the virus was introduced in Europe in 1996. While the USUV has received little attention in Africa, the virus emergence has prompted numerous studies with robust epidemiological surveillance programs in Europe. The natural transmission cycle of USUV involves mosquitoes (vectors) and birds (amplifying hosts) with humans and other mammals considered incidental ("dead-end") hosts. In Africa, the virus was isolated in mosquitoes, rodents and birds and serologically detected in horses and dogs. In Europe, USUV was detected in bats, whereas antibodies were found in different animal species (horses, dogs, squirrels, wild boar, deer and lizards). While bird mortalities were not reported in Africa, in Europe USUV was shown to be highly pathogenic for several bird species, especially blackbirds ( and great gray owls (). Furthermore, neurotropism of USUV for humans was reported for the first time in both immunocompromised and immunocompetent patients. Epizootics and genetic diversity of USUV in different bird species as well as detection of the virus in mosquitoes suggest repeated USUV introductions into Europe with endemization in some countries. The zoonotic potential of USUV has been reported in a growing number of human cases. Clinical cases of neuroinvasive disease and USUV fever, as well as seroconversion in blood donors were reported in Europe since 2009. While most USUV strains detected in humans, birds and mosquitoes belong to European USUV lineages, several reports indicate the presence of African lineages as well. Since spreading trends of USUV are likely to continue, continuous multidisciplinary interventions ("One Health" concept) should be conducted for monitoring and prevention of this emerging arboviral infection.
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http://dx.doi.org/10.3390/pathogens9090699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560012PMC
August 2020

Synthesis, characterization, antimicrobial and cytotoxic activity of novel half-sandwich Ru(II) arene complexes with benzoylthiourea derivatives.

J Inorg Biochem 2020 09 26;210:111164. Epub 2020 Jun 26.

Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, Serbia. Electronic address:

Three new ruthenium(II)-arene complexes, [Ru(η-p-cymene)(L)Cl] (C1) where L is N-((4 methoxyphenyl)carbamothioyl)benzamide; [Ru(η-p-cymene)(L)Cl] (C2) where L is 4-(3-benzoylthioureido)benzoic acid and [Ru(η-p-cymene)(L)Cl] (C3) where L is methyl 4-(3- benzoylthioureido)benzoate have been synthetized, characterized and evaluated for their antimicrobial and anticancer activity. Characterization was performed using H and C NMR, IR spectroscopy, mass spectrometry, electrical conductivity measurements and X-Ray diffraction analysis. X-Ray diffraction analysis of C1 showed typical expected "piano-stool" geometry with ruthenium coordinated to ligand via nitrogen and sulfur atoms of benzoylthiourea derivatives. Interesting, in herein described complex, upon coordination the four-membered ring was formed, instead of six-membered chelate common for this type of ligands. Cytotoxic activity was determined in human cervix adenocarcinoma (HeLa) cell line and IC values ranged from 29.68 to 52.36 μM and the complexes were more active than related ligands (except in case of C2 where it is found that IC value is close to IC value of related ligand). Complex [Ru(η-p-cymene)(L)Cl] (C1) expressed the highest cytotoxic activity with IC value of 29.7 μM. Complexes and ligands were tested against nine Gram-positive and Gram-negative bacteria and one yeast- Candida albicans. Clinical Candida spp. strains from microbiological laboratories were included in testing processes as well. Minimum inhibitory concentrations values ranged from 62.5 μg/ml for complexes against Candida albicans to over 1000 μg/ml for several bacterial species.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111164DOI Listing
September 2020

Fatal case of West Nile encephalitis associated with acute anteroseptal ST elevation myocardial infarction (STEMI): a case report.

New Microbiol 2020 Jan 13;43(1):51-53. Epub 2019 Dec 13.

Department of Virology, Croatian Institute of Public Health, Zagreb Croatia.

Cardiac involvement has rarely been reported in West Nile (WNV) infection. We report a fatal case of WNV encephalitis associated with an acute anteroseptal ST elevation myocardial infarction. The patient was hospitalized with a fever, headache, nausea and vomiting. The physical examination revealed positive meningeal signs and an altered level of consciousness. High levels of cardiac enzymes (creatine phosphokinase/MB fraction, lactate dehydrogenase, myoglobin and cardiac troponin I) and ST elevation on electrocardiogram were found. Both CSF and urine samples were positive for WNV RNA. This case highlights the need of awareness of the possibility of a WNV-related myocardial infection, including myocardial infarction.
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January 2020

Emerging and neglected zoonoses in transplant population.

World J Transplant 2020 Mar;10(3):47-63

Department of Virology, Croatian Institute of Public Health; School of Medicine, University of Zagreb, Zagreb 10000, Croatia.

Zoonoses represent a problem of rising importance in the transplant population. A close relationship and changes between human, animal and environmental health ("One Health" concept) significantly influence the transmission and distribution of zoonotic diseases. The aim of this manuscript is to perform a narrative review of the published literature on emerging and neglected zoonoses in the transplant population. Many reports on donor-derived or naturally acquired (re-)emerging arboviral infections such as dengue, chikungunya, West Nile, tick-borne encephalitis and Zika virus infection have demonstrated atypical or more complicated clinical course in immunocompromised hosts. Hepatitis E virus has emerged as a serious problem after solid organ transplantation (SOT), leading to diverse extrahepatic manifestations and chronic hepatitis with unfavorable outcomes. Some neglected pathogens such as lymphocytic choriomeningitis virus can cause severe infection with multi-organ failure and high mortality. In addition, ehrlichiosis may be more severe with higher case-fatality rates in SOT recipients. Some unusual or severe presentations of borreliosis, anaplasmosis and rickettsioses were also reported among transplant patients. Moreover, toxoplasmosis as infectious complication is a well-recognized zoonosis in this population. Although rabies transmission through SOT transplantation has rarely been reported, it has become a notable problem in some countries. Since the spreading trends of zoonoses are likely to continue, the awareness, recognition and treatment of zoonotic infections among transplant professionals should be imperative.
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http://dx.doi.org/10.5500/wjt.v10.i3.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109593PMC
March 2020

West Nile Virus: An Emerging Threat in Transplant Population.

Vector Borne Zoonotic Dis 2020 08 31;20(8):613-618. Epub 2020 Mar 31.

School of Medicine, University of Zagreb, Zagreb, Croatia.

West Nile virus (WNV) has become one of the new challenges for transplant programs. In addition to transmission by mosquito bite, interhuman transmission is possible through blood products or organ transplantation. Majority of WNV infections present as asymptomatic or mild febrile illness, with less than 1% of infected developing neuroinvasive disease. Many studies report naturally acquired or donor-derived WNV infections in solid-organ transplant recipients, mainly kidney, but also liver, heart, lungs and pancreas. Given the much higher risk of neuroinvasive disease (40% and even higher) based on serologic and clinical studies and increased mortality in transplant population, WNV infection should be considered in all patients presented with fever and neurological symptoms after transplantation, especially during the arbovirus transmission season.
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http://dx.doi.org/10.1089/vbz.2019.2608DOI Listing
August 2020

Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS.

Molecules 2020 Mar 17;25(6). Epub 2020 Mar 17.

Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland.

Establishing the metabolism pathway of the drug undergoing the hepatic biotransformation pathway is one of the most important aspects in the preclinical discovery process since the presence of toxic or reactive metabolites may result in drug withdrawal from the market. In this study, we present the structural elucidation of six, not described yet, metabolites of an antipsychotic molecule: molindone. The elucidation of metabolites was supported with a novel photocatalytical approach with the use of WO and WS assisted photochemical reactions. An UHPLC-ESI-Q-TOF combined system was used for the registration of all obtained metabolite profiles as well as to record the high resolution fragmentation spectra of the observed transformation products. As a reference in the in vitro metabolism simulation method, the incubation with human liver microsomes was used. Chemometric comparison of the obtained profiles pointed out the use of the WO approach as being more convenient in the field of drug metabolism studies. Moreover, the photocatalysis was used in the direction of the main drug metabolite synthesis in order to further isolation and characterization.
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http://dx.doi.org/10.3390/molecules25061367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144366PMC
March 2020

Emerging Trends in the Epidemiology of West Nile and Usutu Virus Infections in Southern Europe.

Front Vet Sci 2019 6;6:437. Epub 2019 Dec 6.

OIE Reference Center for West Nile Disease, Istituto Zooprofilattico Sperimentale "G. Caporale", Teramo, Italy.

The epidemiology of West Nile (WNV) and Usutu virus (USUV) has changed dramatically over the past two decades. Since 1999, there have been regular reports of WNV outbreaks and the virus has expanded its area of circulation in many Southern European countries. After emerging in Italy in 1996, USUV has spread to other countries causing mortality in several bird species. In 2009, USUV seroconversion in horses was reported in Italy. Co-circulation of both viruses was detected in humans, horses and birds. The main vector of WNV and USUV in Europe is , however, both viruses were found in native mosquito species (). Experimental competence to transmit the WNV was also proven for native and invasive mosquitoes of and genera (). Recently, and naturally-infected with USUV were reported. While neuroinvasive human WNV infections are well-documented, USUV infections are sporadically detected. However, there is increasing evidence of a role of USUV in human disease. Seroepidemiological studies showed that USUV circulation is more common than WNV in some endemic regions. Recent data showed that WNV strains detected in humans, horses, birds, and mosquitoes mainly belong to lineage 2. In addition to European USUV lineages, some reports indicate the presence of African USUV lineages as well. The trends in WNV/USUV range and vector expansion are likely to continue in future years. This mini-review provides an update on the epidemiology of WNV and USUV infections in Southern Europe within a multidisciplinary "One Health" context.
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http://dx.doi.org/10.3389/fvets.2019.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908483PMC
December 2019

The Role of Emerging and Neglected Viruses in the Etiology of Hepatitis.

Curr Infect Dis Rep 2019 Nov 21;21(12):51. Epub 2019 Nov 21.

School of Medicine, University of Zagreb, Zagreb, Croatia.

Purpose Of Review: In this review, we present the overview of emerging and neglected viruses associated with liver involvement.

Recent Findings: Hepatitis E virus (HEV) emerged in the last two decades, causing hepatitis in many parts of the world. Moreover, liver involvement was also described in some emerging arboviral infections. Many reports showed dengue-associated liver injury; however, chikungunya, West Nile, tick-borne encephalitis, and Zika virus are rarely associated with clinically manifest liver disease. In addition, some neglected highly prevalent viruses such as adenoviruses and parvovirus B19 are capable of causing hepatitis in specific population groups. Anelloviruses (torque teno virus/torque teno mini virus/torque teno midi virus, SEN virus), human bocavirus, pegiviruses, and lymphocytic choriomeningitis virus have shown a little potential for causing hepatitis, but their role in the etiology of liver disease remains to be determined. In addition to the well-known hepatotropic viruses, many emerging and neglected viruses have been associated with liver diseases. The number of emerging zoonotic viruses has been increasingly recognized. While zoonotic potential of HEV is well documented, the recent identification of new hepatitis-related animal viruses such as HEV strains from rabbits and camels, non-primate hepaciviruses in domestic dogs and horses, as well as equine and porcine pegivirus highlights the possible zoonotic transmission in the context of "One Health." However, zoonotic potential and hepatotropism of animal hepatitis viruses remain to be determined.
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http://dx.doi.org/10.1007/s11908-019-0709-2DOI Listing
November 2019

Epidemiology of hepatitis E in South-East Europe in the "One Health" concept.

World J Gastroenterol 2019 Jul;25(25):3168-3182

Department of Virology, Croatian Institute of Public Health; School of Medicine, University of Zagreb, Zagreb 10000, Grad Zagreb, Croatia.

The significance of hepatitis E virus (HEV) as an important public health problem is rising. Until a decade ago, cases of HEV infection in Eur-ope were mainly confined to returning travelers, but nowadays, hepatitis E represents an emerging zoonotic infection in many European countries. The aim of this manuscript is to perform a systematic review of the published literature on hepatitis E distribution in humans, animals and environmental samples ("One Health" concept) in the South-Eastern European countries. Comparison of the available data showed that the anti-HEV seroprevalence in the South-Eastern Europe varies greatly, depending on the population studied, geographical area and methods used. The IgG seroprevalence rates in different population groups were found to be 1.1%-24.5% in Croatia, up to 20.9% in Bulgaria, 5.9-%17.1% in Romania, 15% in Serbia, up to 9.7% in Greece and 2%-9.7% in Albania. Among possible risk factors, older age was the most significant predictor for HEV seropositivity in most studies. Higher seroprevalence rates were found in animals. HEV IgG antibodies in domestic pigs were detected in 20%-54.5%, 29.2%-50%, 38.94%-50% and 31.1%-91.7% in Serbia, Bulgaria, Romania and Croatia, respectively. In wild boars seroprevalence rates were up to 10.3%, 30.3% and 31.1% in Romania, Slovenia and Croatia, respectively. A high HEV RNA prevalence in wild boars in some countries (Croatia and Romania) indicated that wild boars may have a key role in the HEV epidemiology. There are very few data on HEV prevalence in environmental samples. HEV RNA was detected in 3.3% and 16.7% surface waters in Slovenia and Serbia, respectively. There is no evidence of HEV RNA in sewage systems in this region. The available data on genetic characterization show that human, animal and environmental HEV strains mainly belong to the genotype 3.
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http://dx.doi.org/10.3748/wjg.v25.i25.3168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626717PMC
July 2019

West Nile virus retinitis in a patient with neuroinvasive disease.

Rev Soc Bras Med Trop 2019 05 30;52:e20190065. Epub 2019 May 30.

Department of Virology, Croatian Institute of Public Health, Zagreb, Croatia.

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http://dx.doi.org/10.1590/0037-8682-0065-2019DOI Listing
May 2019

Prevalence and molecular epidemiology of West Nile and Usutu virus infections in Croatia in the 'One health' context, 2018.

Transbound Emerg Dis 2019 Sep 26;66(5):1946-1957. Epub 2019 May 26.

OIE Reference Center for West Nile Disease, Istituto Zooprofilattico Sperimentale "G. Caporale", Teramo, Italy.

In 2018, Croatia reported the largest outbreak of West Nile virus (WNV) infections as well as the re-occurrence of human Usutu virus (USUV) infections. For the first time, fatal WNV and USUV infections were detected in wild birds. We analysed epidemiological characteristics and molecular epidemiology of WNV and USUV infections detected during 2018 transmission season. From April to November, 178 patients with neuroinvasive disease and 68 patients with febrile disease were tested for WNV and USUV. Viral RNA was detected in cerebrospinal fluid (CSF) and urine samples using a real-time RT-PCR. Positive samples were tested by nested RT-PCR and nucleotide sequencing. IgM/IgG antibodies were detected in serum/CSF samples using ELISA with confirmation of cross-reactive samples by virus neutralization test (VNT). WNV neuroinvasive disease was confirmed in 54 and WNV fever in seven patients from 10 continental Croatian counties. Areas affected in 2018 were those in which cases occurred in previous seasons, while in three areas human cases were reported for the first time. Phylogenetic analysis of six strains from patients residing in different geographic areas showed circulation of WNV lineage 2. In three patients, neuroinvasive USUV infection was confirmed by RT-PCR or VNT. Sequence analysis of one detected strain revealed USUV Europe 2 lineage. During the same period, a total of 2,574 horse and 1,069 poultry serum samples were tested for WNV antibodies using ELISA. Acute asymptomatic WNV infection (IgM antibodies) was documented in 20/0.7% horses. WNV IgG antibodies were found in 307/11.9% horses and in 125/12.7% poultry. WNV RNA was detected in two goshawks and USUV RNA was detected in one blackbird from north-western Croatia. In the Zagreb area, 3,670 female mosquitoes were collected. One Culex pipiens pool collected in July tested positive for USUV RNA. Our results highlight the importance of continuous multidisciplinary 'One health' surveillance of these emerging arboviruses.
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http://dx.doi.org/10.1111/tbed.13225DOI Listing
September 2019

Co-circulation of genetically distinct highly pathogenic avian influenza A clade 2.3.4.4 (H5N6) viruses in wild waterfowl and poultry in Europe and East Asia, 2017-18.

Virus Evol 2019 Jan 22;5(1):vez004. Epub 2019 Apr 22.

OIE/FAO/EURL International Reference Laboratory for Avian Influenza, Swine Influenza and Newcastle Disease, Animal and Plant Health Agency (APHA)-Weybridge, Addlestone, Surrey, UK.

Highly pathogenic avian influenza (HPAI) H5 clade 2.3.4.4 viruses were first introduced into Europe in late 2014 and re-introduced in late 2016, following detections in Asia and Russia. In contrast to the 2014-15 H5N8 wave, there was substantial local virus amplification in wild birds in Europe in 2016-17 and associated wild bird mortality, with evidence for occasional gene exchange with low pathogenic avian influenza (LPAI) viruses. Since December 2017, several European countries have again reported events or outbreaks with HPAI H5N6 reassortant viruses in both wild birds and poultry, respectively. Previous phylogenetic studies have shown that the two earliest incursions of HPAI H5N8 viruses originated in Southeast Asia and subsequently spread to Europe. In contrast, this study indicates that recent HPAI H5N6 viruses evolved from the H5N8 2016-17 viruses during 2017 by reassortment of a European HPAI H5N8 virus and wild host reservoir LPAI viruses. The genetic and phenotypic differences between these outbreaks and the continuing detections of HPAI viruses in Europe are a cause of concern for both animal and human health. The current co-circulation of potentially zoonotic HPAI and LPAI virus strains in Asia warrants the determination of drivers responsible for the global spread of Asian lineage viruses and the potential threat they pose to public health.
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http://dx.doi.org/10.1093/ve/vez004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476160PMC
January 2019

Rhamnolipid inspired lipopeptides effective in preventing adhesion and biofilm formation of Candida albicans.

Bioorg Chem 2019 06 14;87:209-217. Epub 2019 Mar 14.

University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, Belgrade, Serbia. Electronic address:

Rhamnolipids are biodegradable low toxic biosurfactants which exert antimicrobial and anti-biofilm properties. They have attracted much attention recently due to potential applications in areas of bioremediation, therapeutics, cosmetics and agriculture, however, the full potential of these versatile molecules is yet to be explored. Based on the facts that many naturally occurring lipopeptides are potent antimicrobials, our study aimed to explore the potential of replacing rhamnose in rhamnolipids with amino acids thus creating lipopeptides that would mimic or enhance properties of the parent molecule. This would allow not only for more economical and greener production but also, due to the availability of structurally different amino acids, facile manipulation of physico-chemical and biological properties. Our synthetic efforts produced a library of 43 lipopeptides revealing biologically more potent molecules. The structural changes significantly increased, in particular, anti-biofilm properties against Candida albicans, although surface activity of the parent molecule was almost completely abolished. Our findings show that the most active compounds are leucine derivatives of 3-hydroxy acids containing benzylic ester functionality. The SAR study demonstrated a further increase in activity with aliphatic chain elongation. The most promising lipopeptides 15, 23 and 36 at 12.5 µg/mL concentration allowed only 14.3%, 5.1% and 11.2% of biofilm formation, respectively after 24 h. These compounds inhibit biofilm formation by preventing adhesion of C. albicans to abiotic and biotic surfaces.
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http://dx.doi.org/10.1016/j.bioorg.2019.03.023DOI Listing
June 2019

Comparison of 2016-17 and Previous Epizootics of Highly Pathogenic Avian Influenza H5 Guangdong Lineage in Europe.

Emerg Infect Dis 2018 12;24(12):2270-2283

We analyzed the highly pathogenic avian influenza (HPAI) H5 epizootic of 2016-17 in Europe by epidemiologic and genetic characteristics and compared it with 2 previous epizootics caused by the same H5 Guangdong lineage. The 2016-17 epizootic was the largest in Europe by number of countries and farms affected and greatest diversity of wild birds infected. We observed significant differences among the 3 epizootics regarding region affected, epidemic curve, seasonality, and outbreak duration, making it difficult to predict future HPAI epizootics. However, we know that in 2005-06 and 2016-17 the initial peak of wild bird detections preceded the peak of poultry outbreaks within Europe. Phylogenetic analysis of 2016-17 viruses indicates 2 main pathways into Europe. Our findings highlight the need for global surveillance of viral changes to inform disease preparedness, detection, and control.
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http://dx.doi.org/10.3201/eid2412.171860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256410PMC
December 2018

Diagnostic significance of immunoglobulin G avidity in symptomatic and asymptomatic West Nile virus infection.

Rev Soc Bras Med Trop 2018 Sep-Oct;51(5):591-595

OIE Reference Centre for West Nile Disease, Istituto Zooprofilattico Sperimentale "G. Caporale", Teramo, Italy.

Introduction: West Nile virus (WNV) immunoglobulin M (IgM) antibodies have been shown to persist for up to 500 days in certain patients. To evaluate the usefulness of immunoglobulin G (IgG) avidity assessment in the diagnosis of WNV infection, we analyzed 54 WNV IgM- and/or IgG-positive serum samples from 39 patients with neuroinvasive disease and 15 asymptomatic cases tested during a seroprevalence investigation.

Methods: Serological tests (WNV IgM/IgG antibody detection, IgG avidity) were performed using commercially available enzyme-linked immunosorbent assays.

Results: WNV IgM antibodies were detected in 47 (87%) samples. Acute/recent WNV infection was confirmed based on low/borderline avidity index (AI) in 44 IgM-positive samples (93.6%). In three IgM-positive samples (6.4%), high IgG AIs were detected, thus indicating persisting IgM antibodies from previous infections. All IgM-negative samples showed high AIs. Patients with WNV neuroinvasive disease tested within 30 days showed low AIs. In six patients tested 34-50 days after disease onset, AI was borderline (42%-60%), suggesting earlier WNV IgG maturation. Samples with the highest IgM values were associated with the lowest AIs (Spearman's rho coefficient -0.767, p < 0.001).

Conclusions: Our results indicate that IgG avidity differentiates current/recent WNV infection from persistent IgM seropositivity from the previous WNV transmission season both in patients with WNV neuroinvasive disease and in asymptomatic persons. A strong negative correlation between IgM antibody levels and AI indicates that in cases with very high IgM levels, determination of IgG avidity may not be necessary. As many patients showed rapid avidity maturation, low IgG avidity is indicative of WNV infection within the previous month.
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http://dx.doi.org/10.1590/0037-8682-0482-2017DOI Listing
October 2018

In vitro antioxidant activity of thiazolidinone derivatives of 1,3-thiazole and 1,3,4-thiadiazole.

Chem Biol Interact 2018 Apr 21;286:119-131. Epub 2018 Mar 21.

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.

The initial steps in preclinical drug developing research concern the synthesis of new compounds for specific therapeutic use which needs to be confirmed by in vitro and then in vivo testing. Nine thiazolidinone derivatives (numerically labeled 1-9) classified as follows: 1,3-thiazole-based compounds (1 and 2); 1,3,4-thiadiazole based compounds (3 and 4); substituted 5-benzylideno-2-adamantylthiazol[3,2-b][1,2,4]triazol-6(5H)ones (5-8); and an ethylaminothiazole-based chalcone (9), were tested for antioxidant activity (AOA) by using three in vitro assays: DPPH (1,1-diphenyl-2-picrylhydrazyl scavenging capacity test); FRAP (ferric reducing antioxidant power test); and TBARS (thiobarbituric acid reactive substances test). Compounds 1-4 and 9 in particular are newly synthesized compounds. Also, traditional antioxidants Vitamins E and C and α-lipoic acid (α-LA) were tested. The results of DPPH testing: Vitamin C 94.35%, Vitamin E 2.99% and α-LA 1.57%; compounds: 4 33.98%; 2 18.73%; 1 15.62%; 5 6.59%; 3 4.99%; 6-9 demonstrated almost no AOA. The results of TBARS testing (% of LPO inhibition): Vitamin C 62.32%; Vitamin E 36.29%; α-LA 51.36%; compounds: 1 62.11%; 5 66.71%; 9 60.93%; 4, 6 and 7 demonstrated ∼50%; 3 and 8 displayed ∼38%; 2 23.51%. By FRAP method, Vitamins E and C showed equal AOA, ∼100%, unlike α-LA (no AOA), and AOA of the tested compounds (expressed as a fraction of the AOA of Vitamin C) were: 2 and 4-75%; 8, 3 and 1-45%; 5-7 and 9-27%. Different red-ox reaction principles between these assays dictate different AOA outcomes for a single compound. Vitamin C appeared to be the superior antioxidant out of the traditional antioxidants; and compound 4 was superior to other tested thiazolidinone derivatives. Vitamin C appeared to be the superior antioxidant out of the traditional antioxidants; and compound 4 was superior to other tested thiazolidinone derivatives. Phenyl-functionalized benzylidene, amino-carbonyl functional domains and chelating ligand properties of the thiazolidinone derivatives correlated with AOA.
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http://dx.doi.org/10.1016/j.cbi.2018.03.013DOI Listing
April 2018

Preparation of pyrrolizinone derivatives via sequential transformations of cyclic allyl imides: synthesis of quinolactacide and marinamide.

Org Biomol Chem 2018 03 7;16(12):2125-2133. Epub 2018 Mar 7.

University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia.

A facile synthetic route has been developed for the preparation of pyrrolizinone derivatives employing N-allyl imides as starting materials. The nucleophilic addition of a vinyl Grignard reagent/RCM/elimination sequence afforded pyrrolizinones in good yields and has been applied for the preparation of naturally occurring quinolactacide and marinamide.
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http://dx.doi.org/10.1039/c8ob00260fDOI Listing
March 2018

Characterization and Epidemiology of Pigeon Paramyxovirus Type-1 Viruses (PPMV-1) Isolated in Macedonia.

Avian Dis 2017 Jun;61(2):146-152

C Poultry Center, Croatian Veterinary Institute, Heinzelova 55, HR-10000 Zagreb, Croatia.

We have characterized in this study 10 PPMV-1 isolated from domestic pigeons and one PPMV-1 isolated from a feral pigeon in the period 2007-2012, using both classical methods (HI test and ICPI test) and molecular methods (RT-qPCR, RT-PCR, and nucleotide sequencing). Using phylogenetic analysis of partial fusion gene sequences, these viruses clustered with recent European PPMV-1 isolates (EU/re) within the genotype VIb/1. All isolates possessed virulent cleavage site motifs with variable morbidity and mortality in pigeons. The intracerebral pathogenecity indices of the five isolates ranged from 0.59 to 1.53. The repetitive isolation of PPMV-1 viruses for several consecutive years led toward establishing enzootic presence of the disease in pigeons. A high nucleotide sequence homology between the Macedonian isolates and EU/re isolates was shown. Co-circulation of different isolates in the same holdings was detected. This is the first study to extensively describe the molecular epidemiology of PPMV-1 isolated in Macedonia.
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http://dx.doi.org/10.1637/11517-101816-Reg.1DOI Listing
June 2017

An overview of mosquitoes and emerging arboviral infections in the Zagreb area, Croatia.

J Infect Dev Ctries 2016 Dec 30;10(12):1286-1293. Epub 2016 Dec 30.

Andrija Stampar Teaching Institute of Public Health, Zagreb, Croatia.

Mosquito control in the Zagreb area has been conducted for many years, whereas the fauna has only been investigated in the last 20 years. So far 30 mosquito species have been detected in the city area. Culex pipiens form molestus is the dominant mosquito species in indoor breeding sites. In forested areas and areas exposed to flooding, the active period is early spring and the dominant species are Ochlerotatus sticticus, Ochlerotatus cantans, Ochlerotatus geniculatus and Aedes vexans. The eudominant mosquito species found in the artificial breeding sites are Culex pipiens and the Asian tiger mosquito, Aedes albopictus. Invasive Ae. albopictus, present in the Zagreb area since 2004, has expanded to a larger area of the city during the last three years. The recent emergence of the human West Nile virus and Usutu virus neuroinvasive disease in Zagreb and its surroundings highlighted the role of mosquitoes as vectors of emerging arboviruses. The paper focuses on mosquito species and arboviral infections detected in humans and animals in the Zagreb area, Croatia.
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http://dx.doi.org/10.3855/jidc.7988DOI Listing
December 2016
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