Publications by authors named "Jelena Blagojevic"

50 Publications

Intestinal helminth infections in the golden jackal (Canis aureus L.) from Vojvodina: Hotspot area of multilocular echinococcosis in Serbia.

Acta Vet Hung 2021 Sep 6. Epub 2021 Sep 6.

3 Department of Biology and Ecology, Faculty of Science, University of Novi Sad, Novi Sad, Serbia.

In the present study, 64 golden jackals were examined for intestinal helminths in three regions of Vojvodina, Serbia. Among the examined jackals 57.8% were infected with at least one parasite species. Using the intestinal scraping technique (SCT), eight species of intestinal helminths were found: Alaria alata (7.8%), Toxascaris leonina (9.4%), Toxocara canis (4.7%), Uncinaria stenocephala (20.3%), Echinococcus multilocularis (14.1%), Mesocestoides sp. (42.2%), Taenia pisiformis, and Taenia hydatigena (the overall prevalence of Taenia infection was 6.3%). To the best of our knowledge, this is the first report of T. leonina in jackals from Serbia. In comparison with the SCT results, coprological tests were less sensitive and specific for parasite identification, as only two nematode species (T. leonina and T. canis) as well as ancylostomatid and taeniid eggs were identified. The total prevalence of intestinal helminths was higher in males (71.9% males, 45% females), but the difference was not statistically significant (χ 2 = 3.76; P = 0.052). Co-infection with two species of intestinal helminths was found in 35% of the examined golden jackal individuals, three-species co-infection was demonstrated in 21.6%, whereas four-species co-infection was detected in 2.7% of the golden jackals examined. Echinococcus multilocularis has previously been recorded in jackals and foxes in Serbia, but only in Vojvodina. Our results corroborate the findings of previous studies, and indicate that the Vojvodina Province, more specifically the Srem region, is probably a high-risk area for E. multilocularis transmission to humans.
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http://dx.doi.org/10.1556/004.2021.00030DOI Listing
September 2021

New Data on Organization and Spatial Localization of B-Chromosomes in Cell Nuclei of the Yellow-Necked Mouse .

Cells 2021 Jul 19;10(7). Epub 2021 Jul 19.

Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.

The gene composition, function and evolution of B-chromosomes (Bs) have been actively discussed in recent years. However, the additional genomic elements are still enigmatic. One of Bs mysteries is their spatial organization in the interphase nucleus. It is known that heterochromatic compartments are not randomly localized in a nucleus. The purpose of this work was to study the organization and three-dimensional spatial arrangement of Bs in the interphase nucleus. Using microdissection of Bs and autosome centromeric heterochromatic regions of the yellow-necked mouse () we obtained DNA probes for further two-dimensional (2D)- and three-dimensional (3D)- fluorescence in situ hybridization (FISH) studies. Simultaneous hybridization of obtained here B-specific DNA probes and autosomal C-positive pericentromeric region-specific probes further corroborated the previously stated hypothesis about the pseudoautosomal origin of the additional chromosomes of this species. Analysis of the spatial organization of the Bs demonstrated the peripheral location of B-specific chromatin within the interphase nucleus and feasible contact with the nuclear envelope (similarly to pericentromeric regions of autosomes and sex chromosomes). It is assumed that such interaction is essential for the regulation of nuclear architecture. It also points out that Bs may follow the same mechanism as sex chromosomes to avoid a meiotic checkpoint.
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http://dx.doi.org/10.3390/cells10071819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305704PMC
July 2021

THE ROLE OF CHEST CT IN DECIPHERING INTERSTITIAL LUNG INVOLVEMENT: SYSTEMIC SCLEROSIS VERSUS COVID-19.

Rheumatology (Oxford) 2021 Jul 28. Epub 2021 Jul 28.

Department of Experimental and Clinical Medicine, University of Florence, and Infectious and TropicalDiseases Unit, AOUC, Florence, Italy.

Objective: To identify the main computed tomography (CT) features that may help distinguishing a progression of interstitial lung disease (ILD) secondary to Systemic sclerosis (SSc) from COVID-19 pneumonia.

Methods: This multicentric study included 22 international readers divided in the radiologist group (RAD) and non-radiologist group (nRAD). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.

Results: Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p < 0.0001) and signs of fibrosis in GGO in the lower lobes (p < 0.0001) remained independently associated with COVID-19 pneumonia or SSc-ILD, respectively. A predictive score was created which resulted positively associated with the COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity).

Conclusion: The CT differential diagnosis between COVID-19 pneumonia and SSc-ILD is possible through the combination the proposed score and the radiologic expertise. The presence of consolidation in the lower lobes may suggest a COVID-19 pneumonia while the presence of fibrosis inside GGO may indicate a SSc-ILD.
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http://dx.doi.org/10.1093/rheumatology/keab615DOI Listing
July 2021

Is there today a place for corticosteroids in the treatment of scleroderma?

Autoimmun Rev 2019 Dec 19;18(12):102403. Epub 2019 Oct 19.

Service de Médecine Interne, Hôpital Cochin, Centre de Référence National pour les Maladies Systémiques Autoimmunes Rares, DHU Authors, Assistance Publique-Hôpitaux de Paris, Paris, France; Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, France.

In systemic sclerosis (SSc), the use of corticosteroids (CS) is controversial due to their association with scleroderma renal crisis (SRC). However, patients with very early and early disease, characterised by main inflammatory component, may benefit from CS therapy. The aim of this review is to discuss pros and cons of CS treatment in SSc, providing current evidence about the use of CS in SSc. Moreover, we discuss also the underlying pathogenetic mechanisms that may be the background for the potential harms and efficacy of CS in SSc.
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http://dx.doi.org/10.1016/j.autrev.2019.102403DOI Listing
December 2019

The prevalence of pathogenic forms of in natural populations of small wild mammals in Serbia.

Acta Vet Hung 2019 09;67(3):338-346

University of Belgrade, Institute for Biological Research 'Siniša Stanković', Bulevar despota Stefana 142, Belgrade 11060, Serbia.

The greatest epidemiological significance of leptospirosis in Europe comes from the fact that it is the most widespread zoonosis in the world. However, epizootiological data, especially information on maintenance hosts such as small wild mammals, are largely missing. To fill this gap in data in Serbia, we used RT-PCR for the detection of pathogenic species and analysed 107 animals belonging to six species of small wild mammals and ) collected from two localities. The animals from the first locality that was situated in a tourist area, were collected for four consecutive years (2014-2017). We found persistent incidence of infection from year to year ranging from 6.67% to 78.57%. The average frequency of infected animals was 33.3% with the highest frequency in 2014, the year characterised by a very high number of flooding days. All animals proved to be infected with pathogenic species that were collected from the second locality situated in an agricultural area in a single year, 2014. The findings show a variable but constant presence of pathogenic species in populations of small wild mammals in the studied areas, which indicates the need for constant monitoring.
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http://dx.doi.org/10.1556/004.2019.035DOI Listing
September 2019

The Renal Resistive Index in systemic sclerosis: Determinants, prognostic implication and proposal for specific age-adjusted cut-offs.

Eur J Intern Med 2019 Dec 17;70:43-49. Epub 2019 Sep 17.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Via Delle Oblate 4, 50134 Florence, Italy; Department of Geriatric Medicine, Division of Rheumatology, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.

Background: Renal Resistive Index (RRI), reflects changes in both renal vascular and tubular-interstitial compartments and in systemic vascular compliance related to age and comorbidities.

Objectives: a) To investigate determinants of RRI in SSc population, b) its association with SSc-related features and c) to test its prognostic impact on organ specific worsening or death.

Methods: 380 SSc patients ≥18 years were enrolled after giving informed consent. Baseline data on RRI, laboratory, instrumental and therapeutic features were retrospectively collected. Age-SSc adjusted cut-offs were created by dividing the population in age quartiles and considering RRI values >75th percentile as pathologic. Clinical follow-up was performed until last available visit or the development/worsening of specific internal organ involvement or death.

Results: RRI was independently predicted by age and systolic pulmonary arterial pressure on Echo. Therefore, we created Age-SSc adjusted pathologic RRI cut-offs, which were significantly associated with various disease related skin and lung fibrotic manifestations, as well as vasculopathic complications. After a mean follow-up of 3.6 ± 2.6 years, RRI was one of the independent predictors (together with modified Rodnan skin score, interstitial lung disease, presence of dyspnoea and late nailfold-videocapillaroscopy pattern) for mortality, with 0.68 as best cut-off (sensitivity 88.5%, specificity 50.9%).

Conclusion: If corroborated, Renal Resistive Index cut-offs might be used to evaluate renal and extrarenal involvement in SSc and could serve as predictors of mortality.
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http://dx.doi.org/10.1016/j.ejim.2019.09.001DOI Listing
December 2019

Pregnancy in Systemic Sclerosis: Results of a Systematic Review and Metaanalysis.

J Rheumatol 2020 06 1;47(6):881-887. Epub 2019 Sep 1.

From the Department of Experimental and Clinical Medicine, University of Florence, and the Department of Geriatric Medicine, Division of Rheumatology and Scleroderma Unit, Azienda Ospedaliero Universitaria Careggi (AOUC), Florence, Italy; Department of Family Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Faculty of Medicine, Alexandria University, Alexandria, Egypt; Department of Emergency Medicine, Division of Medicine IV AOUC; Department of Maternal-Neonatal Caref, Careggi University Hospital, Florence, Italy; University of California at Los Angeles, Los Angeles, California; University of Washington, Seattle, Washington, USA; University of Florence, Florence, Italy.

Objective: Through a systematic literature search (SLR) and metaanalysis, to determine maternal and fetal outcomes in pregnancies involving systemic sclerosis (SSc), to analyze the effect of pregnancy on disease activity, and to examine predictors of fetal and maternal outcomes.

Methods: An SLR was performed for articles on SSc and pregnancy published between 1950 and February 1, 2018. Reviewers double-extracted articles to obtain agreement on > 95% of predefined critical outcomes.

Results: Out of 461 publications identified, 16 were included in the metaanalysis. The metaanalysis showed that pregnancies involving SSc were at higher risk of miscarriage (OR 1.6, 95% CI 1.22-2.22), fetuses with intrauterine growth retardation (IUGR; OR 3.2, 95% CI 2.21-4.53), preterm births (OR 2.4, 95% CI 1.14-4.86), and newborns with low birth weight (OR 3.8, 95% CI 2.16-6.56). Patients with SSc had a 2.8 times higher chance of developing gestational hypertension (HTN; OR 2.8, 95% CI 2.28-3.39) and a 2.3 times higher chance of cesarean delivery compared to controls (OR 2.3, 95% CI 1.37-3.8). The definitions of disease worsening/new visceral organ involvement were too inexact to have any confidence in the results, although worsening or new disease manifestations during pregnancy in 44/307 cases (14.3%) and 6 months postpartum in 32/306 cases (10.5%) were reported. The data did not permit definition of predictors of disease progression and of maternal and fetal outcomes.

Conclusion: Pregnancies involving SSc have increased frequency of miscarriages, IUGR, preterm deliveries, and newborns with low birth weight compared to healthy controls. Women with SSc were more prone to develop gestational HTN and to undergo cesarean delivery. Disease manifestations seem to remain stable or improve in most patients.
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http://dx.doi.org/10.3899/jrheum.181460DOI Listing
June 2020

Enthesopathy and involvement of synovio-entheseal complex in systemic sclerosis: an ultrasound pilot study.

Rheumatology (Oxford) 2020 03;59(3):580-585

Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, and Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy.

Objectives: SSc is a chronic autoimmune disease characterized by inflammation of the skin and multiple internal organs. Articular involvement is one of the main features of SSc, and typical hallmarks of SpA have been found in SSc patients. The aim of the present study was to estimate the prevalence of entheseal and synovio-entheseal complex (SEC) alterations in a cohort of SSc patients.

Methods: One hundred SSc patients and 25 healthy subjects were included in this cross-sectional study. The enthesis sites of lateral epicondylar common extensor tendons (CET) and the enthesis of the Glasgow Ultrasound Enthesis Scoring System were evaluated. SEC involvement was evaluated only at CET enthesis.

Results: In SSc, the Glasgow Ultrasound Enthesis Scoring System score was significantly higher (median 4.0, interquartile range 2.0-7.0) than in controls (median 1.0, interquartile range 0.0-3.0) (P < 0.0001). CET enthesis of SSc patients showed more frequent US B-mode alterations than that of controls (χ2 = 11.47, P = 0.0007 for size; χ2 = 13.79, P = 0.0002 for cortical irregularity, χ2 = 5.24, P = 0.022 for calcification/enthesophytes). Power Doppler US signal at CET enthesis was significantly more frequent in SSc patients than in healthy controls (χ2 = 9.11, P = 0.0025), as was the concomitant SEC involvement (χ2 = 8.52, P = 0.0035).

Conclusion: These data show that SSc patients frequently present US features of enthesopathy. Moreover, CET enthesopathy was correlated with SEC inflammation, suggesting that entheseal inflammation in SSc may share the same micro-anatomical targets as found in SpA.
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http://dx.doi.org/10.1093/rheumatology/kez322DOI Listing
March 2020

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

Clin Rheumatol 2020 Jan 20;39(1):27-36. Epub 2019 May 20.

NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Introduction: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1.

Method: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed.

Results: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone.

Conclusions: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.
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http://dx.doi.org/10.1007/s10067-019-04564-8DOI Listing
January 2020

Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines [corrected].

RMD Open 2018 26;4(Suppl 1):e000784. Epub 2019 Feb 26.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, IRCCS Polyclinic Hospital San Martino, University of Genoa, Genoa, Italy.

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients ' and clinicians' unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union's Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. ii) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; iii) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients ' preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations.
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http://dx.doi.org/10.1136/rmdopen-2018-000784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397434PMC
February 2019

Y chromosome genetic data defined by 23 short tandem repeats in a Serbian population on the Balkan Peninsula.

Ann Hum Biol 2019 Feb 24;46(1):77-83. Epub 2019 Apr 24.

e Department of Genetics and Bioengineering , International Burch University, Francuske revolucije bb , Ilidža , Bosnia and Herzegovina.

Background: Serbs mainly live in the territory of the recently re-established state of Serbia. However, the turbulent history in the Balkan Peninsula has led to settlement of Serbs not only within present day Serbia, but also in different parts of neighbouring countries.

Aim: To define polymorphisms of 23 Y-chromosomal short tandem repeat (STR) loci in a modern Serbian population from the central part of the Balkan Peninsula.

Subjects And Methods: The reference sample consisted of 303 men declared as Serbs over three generations. Localities of the collected materials include the territories of Serbia, Bosnia and Herzegovina, Croatia and Montenegro. DNA samples were typed using the PowerPlexY23 amplification kit.

Results: The highest locus diversity was observed for DYS385 and DYS481. In this study the most abundant haplogroups were I2a, E1b1b, R1a and I1. The largest genetic distances between the Serbs and other close Southern Slavs were for the Macedonians and Slovenians.

Conclusion: This study is the first one to define STR polymorphism of Serbian people not only from Serbia but also from other parts of the Balkan Peninsula. The presented genetic data may be useful in further examinations of the genesis and genetic structuring of the present-day Serbian gene pool.
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http://dx.doi.org/10.1080/03014460.2019.1584242DOI Listing
February 2019

Population genetic structure of the Mediterranean horseshoe bat Rhinolophus euryale in the central Balkans.

PLoS One 2019 30;14(1):e0210321. Epub 2019 Jan 30.

Department of genetic research, Institute for biological research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.

Migratory behaviour, sociality and roost selection have a great impact on the population structure of one species. Many bat species live in groups, and movements between summer and hibernation sites are common in temperate bats. The Mediterranean horseshoe bat Rhinolophus euryale is a cave-dwelling species that exhibits roost philopatry and undertakes seasonal movements which are usually shorter than 50 km. Its distribution in Serbia is restricted to karstic areas in western and eastern parts of the country, with a lack of known roosts between them. In this study, microsatellite markers were used to evaluate genetic variation in this species in the Central Balkans. Specifically, spatial genetic structuring between geographic regions and relatedness within different colony types were assessed. All analysed loci were polymorphic, and there was no significant inbreeding coefficient recorded. A moderate degree of genetic differentiation among the sampled colonies was found, and significant isolation by distance was recorded. Our results revealed that populations show a tendency to segregate into three clusters. Unexpectedly, populations from Montenegro and Eastern Serbia tended to group into one cluster, while populations from Western Serbia and Slovenia represented second and third cluster, respectively. The majority of variance was partitioned within colonies, and only a small but significant portion among clusters. Average relatedness within colony members was close to zero, did not differ significantly between the different colony types, and kinship is unlikely to be a major grouping mechanism in this species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353099PMC
October 2019

B Chromosomes in Populations of Mammals Revisited.

Genes (Basel) 2018 Oct 9;9(10). Epub 2018 Oct 9.

Institute for Biological Research "Siniša Stanković", Department of Genetic Research, University of Belgrade, Bulevar despota Stefana 142, Belgrade 11060, Serbia.

The study of B chromosomes (Bs) started more than a century ago, while their presence in mammals dates since 1965. As the past two decades have seen huge progress in application of molecular techniques, we decided to throw a glance on new data on Bs in mammals and to review them. We listed 85 mammals with Bs that make 1.94% of karyotypically studied species. Contrary to general view, a typical B chromosome in mammals appears both as sub- or metacentric that is the same size as small chromosomes of standard complement. Both karyotypically stable and unstable species possess Bs. The presence of Bs in certain species influences the cell division, the degree of recombination, the development, a number of quantitative characteristics, the host-parasite interactions and their behaviour. There is at least some data on molecular structure of Bs recorded in nearly a quarter of species. Nevertheless, a more detailed molecular composition of Bs presently known for six mammalian species, confirms the presence of protein coding genes, and the transcriptional activity for some of them. Therefore, the idea that Bs are inert is outdated, but the role of Bs is yet to be determined. The maintenance of Bs is obviously not the same for all species, so the current models must be adapted while bearing in mind that Bs are not inactive as it was once thought.
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http://dx.doi.org/10.3390/genes9100487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210394PMC
October 2018

European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis.

Rheumatology (Oxford) 2019 02;58(2):254-259

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, UK.

Objectives: To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort.

Methods: Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software.

Results: Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score.

Conclusion: Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.
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http://dx.doi.org/10.1093/rheumatology/key271DOI Listing
February 2019

Low-pass single-chromosome sequencing of human small supernumerary marker chromosomes (sSMCs) and Apodemus B chromosomes.

Chromosoma 2018 09 30;127(3):301-311. Epub 2018 Jan 30.

Institute of Molecular and Cellular Biology Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.

Supernumerary chromosomes sporadically arise in many eukaryotic species as a result of genomic rearrangements. If present in a substantial part of species population, those are called B chromosomes, or Bs. This is the case for 70 mammalian species, most of which are rodents. In humans, the most common types of extra chromosomes, sSMCs (small supernumerary marker chromosomes), are diagnosed in approximately 1 of 2000 postnatal cases. Due to low frequency in population, human sSMCs are not considered B chromosomes. Genetic content of both B-chromosomes and sSMCs in most cases remains understudied. Here, we apply microdissection of single chromosomes with subsequent low-pass sequencing on Ion Torrent PGM and Illumina MiSeq to identify unique and repetitive DNA sequences present in a single human sSMC and several B chromosomes in mice Apodemus flavicollis and Apodemus peninsulae. The pipeline for sequencing data analysis was made available in Galaxy interface as an addition to previously published command-line version. Human sSMC was attributed to the proximal part of chromosome 15 long arm, and breakpoints leading to its formation were located into satellite DNA arrays. Genetic content of Apodemus B chromosomes was species-specific, and minor alterations were observed in both species. Common features of Bs in these Apodemus species were satellite DNA and ERV enrichment, as well as the presence of the vaccinia-related kinase gene Vrk1. Understanding of the non-essential genome elements content provides important insights into genome evolution in general.
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http://dx.doi.org/10.1007/s00412-018-0662-0DOI Listing
September 2018

Proangiogenic effects of soluble α-Klotho on systemic sclerosis dermal microvascular endothelial cells.

Arthritis Res Ther 2017 Feb 10;19(1):27. Epub 2017 Feb 10.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, AOUC, Largo Brambilla 3, 50134, Florence, Italy.

Background: Systemic sclerosis (SSc) is characterized by endothelial cell (EC) apoptosis, impaired angiogenesis and peripheral microvasculopathy. Soluble α-Klotho (sKl) is a pleiotropic molecule with multiple effects on ECs, including antioxidant and vasculoprotective activities. On the EC surface, sKl interacts with vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and transient receptor potential canonical-1 (TRPC-1) cation channel to control EC homeostasis. Here, we investigated whether sKl might act as a protective factor to improve angiogenesis in dermal microvascular endothelial cells (MVECs) from SSc patients (SSc-MVECs).

Methods: Wound healing assay was performed on healthy dermal MVECs (H-MVECs) challenged with sera from healthy controls or SSc patients with or without the addition of sKl. Capillary morphogenesis on Matrigel was assessed in H-MVECs and SSc-MVECs at basal conditions and treated with sKl, as well as in H-MVECs challenged with healthy or SSc sera in presence or absence of sKl. The expression of α-Klotho, VEGFb, VEGFR-2, TRPC-1, Ki67 and active caspase-3 in H-MVECs and SSc-MVECs was investigated by western blotting. Immunostaining for α-Klotho was performed in H-MVECs and SSc-MVECs, and in healthy and SSc skin sections.

Results: Treatment with sKl effectively counteracted the inihibitory effects of SSc sera on wound healing ability and angiogenic performance of H-MVECs. The addition of sKl significantly improved angiogenesis and maintained over time capillary-like tube formation in vitro by SSc-MVECs. Stimulation of SSc-MVECs with sKl resulted in the upregulation of the proliferation marker Ki67 in parallel with the downregulation of proapoptotic active caspase-3. The expression of α-Klotho was significantly lower in SSc-MVECs than in H-MVECs. The expression of TRPC-1 was also significantly decreased, while that of VEGFR-2 and VEGFb was significantly increased, in SSc-MVECs compared with H-MVECs. Challenge with sKl either significantly increased TRPC-1 or decreased VEGFb in SSc-MVECs. Ex vivo analyses revealed that α-Klotho immunostaining was almost absent in the dermal microvascular network of SSc skin compared with control skin.

Conclusions: Our findings provide the first evidence that α-Klotho is significantly decreased in the microvasculature in SSc skin and that sKl administration may effectively improve SSc-MVEC functions in vitro by acting as a powerful proangiogenic factor.
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http://dx.doi.org/10.1186/s13075-017-1233-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301388PMC
February 2017

Substitution rate and natural selection in parvovirus B19.

Sci Rep 2016 10 24;6:35759. Epub 2016 Oct 24.

Institute for Microbiology and Immunology, School of Medicine, University of Belgrade, 1/1 Dr Subotića St, 11000 Belgrade, R Serbia.

The aim of this study was to estimate substitution rate and imprints of natural selection on parvovirus B19 genotype 1. Studied datasets included 137 near complete coding B19 genomes (positions 665 to 4851) for phylogenetic and substitution rate analysis and 146 and 214 partial genomes for selection analyses in open reading frames ORF1 and ORF2, respectively, collected 1973-2012 and including 9 newly sequenced isolates from Serbia. Phylogenetic clustering assigned majority of studied isolates to G1A. Nucleotide substitution rate for total coding DNA was 1.03 (0.6-1.27) x 10 substitutions/site/year, with higher values for analyzed genome partitions. In spite of the highest evolutionary rate, VP2 codons were found to be under purifying selection with rare episodic positive selection, whereas codons under diversifying selection were found in the unique part of VP1, known to contain B19 immune epitopes important in persistent infection. Analyses of overlapping gene regions identified nucleotide positions under opposite selective pressure in different ORFs, suggesting complex evolutionary mechanisms of nucleotide changes in B19 viral genomes.
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http://dx.doi.org/10.1038/srep35759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075947PMC
October 2016

Effects of rituximab in connective tissue disorders related interstitial lung disease.

Clin Exp Rheumatol 2016 Sep-Oct;34 Suppl 100(5):181-185. Epub 2016 Oct 14.

Paris Descartes University, Rheumatology A Department, APHP, Cochin Hospital, Paris, France.

Objectives: Interstitial lung disease (ILD) is a key prognostic factor in connective tissue disorders (CTDs). The aim of our study was to assess the changes in pulmonary functional tests (PFTs) in various CTDs, including anti-synthetase syndrome (SYN), systemic sclerosis (SSc) and mixed connective tissue disorder (MCTD), following the use of rituximab therapy.

Methods: A multicentre retrospective analysis of patients with ILD secondary to SYN (n=15), MCTD (n=6) and SSc (n=23). PFTs were performed at baseline and at 1 and 2 years of follow-up. The primary outcome was the change in forced vital capacity (FVC) at 1 year.

Results: In the SYN population, median FVC changed from 53.0% (42.0-90.0) at baseline to 51.4% (45.6-85.0) at 1 year and 63.0 (50-88) (p=0.6) at 2 years (p=0.14). In SSc, FVC changed from 81.0% (66.0-104.0) at baseline to 89.0% (65.0-113.0) at 1 year (p=0.1) and 74.5 (50-91) at 2 years (p=0.07). In the MCTD population, FVC changed from 64.5% (63.0-68.0) at baseline to 63.0% (59.0-71.0) at 1 year (p=0.6) and 61 (59-71) after 2 years (p=0.8). DLCO showed a trend for improvement in the SYN population (p=0.06 at 1 year and 0.2 at years) while changes remain non-significant in the SSc and MCTD patients. In SYN patients, the percentage of responders at 1 year for FVC (33.3%) was greater than in SSc (9.5%) (p=0.07) and MCTD (17%) (p=0.45). RTX showed a satisfactory safety profile.

Conclusions: A trend of improvement of PFTs was observed in SYN patients although not reaching significance, while SSc and MCTD patients were stabilised.
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January 2017

Exploring Supernumeraries - A New Marker for Screening of B-Chromosomes Presence in the Yellow Necked Mouse Apodemus flavicollis.

PLoS One 2016 23;11(8):e0160946. Epub 2016 Aug 23.

Department of Genetic Research, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.

Since the density of simple sequence repeats (SSRs) may vary between different chromosomes of the same species in eukaryotic genomes, we screened SSRs of the whole genome of the yellow necked mouse, Apodemus flavicollis, in order to reveal SSR profiles specific for animals carrying B chromosomes. We found that the 2200 bp band was amplified by primer (CAG)4AC to a highly increased level in samples with B chromosomes. This quantitative difference (B-marker) between animals with (+B) and without (0B) B chromosomes was used to screen 20 populations (387 animals). The presence/absence of Bs was confirmed in 96.5% of 342 non mosaic individuals, which recommends this method for noninvasive B-presence detection. A group of 45 animals with mosaic and micro B (μB) karyotypes was considered separately and showed 55.6% of overall congruence between karyotyping and molecular screening results. Relative quantification by qPCR of two different targeted sequences from B-marker indicated that these B-specific fragments are multiplied on B chromosomes. It also confirms our assumption that different types of Bs with variable molecular composition may exist in the same individual and between individuals of this species. Our results substantiate the origin of Bs from the standard chromosomal complement. The B-marker showed 98% sequence identity with the serine/threonine protein kinase VRK1 gene, similarly to findings reported for Bs from phylogenetically highly distant mammalian species. Evolutionarily conserved protein-coding genes found in Bs, including this one in A. flavicollis, could suggest a common evolutionary pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994964PMC
July 2017

Premedication prevents infusion reactions and improves retention rate during infliximab treatment.

Clin Rheumatol 2016 Nov 19;35(11):2841-2845. Epub 2016 Jul 19.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Villa Monna Tessa, Viale Pieraccini 18, 50134, Florence, Italy.

Infliximab (IFX) is an anti-tumor necrosis factor-alpha antibody used to treat inflammatory joint diseases. Infusion reactions (IR) can occur during and after intravenous administration and often require discontinuation of IFX therapy. This retrospective study aimed at evaluating the incidence of IR in patients with joint inflammatory diseases receiving IFX with and without premedication. Clinical charts of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients receiving IFX from January 2002 to December 2014 were reviewed. Patients receiving only one premedication protocol over time were enrolled and clustered based on the type of premedication as follows: group 1 received no premedication; group 2 received paracetamol, esomeprazole, hydrocortisone, and chlorpheniramine maleate; group 3 received paracetamol, hydoxyzine, ranitidine, and 6-methylprednisolone. Adverse events were recorded during the infusion, in the following hours and at control visits. The charts of 105 patients treated with IFX were selected. IR were observed in 23/51 patients of group 1, in 7/35 patients of group 2, and none of 19 patients in group 3. IR incidence was significantly lower in the second (p = 0.021) and third (p < 0.001) compared to the first group. The incidence of IR was significantly lower in group 3 than group 2 (p < 0.043). Moreover, patients in group 1 had a relative risk of developing an IR 2.5 times higher than group 2. In our experience, the use of premedication significantly reduced the number of IR to IFX. In particular, the combination of paracetamol, hydroxyzine, 6-methylprednisolone and ranitidine was more efficacious than paracetamol, esomeprazole, hydrocortisone, and chlorpheniramine maleate combination protocol.
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http://dx.doi.org/10.1007/s10067-016-3351-5DOI Listing
November 2016

Calcinosis in systemic sclerosis: subsets, distribution and complications.

Rheumatology (Oxford) 2016 09 30;55(9):1610-4. Epub 2016 May 30.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.

Objective: To retrospectively analyse the features of calcinosis in a cohort of SSc patients.

Methods: Charts of SSc patients attending the Ulcer Unit of the Rheumatology Department, University of Florence and presenting a clinical suspicion of calcinosis were considered in the study. Data on clinical history, including recent skin changes, and clinical examination of all areas with suspected calcinosis, radiological imaging of the calcinotic area, demographics and SSc-related organ involvement and pain measured by a visual analogue scale were recorded.

Results: In 52 of 112 SSc patients, a total of 316 calcinoses were recorded and were divided into visible and palpable {154 [47.4%], clustered according to their macroscopic features as mousse [49 (31.8%)] and stone [: 105 (68.2%)]} and non-visible but palpable {: 162 [52.6%]: net [5 (3%)], plate [22 (13.8%)] and stone [135 (83.2%)]}. The X-ray-based classification of all calcinoses, both visible and non-visible, was as follows: stone, 289 (91.4%); net, 12 (3.8%) and plate, 15 (4.8%). Skin ulcers complicated 154 of 316 calcinoses (48.7%). Mousse calcinosis was associated with pulmonary arterial hypertension, the stone subset was suggestive of pulmonary involvement and justified further investigation and the net subset was the slowest to heal.

Conclusion: Our data indicate that calcinosis may be classified in SSc as mousse, stone, net and plate according to its clinical and X-ray features. This classification awaits validation for a possible use in clinical practice and to support early treatment and prevention of complications.
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http://dx.doi.org/10.1093/rheumatology/kew193DOI Listing
September 2016

Assessment, Definition, and Classification of Lower Limb Ulcers in Systemic Sclerosis: A Challenge for the Rheumatologist.

J Rheumatol 2016 Mar 1;43(3):592-8. Epub 2016 Feb 1.

From the University of Florence: Department of Clinical and Experimental Medicine, Division of Rheumatology; Department of Internal Medicine; Interinstitutional Department of Didactics, Florence, Italy.J. Blagojevic, MD, Doctoral Candidate, University of Siena and University of Florence Joint Doctoral Program, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; G. Piemonte, BSN, RN, Doctoral Candidate, University of Florence, Department of Clinical and Experimental Medicine, Division of Rheumatology; L. Benelli, BSN, RN, Registered Nurse, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; F. Braschi, BSN, RN, Registered Nurse, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; G. Fiori, MD, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; F. Bartoli, MD, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; S. Guiducci, PhD, Researcher, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; S. Bellando Randone, PhD, Researcher, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; F. Galluccio, MD, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; L. Cometi, MD, Rheumatology Resident, Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence; S. Castellani, PhD, Associate Professor, Department of Clinical and Experimental Medicine, University of Florence; M. Boddi, PhD, Associate Professor, Department of Clinical and Experimental Medicine, University of Florence; A. Moggi Pignone, PhD, Associate Professor, Department of Internal Medicine, University of Florence; L. Rasero, BSN, RN, Associate Professor, Department of Clinical and Experimental Medicin

Objective: To evaluate pathogenesis and clinical features of lower limb ulcers in systemic sclerosis (SSc) and to propose a classification that could be used in clinical practice.

Methods: Charts of 60 patients with SSc who had lower limb cutaneous lesions were reviewed. All patients had videocapillaroscopy and arterial and venous lower limb color Doppler ultrasonography (US). Arteriography was performed if occlusive peripheral arterial disease was suspected.

Results: The 554 lesions were classified as hyperkeratosis, ulcers, and gangrenes. There were 341 (61.6%) hyperkeratoses, 208 (37.5%) ulcers, and 5 (0.9%) gangrenes. Ulcers were divided into pure ulcers, ulcers associated with hyperkeratosis, and ulcers secondary to calcinosis. Involvement of arterial and venous macrocirculation as determined by color Doppler US was observed in 17 (18.3%) and 18 (30%) patients, respectively. Seventeen out of 37 patients with pure ulcers (45.9%) presented neither venous insufficiency nor hemodynamically significant macrovascular arterial disease. In these patients, pure ulcers were most likely caused by isolated SSc-related microvascular involvement (pure microvascular ulcers). The only significant risk factor for development of pure microvascular ulcers in the multivariate analysis was the history of lower limb ulcers (OR 26.67, 95% CI 2.75-259.28; p < 0.001).

Conclusion: Results of our study indicate that lower limb ulcers in SSc often have a multifactorial pathogenesis that may be difficult to manage. Further studies are needed to validate the proposed classification and to assess the most appropriate management of lower limb ulcers in SSc.
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http://dx.doi.org/10.3899/jrheum.150035DOI Listing
March 2016

Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis.

Ann Rheum Dis 2016 08 10;75(8):1541-9. Epub 2015 Sep 10.

Department of Experimental and Clinical Medicine, Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Florence, Italy.

Objectives: In systemic sclerosis (SSc), vascular involvement is characterised by vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR) system disturbances. Neuropilin-1 (NRP1), a receptor for both class-3 semaphorins (Sema3s) and VEGF-A, is required for optimal VEGF-A/VEGFR-2 signalling. Here, we investigated the possible involvement of Sema3A/NRP1 axis in SSc.

Methods: Circulating Sema3A and soluble NRP1 (sNRP1) were measured in patients with SSc and controls. NRP1 and Sema3A expression in skin biopsies was evaluated by immunofluorescence and western blotting. NRP1 expression was assessed in SSc and healthy dermal microvascular endothelial cells (SSc-MVECs and H-MVECs), and in SSc and control endothelial progenitor cell (EPC)-derived endothelial cells (ECs). The possible impact of transcription factor Friend leukaemia integration 1 (Fli1) deficiency on endothelial NRP1 expression was investigated by gene silencing. The binding of Fli1 to NRP1 gene promoter was evaluated using chromatin immunoprecipitation. Capillary morphogenesis was performed on Matrigel.

Results: Decreased sNRP1 levels in SSc were associated with active and late nailfold videocapillaroscopy patterns and digital ulcers. No difference in Sema3A was found between patients and controls. NRP1 was significantly decreased in SSc-MVECs both ex vivo and in vitro. NRP1 and Fli1 significantly decreased in H-MVECs challenged with SSc sera, while they were not different in SSc and control EPC-derived ECs. Fli1 occupied the NRP1 gene promoter and Fli1 gene silencing reduced NRP1 expression in H-MVECs. NRP1 gene silencing in H-MVECs resulted in a significantly impaired angiogenic capacity comparable to that of cells treated with SSc sera.

Conclusion: In SSc, NRP1 deficiency may be an additional factor in the perturbed VEGF-A/VEGFR-2 system contributing to peripheral microvasculopathy and defective angiogenesis.
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http://dx.doi.org/10.1136/annrheumdis-2015-207483DOI Listing
August 2016

Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis.

Arthritis Res Ther 2015 Aug 21;17:221. Epub 2015 Aug 21.

Department of Experimental and Clinical Medicine, Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Viale Pieraccini 18, I-50139, Florence, Italy.

Introduction: The vascular and nervous systems have several anatomic and molecular mechanism similarities. Emerging evidence suggests that proteins involved in transmitting axonal guidance cues, including members of class III semaphorin (Sema3) family, play a critical role in blood vessel guidance during physiological and pathological vascular development. Sema3E is a natural antiangiogenic molecule that causes filopodial retraction in endothelial cells, inhibiting cell adhesion by disrupting integrin-mediated adhesive structures. The aim of the present study was to investigate whether in systemic sclerosis (SSc) Plexin-D1/Sema3E axis could be involved in the dysregulation of vascular tone control and angiogenesis.

Methods: Sema3E levels were measured by quantitative colorimetric sandwich ELISA in serum samples from 48 SSc patients, 45 subjects with primary Raynaud's phenomenon (pRP) and 48 age-matched and sex-matched healthy controls. Immunofluorescence staining on skin sections from 14 SSc patients and 12 healthy subjects was performed to evaluate Sema3E and Plexin-D1 expression. Western blotting was used to assess Plexin-D1/Sema3E axis in human SSc and healthy dermal microvascular endothelial cells (SSc-MVECs and H-MVECs, respectively) at basal condition and after stimulation with recombinant human vascular endothelial growth factor (VEGF), SSc and healthy sera. Capillary morphogenesis on Matrigel was performed on H-MVECs treated with healthy, pRP or SSc sera in the presence of Sema3E and Plexin-D1 soluble peptides.

Results: Serum Sema3E levels were significantly higher both in pRP subjects and SSc patients than in controls. In SSc, Sema3E levels were significantly increased in patients with early nailfold videocapillaroscopy (NVC) pattern compared to active/late patterns and pRP, and in patients without digital ulcers versus those with ulcers. In SSc skin, Sema3E expression was strongly increased in the microvascular endothelium. Cultured SSc-MVECs showed higher levels of phosphorylated Plexin-D1 and Sema3E expression than H-MVECs, and stimulation with SSc sera increased phosphorylated Plexin-D1 and Sema3E in H-MVECs. The addition of Sema3E-binding Plexin-D1 soluble peptide significantly attenuated the antiangiogenic effect of SSc sera on H-MVECs.

Conclusions: Our findings suggest that Plexin-D1/Sema3E axis is triggered in SSc endothelium and may have a role in the dysregulation of angiogenesis and vascular tone control by inducing neuro-vascular mechanism alterations clinically evident in particular in the early disease phases.
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http://dx.doi.org/10.1186/s13075-015-0749-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546224PMC
August 2015

Stacking interactions of hydrogen-bridged rings – stronger than the stacking of benzene molecules.

Chem Commun (Camb) 2015 Aug;51(65):12989-91

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

Analysis of crystal structures from the Cambridge Structural Database showed that 27% of all planar five-membered hydrogen-bridged rings, possessing only single bonds within the ring, form intermolecular stacking interactions. Interaction energy calculations show that interactions can be as strong as -4.9 kcal mol(-1), but dependent on ring structure.
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http://dx.doi.org/10.1039/c5cc04139bDOI Listing
August 2015

Decrease of LL-37 in systemic sclerosis: a new marker for interstitial lung disease?

Clin Rheumatol 2015 Apr 20;34(4):795-8. Epub 2015 Jan 20.

Internal Medicine Department, Gazi University Medical Faculty, Ankara, Turkey,

Interstitial lung disease (ILD) is the leading cause of systemic sclerosis (SSc) related morbidity and mortality. LL-37 peptide is the only cathelicidin of the human antimicrobial peptide family with antimicrobial effects and immunomodulatory activity. LL-37 has anti-fibrotic effects and anti-apoptotic effects on SSc dermal fibroblasts. The aim of the study was to investigate the circulating levels of LL-37 in SSc patients and its association with clinical, laboratory, and instrumental parameters. Fifty-eight SSc patients (30 with and 28 without pulmonary involvement) and 28 healthy controls were enrolled in the study. Pulmonary involvement was defined when ILD was found at HRCT (ground glass, reticular, and honeycombing pattern). Circulating LL-37 levels were measured with ELISA test. In SSc patients with ILD serum, LL-37 concentrations were remarkably lower (1.36 mg/ml) than those in SSc patients without ILD (4.62 ng/ml, p = 0.035) and controls (5.53 ng/ml, p = 0.009). In SSc patients without ILD, serum LL-37 levels were not different from controls (p = 0.812). No significant association or correlation was found between LL-37 levels and any other clinical, serological, or instrumental features. Serum LL-37 levels are significantly lower in patients with SSc ILD. Our results may suggest that lower LL-37 levels may be associated with the development of ILD. Whether circulating levels of LL-37 might be used as an indirect marker of ILD remains to be determined in larger SSc cohorts.
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http://dx.doi.org/10.1007/s10067-014-2854-1DOI Listing
April 2015

Possible influence of B chromosomes on genes included in immune response and parasite burden in Apodemus flavicollis.

PLoS One 2014 5;9(11):e112260. Epub 2014 Nov 5.

Department of Genetic Research, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.

Genetic background underlying wild populations immune response to different parasites is still not well understood. We studied immune response to multiple infections and to competition between different parasite species at different developmental stages in population of yellow-necked mouse, Apodemus flavicollis. Quantitative real-time PCR was used to investigate associations of MHC II-DRB, IL-10 and Tgf-β genes expressions with presence of intestinal parasites at different developmental stages. Furthermore, we were interested whether the host related characteristics (sex, age, body condition, presence of B chromosomes or expression of other genes) or characteristics of present parasites (number of adult parasites of each identified species, egg count of each parasite genus, total number of nematode individuals) affect differential expression of the studied genes. A significant invert association between the expression of MHC II-DRB and Tgf-β gene was found, which together with absence of IL-10 association confirmed modified Th2 as the main type of immune response to nematode infections. Effect of recorded parasites and parasite life-cycle stage on expression levels of MHC II-DRB gene was detected only through interactions with host-related characteristics such as sex, age, and the presence of B chromosomes. The presence of B chromosomes is associated with lower expression level of Tgf-β gene. Although the influence of host genetic background on parasite infection has already been well documented, this is the first study in mammals that gave presence of B chromosomes on immune response full consideration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221283PMC
November 2015

Digital ulcers as a sentinel sign for early internal organ involvement in very early systemic sclerosis.

Rheumatology (Oxford) 2015 Jan 26;54(1):72-6. Epub 2014 Jul 26.

Department of Clinical and Experimental Medicine, Section of Rheumatology, University of Florence, Florence, Italy.

Objective: The aim of this study was to evaluate the presence of digital lesions in very early diagnosis of SSc (VEDOSS) patients and its possible association with internal organ involvement.

Methods: One hundred and ten VEDOSS patients were investigated for the presence of digital ulcers (DUs), digital pitting scars, calcinosis, necrosis or gangrene, nailfold videocapillaroscopic abnormalities, disease-specific autoantibodies (ACA and anti-topo I) and internal organ involvement.

Results: Four patients reported a history of digital pitting scars, while 25 patients presented an active DU or reported a history of DUs. In particular, 16 patients presented with active DUs (14/16 also reporting a history of previous DUs), while the other 9 patients reported a history of DUs only. A statistically significant association between DUs and oesophageal manometry alteration was found in the whole DU population, as well as in the history of DU and the presence of active DU with/without a history of DU subgroups (P < 0.01, P = 0.01 and P < 0.05, respectively). DUs were observed in VEDOSS patients with internal organ involvement but not in those without organ involvement.

Conclusion: DUs are already present in VEDOSS patients characterized by internal organ involvement, significantly correlating and associating with gastrointestinal involvement. DUs may be a sentinel sign for early organ involvement in VEDOSS patients.
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http://dx.doi.org/10.1093/rheumatology/keu296DOI Listing
January 2015

Parallel water/aromatic interactions of non-coordinated and coordinated water.

Chemphyschem 2014 Aug 19;15(11):2386-96. Epub 2014 May 19.

Innovation Center, Department of Chemistry, Studentski trg 12-16, 11000 Belgrade (Serbia).

The parallel interactions of non-coordinated and coordinated water molecules with an aromatic ring were studied by analyzing data in the Cambridge structural database (CSD) and by using quantum chemical calculations. The CSD data show that water/aromatic contacts prefer parallel to OH/π interactions, which indicates the importance of parallel interactions. The results reveal the influence of water coordination to a metal ion; the interactions of aqua complexes are stronger. Coordinated water molecules prefer a parallel-down orientation in which one OH bond is parallel to the aromatic ring, whereas the other OH bond points to the plane of the ring. The interactions of aqua complexes with parallel-down water/benzene orientation are as strong as the much better known OH/π orientations. The strongest calculated interaction energy is -14.89 kcal mol(-1) . The large number of parallel contacts in crystal structures and the quite strong interactions indicate the importance of parallel orientation in water/benzene interactions.
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http://dx.doi.org/10.1002/cphc.201402004DOI Listing
August 2014
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