Publications by authors named "Francesca Bugli"

48 Publications

Disentangling the Possible Drivers of Microbiome: A Threatened Lemur Species of Madagascar.

Front Microbiol 2021 6;12:668274. Epub 2021 Aug 6.

Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy.

Research on the gut microbiome may help with increasing our understanding of primate health with species' ecology, evolution, and behavior. In particular, microbiome-related information has the potential to clarify ecology issues, providing knowledge in support of wild primates conservation and their associated habitats. Indri () is the largest extant living lemur of Madagascar. This species is classified as "critically endangered" by the IUCN Red List of Threatened Species, representing one of the world's 25 most endangered primates. Indris diet is mainly folivorous, but these primates frequently and voluntarily engage in geophagy. Indris have never been successfully bred under human care, suggesting that some behavioral and/or ecological factors are still not considered from the conservation protocols. Here, we explored gut microbiome composition of 18 indris belonging to 5 different family groups. The most represented phyla were Proteobacteria 40.1 ± 9.5%, Bacteroidetes 28.7 ± 2.8%, Synergistetes 16.7 ± 4.5%, and Firmicutes 11.1 ± 1.9%. Further, our results revealed that bacterial alpha and beta diversity were influenced by indri family group and sex. In addition, we investigated the chemical composition of geophagic soil to explore the possible ecological value of soil as a nutrient supply. The quite acidic pH and high levels of secondary oxide-hydroxides of the soils could play a role in the folivorous diet's gut detoxification activity. In addition, the high contents of iron and manganese found the soils could act as micronutrients in the indris' diet. Nevertheless, the concentration of a few elements (i.e., calcium, sulfur, boron, nickel, sodium, and chromium) was higher in non-geophagic than in geophagic soils. In conclusion, the data presented herein provide a baseline for outlining some possible drivers responsible for the gut microbiome diversity in indris, thus laying the foundations for developing further strategies involved in indris' conservation.
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http://dx.doi.org/10.3389/fmicb.2021.668274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378179PMC
August 2021

Metal-Free Antibacterial Additives Based on Graphene Materials and Salicylic Acid: From the Bench to Fabric Applications.

ACS Appl Mater Interfaces 2021 Jun 26;13(22):26288-26298. Epub 2021 May 26.

Department of Chemistry "Ugo Schiff", Università di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy.

The custom functionalization of a graphene surface allows access to engineered nanomaterials with improved colloidal stability and tailored specific properties, which are available to be employed in a wide range of applications ranging from materials to life science. The high surface area and their intrinsic physical and biological properties make reduced graphene oxide and graphene oxide unique materials for the custom functionalization with bioactive molecules by exploiting different surface chemistries. In this work, preparation (on the gram scale) of reduced graphene oxide and graphene oxide derivatives functionalized with the well-known antibacterial agent salicylic acid is reported. The salicylic acid functionalities offered a stable colloidal dispersion and, in addition, homogeneous absorption on a sample of textile manufacture (i.e., cotton fabrics), as shown by a Raman spectroscopy study, thus providing nanoengineered materials with significant antibacterial activity toward different strains of microorganisms. Surprisingly, graphene surface functionalization also ensured resistance to detergent washing treatments as verified on a model system using the quartz crystal microbalance technique. Therefore, our findings paved the way for the development of antibacterial additives for cotton fabrics in the absence of metal components, thus limiting undesirable side effects.
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http://dx.doi.org/10.1021/acsami.1c02330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289172PMC
June 2021

Is the Antimicrobial Activity of Hydrolates Lower than That of Essential Oils?

Antibiotics (Basel) 2021 Jan 18;10(1). Epub 2021 Jan 18.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy.

Among the top five human infections requiring medical treatment is dermatitis. Treatment of bacterial and fungal skin infections is usually based on antibiotic therapy, which is often ineffective due to the involvement of antibiotic-resistant microbial strains. The aim of this study was to compare the antimicrobial activity of essential oils (EOs) and hydrolates (Hys) extracted from six aromatic plants grown in Italy ( and ) towards fungal (, , and ; , , , and ) and bacterial strains ( MRSA, MSSA, , VRE, and ) potentially pathogenic for human skin. The composition and antimicrobial activity of EOs and Hys were evaluated using the Gas-chromatography mass spectrometry and micro dilution-broth test, respectively. The volatiles' conversion factors (CFs) were calculated to compare the activity of Hys with that of the corresponding EOs. Data show that, although the minimum inhibitory concentration values of EOs are lower than the corresponding Hys, the volatiles contained in Hys are more effective at inhibiting microbial growth because they are active at lower concentrations.
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http://dx.doi.org/10.3390/antibiotics10010088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831920PMC
January 2021

I Like the Way You Eat It: Lemur (Indri indri) Gut Mycobiome and Geophagy.

Microb Ecol 2021 Jul 20;82(1):215-223. Epub 2021 Jan 20.

Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.

Here, we investigated the possible linkages among geophagy, soil characteristics, and gut mycobiome of indri (Indri indri), an endangered lemur species able to survive only in wild conditions. The soil eaten by indri resulted in enriched secondary oxide-hydroxides and clays, together with a high concentration of specific essential micronutrients. This could partially explain the role of the soil in detoxification and as a nutrient supply. Besides, we found that soil subject to geophagy and indris' faeces shared about 8.9% of the fungal OTUs. Also, several genera (e.g. Fusarium, Aspergillus and Penicillium) commonly associated with soil and plant material were found in both geophagic soil and indri samples. On the contrary, some taxa with pathogenic potentials, such as Cryptococcus, were only found in indri samples. Further, many saprotrophs and plant-associated fungal taxa were detected in the indri faeces. These fungal species may be involved in the digestion processes of leaves and could have a beneficial role in their health. In conclusion, we found an intimate connection between gut mycobiome and soil, highlighting, once again, the potential consequent impacts on the wider habitat.
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http://dx.doi.org/10.1007/s00248-020-01677-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282574PMC
July 2021

Re-evaluating positive serum samples for SARS-CoV-2-specific IgA and IgG antibodies using an in-house serological assay.

Clin Microbiol Infect 2021 Jan 2. Epub 2021 Jan 2.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

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http://dx.doi.org/10.1016/j.cmi.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836636PMC
January 2021

Impact of the Trophic Effects of the Secretome From a Multistrain Probiotic Preparation on the Intestinal Epithelia.

Inflamm Bowel Dis 2021 05;27(6):902-913

Università Cattolica del Sacro Cuore, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Rome, Italy.

Background: Probiotics are defined as live, nonpathogenic bacteria that confer health benefits beyond their nutritional value. In particular, VSL#3 exhibits demonstrated efficacy in the management of diseases characterized by an increased intestinal permeability. Our study aimed to understand how VSL#3 promotes gut health by secreting bioactive factors and identify which human pathways are modulated by secretome derived from the VSL#3 formula.

Methods: Two different lots of VSL#3 were used, and Caco-2 cell line was treated with conditioned media (CM) prepared using 1 g of the probiotic formula. We evaluated the effects of the probiotics on cellular proliferation and apoptosis by cytometry and the expression of tight junction proteins by western blotting. A proteomics analysis of both culture media and the whole proteome of Caco-2 cells treated with VSL#3-CM was performed by nano-ultra performance liquid chromatography - tandem mass (nUPLC MS/MS) spectrometry.

Results: The probiotic formula increased cell proliferation, decreased cellular apoptosis cells, and increased re-epithelialization in the scratch assay. Several peptides specifically synthetized by all the species within the probiotic preparation were recognized in the proteomics analysis. Human proteins synthesized by CaCo-2 cells were also identified.

Conclusions: To our knowledge, this manuscript describes the first evaluation of the probiotic secretome, and the results showed that the improvement in intestinal barrier functions induced by probiotics seems to be accompanied by the modulation of some human cellular pathways.
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http://dx.doi.org/10.1093/ibd/izaa298DOI Listing
May 2021

Is aromatherapy effective in obstetrics? A systematic review and meta-analysis.

Phytother Res 2020 Dec 9. Epub 2020 Dec 9.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.

The aim of this systematic review is to collect clinical trials conducted using essential oils (EOs) in obstetric symptoms by evaluating if and in which context the aromatherapy practice is effective in obstetrics. The research was conducted by using the databases of EMBASE, Medline, Biosis and Toxcenter, PubMed, and Google Scholar search engine, selecting articles from January 2004 to July 2020. This study was performed according to the MOOSE and PRISMA guidelines. Only the randomized clinical trials were considered, and in cases of multiple publications, it was considered the most up to date information. Biases were highlighted. In the presence of homogeneous data, pooling statistics and meta-analysis were applied. The research led to 71 articles, 17 of which were eligible. Among the trials selected, eight investigated the effectiveness of EOs on anxiety, depression, and stress. Two concerned the treatment of nausea and vomiting, six evaluated the application of EOs on labor for pain treatment, and two showed the effectiveness in the treatment of episiotomy. The heterogeneity of works carried out so far has made it possible to develop a meta-analysis only in the field of pain treatment during childbirth, identifying the effectiveness of the EOs Lavandula spp. and Rosa damascena.
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http://dx.doi.org/10.1002/ptr.6975DOI Listing
December 2020

Phytocomplex Influences Antimicrobial and Health Properties of Concentrated Glycerine Macerates.

Antibiotics (Basel) 2020 Dec 1;9(12). Epub 2020 Dec 1.

Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy.

The purpose of this study was to correlate the chemical composition of four commercial concentrated glycerine macerates (C-GMs), produced through the same extraction method, with their in vitro antimicrobial, antioxidant, and immunomodulatory properties, in order to evaluate their potential for healing upper airway diseases. C-GMs of (CB), (FC), (AG) and (RN) were studied. The quality was evaluated using HPLC and IM-SPME/GC-MS systems; anti-oxidant and anti-microbial activities were assessed by the respective DPPH test, and micro-broth dilution test performed against 10 strains of and 10 probiotic strains. ELISA and MTT tests were used to assess the immunomodulatory activity and the cytotoxicity of C-GMs, respectively. A significant correlation was found between the number of active compounds and the in vitro C-GMs effectiveness. Furthermore, the C-GMs of AG showed the best anti-microbial activity on pathological strains and, together with CB, the best anti-oxidant activity. The ELISA test exhibited a good immunomodulatory activity of RN. In vitro data support the integrated use of C-GMs of CB, AG, and RN in presence of airway diseases, and highlight the importance of standard procedures in cultivation, harvest and post-harvest treatments, as a premise for C-GMs with consistent characteristics.
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http://dx.doi.org/10.3390/antibiotics9120858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760747PMC
December 2020

Essential Oil vs. a Commercial Mixture of Essential Oils: In Vitro Effectiveness on spp. from Poultry and Swine Intensive Livestock.

Antibiotics (Basel) 2020 Oct 31;9(11). Epub 2020 Oct 31.

Dipartimento di Scienze e Tecnologie Agro-Alimentari, Università di Bologna, Viale G. Fanin 42, 40127 Bologna, Italy.

spp. represent a public health concern for humans and animals due to the increase of antibiotic resistances. In this scenario, the use of essential oils (EOs) could be a valid tool against contamination of meat. This work compares the in vitro effectiveness of an Italian mixture of feed additives based on EOs (GR-OLI) with EO of L., recently admitted by European Food Safety Authority (EFSA) for animal use. Twenty-nine serotypes isolated from poultry and pig farms were used to assess GR-OLI and EO antimicrobial propeties. EO was active on the disaggregation of mature biofilm, while GR-OLI was capable of inhibiting biofilm formation and disaggregating preformed biofilm. Furthermore, GR-OLI inhibited bacterial adhesion to Caco-2 cells in a dose-dependent manner. Both products showed inhibition of bacterial growth at all time points tested. Finally, the synergistic action of GR-OLI with commonly used antibiotics against resistant strains was investigated. In conclusion, the mixture could be used both to reduce the meat contamination of spp. before slaughter, and in synergy with low doses of ciprofloxacin against resistant strains. Although EOs as feed additives are already used in animal husbandry, no scientific study has ever highlighted their real antimicrobial potential.
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http://dx.doi.org/10.3390/antibiotics9110763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693145PMC
October 2020

Antimicrobial and Antibiofilm Properties of Graphene Oxide on .

Antibiotics (Basel) 2020 Oct 13;9(10). Epub 2020 Oct 13.

Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 20123 Rome, Italy.

The aim of this study was to evaluate the antibacterial properties of graphene oxide (GO) against in vitro conditions and when used to coat dentin surface to prevent adhesion. The ATCC strain of 29212 has been used to perform a viability test. The pellet was suspended in ultrapure water, NaCl, PBS buffer, CaCl and MgCl, Luria-Bertani broth solutions. The viability was evaluated by the colony forming unit counting method. Atomic force microscopy images and the measure of surface zeta potential variation were analyzed. Dentin discs were covered with a film of GO ( = 15) or were not treated ( = 15). Bacterial suspension was added to each sample of dentine discs and microbial counts were calculated. Statistically significant differences between two groups were assessed by a two-tailed unpaired -test. Bacteria cell morphology was investigated with scanning electron microscopy. The highest growth inhibition was obtained in ddHO and CaCl solution while, in PBS and NaCl, GO had poor antibacterial efficacy with a growth enhancing effect in the latter. GO on dentin discs demonstrated high antibacterial activity. GO film has demonstrated acceptable adhesion properties to root dentin and a role in the inhibition of bacterial film proliferation and biofilm formation.
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http://dx.doi.org/10.3390/antibiotics9100692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602102PMC
October 2020

DDX3X inhibitors, an effective way to overcome HIV-1 resistance targeting host proteins.

Eur J Med Chem 2020 Aug 7;200:112319. Epub 2020 May 7.

Istituto di Genetica Molecolare "Luigi Luca Cavalli - Sforza", IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy. Electronic address:

The huge resources that had gone into Human Immunodeficiency virus (HIV) research led to the development of potent antivirals able to suppress viral load in the majority of treated patients, thus dramatically increasing the life expectancy of people living with HIV. However, life-long treatments could result in the emergence of drug-resistant viruses that can progressively reduce the number of therapeutic options, facilitating the progression of the disease. In this scenario, we previously demonstrated that inhibitors of the human DDX3X helicase can represent an innovative approach for the simultaneous treatment of HIV and other viral infections such as Hepatitis c virus (HCV). We reported herein 6b, a novel DDX3X inhibitor that thanks to its distinct target of action is effective against HIV-1 strains resistant to currently approved drugs. Its improved in vitro ADME properties allowed us to perform preliminary in vivo studies in mice, which highlighted optimal biocompatibility and an improved bioavailability. These results represent a significant advancement in the development of DDX3X inhibitors as a novel class of broad spectrum and safe anti-HIV-1 drugs.
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http://dx.doi.org/10.1016/j.ejmech.2020.112319DOI Listing
August 2020

Potent Activity of Essential Oil and Hydrolate Against Gut Yeast Isolates from Irritable Bowel Syndrome Patients-The Right Mix for Potential Therapeutic Use.

Nutrients 2020 May 7;12(5). Epub 2020 May 7.

Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy.

Background: Irritable bowel syndrome (IBS) is a functional disorder without any pathological alteration, in which the alterations of the /s ratio of the gut microbiota, the balance of pro and anti-inflammatory cytokines and the brain-gut-microbiome axis are important for the development and progression of IBS. The aim of the study was to identify natural products, including essential oils or hydrolates, which were contextually harmless for the gut beneficial strains (e.g. spp.) but inhibitory for the pathogenic ones ( spp.).

Methods: The effectiveness of 6 essential oils and 2 hydrolates was evaluated using microbiological tests, carried out on 50 clinical isolates (, and species) and 9 probiotic strains (, , and ) and immunological and antioxidant assays.

Results: The study led to a mixture based on a 1/100 ratio of var. essential oil / cv Italia hydrolate able to contextually reduce, in a concentration-dependent manner, the ability of species to form hyphal filaments and have an interesting immunomodulatory and anti-oxidant action. This mixture can potentially be useful in the IBS treatment promoting the restoration of the intestinal microbial and immunological balance.
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http://dx.doi.org/10.3390/nu12051329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284808PMC
May 2020

Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis.

Front Bioeng Biotechnol 2019 17;7:406. Epub 2019 Dec 17.

Institute of Science and Technology for Ceramics (ISTEC), National Research Council (CNR), Faenza, Italy.

Cystic fibrosis (CF) is a genetic disease affecting today nearly 70,000 patients worldwide and characterized by a hypersecretion of thick mucus difficult to clear arising from the defective CFTR protein. The over-production of the mucus secreted in the lungs, along with its altered composition and consistency, results in airway obstruction that makes the lungs susceptible to recurrent and persistent bacterial infections and endobronchial chronic inflammation, which are considered the primary cause of bronchiectasis, respiratory failure, and consequent death of patients. Despite the difficulty of treating the continuous infections caused by pathogens in CF patients, various strategies focused on the symptomatic therapy have been developed during the last few decades, showing significant positive impact on prognosis. Moreover, nowadays, the discovery of CFTR modulators as well as the development of gene therapy have provided new opportunity to treat CF. However, the lack of effective methods for delivery and especially targeted delivery of therapeutics specifically to lung tissues and cells limits the efficiency of the treatments. Nanomedicine represents an extraordinary opportunity for the improvement of current therapies and for the development of innovative treatment options for CF previously considered hard or impossible to treat. Due to the peculiar environment in which the therapies have to operate characterized by several biological barriers (pulmonary tract, mucus, epithelia, bacterial biofilm) the use of nanotechnologies to improve and enhance drug delivery or gene therapies is an extremely promising way to be pursued. The aim of this review is to revise the currently used treatments and to outline the most recent progresses about the use of nanotechnology for the management of CF.
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http://dx.doi.org/10.3389/fbioe.2019.00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927921PMC
December 2019

In vitro characterization, ADME analysis, and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains.

Int J Antimicrob Agents 2020 Mar 20;55(3):105865. Epub 2019 Dec 20.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Philadelphia, PA 19122, USA.

Background: Candida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains.

Objective: A compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety.

Methods: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution.

Results: The current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains.

Conclusions: The results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.105865DOI Listing
March 2020

Graphene Oxide Coatings as Tools to Prevent Microbial Biofilm Formation on Medical Device.

Adv Exp Med Biol 2020 ;1282:21-35

Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

The clinical challenge on surface engineering of medical devices to prevent microorganisms adhesion and biofilm formation, has become an essential aspect for medical implants. Antibacterial properties of Graphene Oxide (GO) have been demonstrated across a broad spectrum of bacteria, and the different mechanisms of action with which this nanomaterial interacts with the microbial surface have been elucidated in detail. Innovative protective coatings based on graphene film and hydrogel could represent an innovative solution for the prevention of nosocomial pathogens colonization on implantable device. This brief review mainly focuses on the applications of graphene in nanomedicine with a particular deepening on the antibacterial properties of GO and GO-based nanomaterials. In order to evaluate the possible future applications of GO as an anti-biofilm coating material for medical devices, studies on the ability of graphene coated surface to prevent microbial adhesion are also discussed. A concise review on in vitro toxicity and in vivo safety is also presented.
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http://dx.doi.org/10.1007/5584_2019_434DOI Listing
December 2020

Antibiofilm Activity of Three Different Irrigation Techniques: An in Vitro Study.

Antibiotics (Basel) 2019 Aug 9;8(3). Epub 2019 Aug 9.

Unità Operativa Complessa (UOC) Odontoiatria Generale e Ortodonzia, Dipartimento Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa Collo. Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00168 Rome, Italy.

The microbial infection of the endodontic space occurs in a necrotic tooth as a result of dental caries, trauma, periodontal disease, or previous root canal therapy. The disruption of the biofilms and the reduction of the bacterial load inside root canals are crucial for the success of root canal therapy. The aim of this study was to compare, in vitro, the antibiofilm efficacy of a novel passive sonic irrigation (PSI) device with passive ultrasonic irrigation (PUI) and conventional needle irrigation (CNI). Forty-four single-rooted human teeth were inoculated with a culture of for 28 days. The specimens were randomly divided into three groups: PUI, CNI, and PSI ( = 12). The activation protocols were performed using both 17% EDTA and 5.25% NaOCl. Residual bacterial biofilm was taken by means of a canal brush and colony-forming unit (CFU) were counted. The data were analyzed using one-way ANOVA and Games-Howell's post hoc tests. A major reduction in CFU was observed in the PSI and PUI groups, in comparison with the CNI group. No difference was found ( > 0.05) in terms of CFU reduction between PSI and PUI. PSI could be as effective as PUI in the removal of bacterial biofilms from straight root canals.
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http://dx.doi.org/10.3390/antibiotics8030112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784003PMC
August 2019

A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-]Pyrimidine Dual Src/P-Glycoprotein Inhibitor.

Cancers (Basel) 2019 Jun 19;11(6). Epub 2019 Jun 19.

Department of Pharmacy, Università degli Studi di Genova, 16132 Genova, Italy.

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells' membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.
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http://dx.doi.org/10.3390/cancers11060848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628362PMC
June 2019

Fish-derived antimicrobial peptides: Activity of a chionodracine mutant against bacterial models and human bacterial pathogens.

Dev Comp Immunol 2019 07 18;96:9-17. Epub 2019 Feb 18.

Department for Innovation in Biological, Agrofood and Forest Systems, University of Tuscia, Viterbo, Italy. Electronic address:

The increasing resistance to conventional antibiotics is an urgent problem that can be addressed by the discovery of new antimicrobial drugs such as antimicrobial peptides (AMPs). AMPs are components of innate immune system of eukaryotes and are not prone to the conventional mechanisms that are responsible of drug resistance. Fish are an important source of AMPs and, recently, we have isolated and characterized a new 22 amino acid residues peptide, the chionodracine (Cnd), from the Antarctic icefish Chionodraco hamatus. In this paper we focused on a new Cnd-derived mutant peptide, namely Cnd-m3a, designed to improve the selectivity against prokaryotic cells and the antimicrobial activity against human pathogens of the initial Cnd template. Cnd-m3a was used for immunization of rabbits, which gave rise to a polyclonal antibody able to detect the peptide. The interaction kinetic of Cnd-m3a with the Antarctic bacterium Psychrobacter sp. (TAD1) was imaged using a transmission electron microscopy (TEM) immunogold method. Initially the peptide was associated with the plasma membrane, but after 180 min of incubation, it was found in the cytoplasm interacting with a DNA target inside the bacterial cells. Using fluorescent probes we showed that the newly designed mutant can create pores in the outer membrane of the bacteria E. coli and Psychrobacter sp. (TAD1), confirming the results of TEM analysis. Moreover, in vitro assays demonstrated that Cnd-m3a is able to bind lipid vesicles of different compositions with a preference toward negatively charged ones, which mimics the prokaryotic cell. The Cnd-m3a peptide showed quite low hemolytic activity and weak cytotoxic effect against human primary and tumor cell lines, but high antimicrobial activity against selected Gram - human pathogens. These results highlighted the high potential of the Cnd-m3a peptide as a starting point for developing a new human therapeutic agent.
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http://dx.doi.org/10.1016/j.dci.2019.02.012DOI Listing
July 2019

A protein chimera self-assembling unit for drug delivery.

Biotechnol Prog 2019 03 27;35(2):e2769. Epub 2018 Dec 27.

Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Rome, Italy.

In the modern view of selective drug delivery of bioactive molecules, the attention is moving onto the setup of the perfect carrier more than in the optimization of the active compound. In this respect, virus-like particles constitute bioinspired nanodevices with the intrinsic ability to transport a large class of molecules, ranging from smart drugs to small interfering RNAs. In this work, we demonstrate the efficacy of a novel construct obtained by fusing a self-assembling protein from the human Rotavirus A, VP6, with the Small Ubiquitin Modifier domain, which maintains the ability to form nanoparticles and nanotubes and is able to be used as a drug carrier, even without specific targeting epitopes. The high expression and purification yield, combined with low toxicity of the empty particles, clearly indicate a good candidate for future studies of selective drug delivery. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2769, 2019.
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http://dx.doi.org/10.1002/btpr.2769DOI Listing
March 2019

Graphene oxide coatings prevent Candida albicans biofilm formation with a controlled release of curcumin-loaded nanocomposites.

Nanomedicine (Lond) 2018 11 15;13(22):2867-2879. Epub 2018 Nov 15.

Fondazione Policlinico A. Gemelli IRCCS - Università Cattolica Sacro Cuore. Istituto di Fisica, Largo Francesco Vito 1, 00168, Rome, Italy.

Aim: Fabrication of graphene oxide (GO)-based medical devices coatings that limit adhesion of Candida albicans, a main issue of healthcare-associated infections.

Methods: The GO composites noncovalently functionalized with curcumin (CU), a hydrophobic molecule with active antimicrobial action, polyethylene glycol (PEG) that hinders the absorption of biomolecules or a combination of CU and PEG (GO-CU-PEG) were drop-casted on surfaces and antifungal efficacy was assessed.

Results: We demonstrate that GO-CU-PEG coatings can reduce fungal adhesion, proliferation and biofilm formation. Furthermore, in an aqueous environment, surfaces release curcumin-PEG nanocomposites that have a minimum inhibitory concentration of 9.25 μg/ml against C. albicans.

Conclusion: Prevention of early cell adhesion and creation of a proximal environment unfavorable for growth make these GO-supported biomaterials attractive for innovative medical device manufacturing.
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http://dx.doi.org/10.2217/nnm-2018-0183DOI Listing
November 2018

Expression profiling in a mammalian host reveals the strong induction of genes encoding LysM domain-containing proteins in Enterococcus faecium.

Sci Rep 2018 08 17;8(1):12412. Epub 2018 Aug 17.

Normandie Univ, UNICAEN, U2RM-Stress and Virulence, 14000, Caen, France.

Enterococcus faecium is an important health care-associated pathogen that is difficult to treat due to the high level of antibiotic resistance of clinical isolates. The identification of new potential therapeutic targets or vaccination strategies is therefore urgently needed. In this regard, we carried out a transcriptomic analysis of the E. faecium vancomycin-resistant strain AUS0004, comparing the gene expression of bacteria grown under laboratory conditions and bacteria isolated from an infection site. This analysis highlighted more than 360 genes potentially induced under infection conditions. Owing to their expression profiles, four LysM domain-containing proteins were characterized in more detail. The EFAU004_01059, 1150 and 494 proteins are highly homologous, whereas EFAU004_01209 has a unique domain-architecture and sequence. The analysis of corresponding mutants showed that all LysM proteins played relevant roles in the infection process of E. faecium in mice. The EFAU004_01209 mutant also displayed profound morphological modifications, suggesting it has a role in cell wall synthesis or cell division. Furthermore, the adhesion to kidney cells and growth of the mutant was affected in human urine. All these phenotypes and the surface exposure of EFAU004_01209 identify this protein as an interesting new drug target in E. faecium.
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http://dx.doi.org/10.1038/s41598-018-30882-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098018PMC
August 2018

Erratum: Biomimetic antimicrobial cloak by graphene-oxide agar hydrogel.

Sci Rep 2017 06 1;7(1):2779. Epub 2017 Jun 1.

Institute for Complex Systems, National Research Council (ISC-CNR), Via dei Taurini 19, 00185, Rome, Italy.

A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-017-00063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453989PMC
June 2017

Different effects of matrix degrading enzymes towards biofilms formed by E. faecalis and E. faecium clinical isolates.

Colloids Surf B Biointerfaces 2017 Oct 9;158:349-355. Epub 2017 Jul 9.

Institute of Microbiology, Università Cattolica del SC, L.go F. Vito 1, 00168, Roma, Italy.

E. faecalis and E. faecium cause urinary tract infections highly resistant to therapies due to a protective extracellular matrix. To exploit a new strategy able to treat infections without increasing antibiotic doses, we used enzymes targeting specific biofilm matrix components in combination with Vancomycin. We investigated the activity of Vancomycin combined with two matrix-degrading enzymes, Alginate Lyase (AlgL) and Deoxyribonuclease I (DNase I) against in vitro biofilm of E. faecalis and E. faecium clinical isolates. The heterogeneity of matrix composition leads to defined physiological responses of biofilm communities to their environment: we demonstrated that the use of DNase I and AlgL enzymes affects biofilm structure, cell viability and reduces MBEC values of Vancomycin in E. faecalis and E. faecium, respectively.
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http://dx.doi.org/10.1016/j.colsurfb.2017.07.010DOI Listing
October 2017

The Enterococcus faecalis virulence factor ElrA interacts with the human Four-and-a-Half LIM Domains Protein 2.

Sci Rep 2017 07 4;7(1):4581. Epub 2017 Jul 4.

Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

The commensal bacterium Enterococcus faecalis is a common cause of nosocomial infections worldwide. The increasing prevalence of multi-antibiotic resistant E. faecalis strains reinforces this public health concern. Despite numerous studies highlighting several pathology-related genetic traits, the molecular mechanisms of E. faecalis virulence remain poorly understood. In this work, we studied 23 bacterial proteins that could be considered as virulence factors or involved in the Enterococcus interaction with the host. We systematically tested their interactions with human proteins using the Human ORFeome library, a set of 12,212 human ORFs, in yeast. Among the thousands of tested interactions, one involving the E. faecalis virulence factor ElrA and the human protein FHL2 was evidenced by yeast two-hybrid and biochemically confirmed. Further molecular characterizations allowed defining an FHL2-interacting domain (FID) of ElrA. Deletion of the FID led to an attenuated in vivo phenotype of the mutated strain clearly indicating that this interaction is likely to contribute to the multifactorial virulence of this opportunistic pathogen. Altogether, our results show that FHL2 is the first host cellular protein directly targeted by an E. faecalis virulence factor and that this interaction is involved in Enterococcus pathogenicity.
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http://dx.doi.org/10.1038/s41598-017-04875-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496941PMC
July 2017

Biomimetic antimicrobial cloak by graphene-oxide agar hydrogel.

Sci Rep 2016 Dec 5;6(1):12. Epub 2016 Dec 5.

Institute for Complex Systems, National Research Council (ISC-CNR), Via dei Taurini 19, 00185, Rome, Italy.

Antibacterial surfaces have an enormous economic and social impact on the worldwide technological fight against diseases. However, bacteria develop resistance and coatings are often not uniform and not stable in time. The challenge is finding an antibacterial coating that is biocompatible, cost-effective, not toxic, and spreadable over large and irregular surfaces. Here we demonstrate an antibacterial cloak by laser printing of graphene oxide hydrogels mimicking the Cancer Pagurus carapace. We observe up to 90% reduction of bacteria cells. This cloak exploits natural surface patterns evolved to resist to microorganisms infection, and the antimicrobial efficacy of graphene oxide. Cell integrity analysis by scanning electron microscopy and nucleic acids release show bacteriostatic and bactericidal effect. Nucleic acids release demonstrates microorganism cutting, and microscopy reveals cells wrapped by the laser treated gel. A theoretical active matter model confirms our findings. The employment of biomimetic graphene oxide gels opens unique possibilities to decrease infections in biomedical applications and chirurgical equipment; our antibiotic-free approach, based on the geometric reduction of microbial adhesion and the mechanical action of Graphene Oxide sheets, is potentially not affected by bacterial resistance.
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http://dx.doi.org/10.1038/s41598-016-0010-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431354PMC
December 2016

Bacteria Meet Graphene: Modulation of Graphene Oxide Nanosheet Interaction with Human Pathogens for Effective Antimicrobial Therapy.

ACS Biomater Sci Eng 2017 Apr 2;3(4):619-627. Epub 2017 Mar 2.

Physics Institute, Catholic University of Sacred Hearth, Largo Francesco Vito 1, 00168 Rome, Italy.

The development of new pharmacological strategies that evade bacterial resistance has become a compelling worldwide challenge. Graphene oxide (GO) can represent the nanotechnology answer being economical and easy to produce and to degrade and having multitarget specificity against bacteria. Several groups tried to define the interaction between GO sheets and human pathogens. Unfortunately, controversial results from inhibition to bacterial growth enhancement have been reported. The main difference among all experimental evidence relies on the environmental conditions adopted to study the bacteria-GO interaction. Indeed GO, stable in deionized water, undergoes a rapid and salt-specific DLVO-like aggregation that influences antimicrobial effects. Considering this phenomenon, the interaction of bacteria with GO aggregates having different sizes, morphologies, and surface potential can create a complex scenario that explains the contrasting results reported so far. In this article, we demonstrate that by modulating the GO stability in solution, the antibacterial or growth enhancement effect can be controlled on and . GO at low concentration cuts microorganism membranes and at high concentration forms complexes with pathogens and inhibits or enhances bacterial growth in a surface potential-dependent manner. With the framework defined in this study, the clinical application of GO gets closer, and controversial results in literature can be explained.
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http://dx.doi.org/10.1021/acsbiomaterials.6b00812DOI Listing
April 2017

Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance.

Sci Rep 2017 03 27;7:45120. Epub 2017 Mar 27.

Department of Biology, University of Rome Tor Vergata Rome, Italy.

Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.
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http://dx.doi.org/10.1038/srep45120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366871PMC
March 2017

Epicardial adipose tissue microbial colonization and inflammasome activation in acute coronary syndrome.

Int J Cardiol 2017 Jun 16;236:95-99. Epub 2017 Feb 16.

Institute of Cardiology, Catholic University, Rome, Italy. Electronic address:

Background: Epicardial adipose tissue (EAT) has a close functional and anatomic relationship with epicardial coronary arteries. Accumulating evidence suggests that host microbiome alterations may play a role in several inflammatory/immune disorders, triggering a robust proinflammatory response also involving interleukin-1β (IL-1β) and the NALP3 inflammasome. In the current study, we explore the hypothesis that in patients with non-ST elevation acute coronary syndrome (ACS), EAT contains potentially pro-atherosclerotic bacteria that might elicit inflammasome activation.

Methods: EAT samples were obtained during coronary artery bypass grafting from ACS (n=18) and effort stable angina (SA; n=16) patients, and as controls, from patients with angiographically normal coronary arteries undergoing surgery for mitral insufficiency (MVD; n=13). In all patients, NALP3 and proIL-1β mRNA expressions were evaluated with qRT-PCR. In 3 patients from each group, EAT microbiota composition was determined using next-generation sequencing technologies.

Results: In EAT, mRNA expression of both NALP3 and pro-IL1β was significantly higher in ACS than in SA and MVD (P=0.028 and P=0.005, respectively). A broad range of bacterial species (n=76) was identified in both ACS and SA, with different predominant species. In contrast, microbial DNA was barely observed in MVD.

Conclusions: Our study demonstrated the presence of bacterial DNA directly into EAT, surrounding diseased coronary arteries, of patients with ACS. Furthermore, ACS is associated with NALP3/inflammasome pathway activation in EAT. Our data suggest that the EAT environment is susceptible to microbial colonization that might stimulate a proinflammatory response. These findings add new elements to the pathogenesis of ACS and suggest novel therapeutic targets.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.040DOI Listing
June 2017

Effects of Proton Pump Inhibitors on the Gastric Mucosa-Associated Microbiota in Dyspeptic Patients.

Appl Environ Microbiol 2016 11 27;82(22):6633-6644. Epub 2016 Oct 27.

Institute of Public Health (Section of Hygiene), Università Cattolica del Sacro Cuore, Rome, Italy.

Besides being part of anti-Helicobacter pylori treatment regimens, proton pump inhibitors (PPIs) are increasingly being used to treat dyspepsia. However, little is known about the effects of PPIs on the human gastric microbiota, especially those related to H. pylori infection. The goal of this study was to characterize the stomach microbial communities in patients with dyspepsia and to investigate their relationships with PPI use and H. pylori status. Using 16S rRNA gene pyrosequencing, we analyzed the mucosa-associated microbial populations of 24 patients, of whom 12 were treated with the PPI omeprazole and 9 (5 treated and 4 untreated) were positive for H. pylori infection. The Proteobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Actinobacteria phyla accounted for 98% of all of the sequences, with Helicobacter, Streptococcus, and Prevotella ranking among the 10 most abundant genera. H. pylori infection or PPI treatment did not significantly influence gastric microbial species composition in dyspeptic patients. Principal-coordinate analysis of weighted UniFrac distances in these communities revealed clear but significant separation according to H. pylori status only. However, in PPI-treated patients, Firmicutes, particularly Streptococcaceae, were significantly increased in relative abundance compared to those in untreated patients. Consistently, Streptococcus was also found to significantly increase in relation to PPI treatment, and this increase seemed to occur independently of H. pylori infection. Our results suggest that Streptococcus may be a key indicator of PPI-induced gastric microbial composition changes in dyspeptic patients. Whether the gastric microbiota alteration contributes to dyspepsia needs further investigation.

Importance: Although PPIs have become a popular treatment choice, a growing number of dyspeptic patients may be treated unnecessarily. We found that patients treated with omeprazole showed gastric microbial communities that were different from those of untreated patients. These differences regarded the abundances of specific taxa. By understanding the relationships between PPIs and members of the gastric microbiota, it will be possible to envisage new strategies for better managing patients with dyspepsia.
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http://dx.doi.org/10.1128/AEM.01437-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086557PMC
November 2016

Serum Endotoxin Activity Measured with Endotoxin Activity Assay Is Associated with Serum Interleukin-6 Levels in Patients on Chronic Hemodialysis.

Blood Purif 2016 31;42(4):294-300. Epub 2016 Aug 31.

Hemodialysis Service, Institute of Clinical Surgery, Geriatrics and Psychiatry Catholic, Rome, Italy.

Background: This study aims to evaluate, in patients on chronic hemodialysis (PHD), the levels of endotoxin through a chemiluminescent bioassay based on the oxidative burst reaction of activated neutrophils to complement coated LPS-IgM immune complexes and define the variables possibly correlated.

Methods: In 61 PHD, we measured serum endotoxin activity (EA) with the Endotoxin Activity Assay (EAA™) and we defined the possible association with demographic, clinical and laboratory variables.

Results: Mean serum EA was 0.43 ± 0.26 UI. EA was low (<0.40) in 29 patients (47.5%), intermediate (0.40-0.60) in 14 (23%) and high (>0.60) in 18 (29.5%). A significant exponential relationship was detected between EA and serum interleukin-6 (IL-6) levels (r = 0.871). At the multiple regression analysis, intermediate-high EA was directly associated only with serum IL-6 levels. In a second model of multiple regression analysis without the variable serum IL-6 levels, intermediate-high EA was directly associated with constipation and serum troponin levels and inversely associated with serum albumin and the monthly number of sevelamer tablets.

Conclusions: A high percentage of PHD has intermediate or high EA. Intermediate-high EA is significantly associated with serum IL-6 levels.
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http://dx.doi.org/10.1159/000449096DOI Listing
December 2016
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