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Primary ciliary dyskinesia (PCD) is a disease caused by impaired function of motile cilia. PCD mainly affects the lungs and reproductive organs. Inheritance is autosomal recessive and X-linked. PCD patients have diverse clinical manifestations, thus making the establishment of proper diagnosis challenging. The utility of next-generation sequencing (NGS) technology for diagnostic purposes allows for better understanding of the PCD genetic background. However, identification of specific disease-causing variants is difficult. The main aim of this study was to create a unique guideline that will enable the standardization of the assessment of novel genetic variants within PCD-associated genes. The designed pipeline consists of three main steps: (1) sequencing, detection, and identification of genes/variants; (2) classification of variants according to their effect; and (3) variant characterization using in silico structural and functional analysis. The pipeline was validated through the analysis of the variants detected in a well-known PCD disease-causing gene (DNAI1) and the novel candidate gene (SPAG16). The application of this pipeline resulted in identification of potential disease-causing variants, as well as validation of the variants pathogenicity, through their analysis on transcriptional, translational, and posttranslational levels. The application of this pipeline leads to the confirmation of PCD diagnosis and enables a shift from candidate to PCD disease-causing gene.

Introduction Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. Methods Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. Results We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. Conclusion Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.

predstavlja značajan javno-zdravstveni problem i dostiže razmere pandemije. Imajući u vidu da je gojaznost u detinjstvu udružena sa endokrinološkim, metaboličkim, kardiovaskularnim i drugim poremećajima zdravlja, može se očekivati posledično smanjenje kvaliteta i prosečne dužine života kod odraslih. Mnoge studije su pokazale korisne efekte različitih dijeta i oblika fizičke aktivnosti na sastav tela, metaboličke parametre i kardiorespiratorni kapacitet gojazne dece i adolescenata, ali je malo studija koje su obuhvatile sve navedene parametre. Fizički trening, nezavisno od dijetetskih intervencija, dovodi do poboljšanja kardiorespiratornog kapaciteta i sastava tela gojazne dece. Ciljevi studije su bili ispitivanje uticaja hipokalorijske dijete i aerobnog intervalnog treninga na promene telesnog sastava, metaboličkih parametara, kardiorespiratornog kapaciteta, navika u ishrani, dnevnog energetskog unosa i nivoa bazalnog metabolizma gojaznih adolescentkinja. Materijal i metode: U ovu studiju prospektivnog tipa uključeno je četrdeset četiri adolescentkinje sa područja grada Beograda, uzrasta trinaest do devetnaest godina, koje su imale indeks telesne mase veći od 95. percentila za odgovarajući uzrast i pol, zbog čega su upućivane iz ustanova primarne zdravstvene zaštite u Institut za zdravstvenu zaštitu majke i deteta Srbije. Ispitanice su randomizovane u tromesečnu intervenciju i raspoređene u dve grupe: 1) adolescentkinjе koje su bile na uravnoteženoj hipokalorijskoj dijeti (n = 22) i 2) adolescentkinje koje su bile na uravnoteženoj hipokalorijskoj dijeti i aerobnom intervalnom treningu (n = 22). Izvršena su antropometrijska merenja, biohemijska i hormonska ispitivanja. Procenjen je kardiorespiratorni kapacitet, nivo fizičke aktivnosti i ishrana adolescentkinja. Insulinska rezistencija je procenjivana pomoću homeostatskog indeksa insulinske rezistencije (HOMA-IR), indeksa osetljivosti na insulin (ISI) Matsuda, AUCglukoze i AUCinsulina. Rezultati: Posle tromesečne inte, The very high prevalence of obesity in population of children and adolescents worldwide is a significant public health problem and is reaching a pandemic levels. Given that childhood obesity is associated with endocrinological, metabolic, cardiovascular and other health disorders, a consequent decrease in quality and average life expectancy in adults can be expected. Many studies have shown the beneficial effects of different diets and forms of physical activity on body composition, metabolic parameters, and cardiorespiratory capacity of obese children and adolescents, but few studies have included all of these parameters. Physical training, independently of dietary interventions, leads to an improvement in cardiorespiratory capacity and body composition of obese children. The aim of the study was to examine the effect of hypocaloric diet and aerobic interval training on changes in body composition, metabolic parameters, cardiorespiratory capacity, eating habits, daily energy intake and basal metabolism levels of adolescent girls with obesity. Methods: Forty-four adolescent girls from Belgrade, aged thirteen to nineteen years, who had a body mass index greater than the 95th percentile for the appropriate age and gender were included in this prospective study and for that reason they were referred from Primary Health Care Centers to Mother and Child Healthcare Instutute of Serbia. Subjects were randomized to a three-month intervention and divided into two groups: 1) adolescent girls on a balanced hypocaloric diet (n = 22) and 2) adolescent girls who were on a balanced hypocaloric diet and aerobic interval training (n = 22). Anthropometric measurements, biochemical and hormonal testings were performed. Cardiorespiratory capacity, physical activity level, and adolescent diet were assessed. Insulin resistance was determined using the homeostatic model assessment (HOMA-IR), the insulin sensitivity index (ISI) of Matsuda, AUCglucose and AUCinsulin. Results: After 3-month

Као последица механичке вентилације плућа настаје колапс алвеола, формирају се ателектазе, повећава се интрапулмонални шант и долази до поремећаја оксигенације и елиминације угљен диоксида. Реаерација колабираних алвеола и примена позитивног притиска на крају експиријума стабилизује алвеоле и побољшава функцију плућа. Тренутне препоруке о начину примене позитивног притиска на крају експиријума код деце нису још увек јасно дефинисане. Циљ рада је процена ефикасности споре усходне и нисходне титрације позитивног притиска на крају експиријума од 5 до 11 cmH2O у побољшању функције плућа код деце предшколског узраста током опште анестезије са мишићном релаксацијом. Материјал и методе: У овој проспективној, интервентној студији учествовало је седамдесеторо деце узраста од 3 до 7 година подељених у две групе, испитивану ( n=35) и контролну( n=35). Студија је спроведена у Хируршкој клиници Института за мајку и дете од јанура до јуна 2017. Критеријуми за укључивање у студију су били: деца АСА 1 и 2 статуса и деца која се не подвргавају кардиоторакалној хирирургији. Критеријуми за искључивање су били присуство: инфекције дисајних путева, кардиолошких болести, болести респираторног система, гастроезофагеалног рефлукса, као и алергије на изабране анестетике и стања код којих су изабрани анестетици контраидниковани. У испитиваној групи је примењивана спора титрација позитивног притиска на крају експиријума (positive end-expiratory pressure –PEEP) од 5 до 11 cmH2O 20 минута пред крај опште анестезије. Контролна група је вентилирана са PEEP-ом од 3 cmH2O све време током опште анестезије. Главни параметри испитивања су били: промене оксигенације (PaO2) 6 (PaO2/FiO2), елиминације угљен диоксида, (PaCO2), промене плућне комплијансе (Cdyn) и интрапулмоналног шанта, P(A-a)O2 након титрације PEEP-а..., Mechanical ventilation impairs oxygenation and increases intrapulmonary shunt. Positive end-expiratory pressure (PEEP) slows derecruitment, improves lung function but can compromise hemodynamics. Current recomendationts advocate use of positive end expiratory pressure (PEEP) in children but levels of PEEP are not yet well established.The objective of this research is to evaluate stepwise up and down PEEP titration in preschool children during general anesthesia. Materials and methods: This was a single tertiary care center an open-label, randomized parallel group controlled clinical trial. Study included 70 children, 3-7 years, devided into two groupsintervention (n=35) and control (n=35). Study was conducted at Institute for mother and child health care. Incusion criteria were: ASA I and II, under general anesthesia for non-cardiothoracic surgery. Exclusion criteria were: present respiratory infection, presence of cardiorespiratory comorbidity, presence of gastroesophageal reflux, allergy to chosen anesthetic maedicationa as well as contitions where chosen anesthetics were contraindicated. Children were randomly allocated either to receive PEEP titration 5-11 cmH2O 20 minutes before the end of anesthesia (intervention group) or to be ventilated until the end of anesthesia with constant positive endexpiratory pressure of 3 cmH2O (control group).Outcome measures were: changes in oxygenation (PaO2 PaO2/FiO2), ventilation (PaCO2), dynamic lung compliance (Cdzn) and alveolar-arterial gradient P(A-a)O2 between and within groups. Measurements were made at two time points: TI 20 minutes before PEEP titratiron and TII after PEEP titration..

The aim of the study was to compare the effects of high-intensity interval training (HIIT) and nutrition advice on cardiometabolic biomarkers, hormonal parameters, and cardiorespiratory fitness in adolescent girls with obesity. Adolescent girls with obesity (n = 44, aged 13-19 years) were randomized into a 12-week intervention as follows: (i) dietary advice and HIIT (n = 22), and (ii) dietary advice only (n = 22). The concentration of biomarkers of inflammation, biochemical and hormonal testing, oral glucose tolerance test, cardiorespiratory fitness, physical activity levels, and nutrition were assessed. After a 3-month intervention, the diet+HIIT group significantly increased insulin sensitivity index (-0.34 +/- 1.52 vs. 1.05 +/- 3.21; p = 0.001) and work load (0.6 +/- 11.3 W vs. 14.6 +/- 20.2 W; p = 0.024) and decreased glucose area under the curve (-0.29 +/- 4.69 vs. -0.98 +/- 4.06; p = 0.040), insulin area under the curve (-9.65 +/- 117.9 vs. -98.7 +/- 201.8; p = 0.003), and high-sensitivity C-reactive protein (hs-CRP) (0.12 +/- 1.92 mg11. vs. -1.47 +/- 3.67 mg/L; p = 0.039) in comparison with the diet group. Regarding within-group changes, both groups had significant improvements in body mass index (BMI), BMI-standard deviation score, body fat percentage, and systolic blood pressure. Positive impact on waist circumference, waist circumference/height ratio, diastolic blood pressure, hs-CRP, work load, maximal heart rate, and resting heart rate was observed only after the diet+HIIT intervention. No significant change was noted in peak oxygen uptake, lipid profile, and hormonal parameters between groups after intervention. Novelty HIIT and nutrition advice increased insulin sensitivity and decreased BMI, body fat, systolic blood pressure, and diastolic blood pressure. Nutrition advice decreased BMI, body fat, and systolic blood pressure in adolescent girls with obesity.

The most frequent chronic respiratory problems in childhood are asthma and cystic fibrosis (CF). The purpose of this paper is to review basic knowledge and recent advances in oral health and associated dental morbidities in children with asthma and CF. This review considered clinical trials and systematic reviews related to oral health in children with CRD. An online base Medline was searched to determine relevant papers, using the combination of the following terms: 'asthma', 'cystic fibrosis', 'caries', 'dental erosion', and 'oral health'. Oral health problems in children with chronic respiratory diseases (CRD) may be influenced by natural course of the disease, pharmacotherapy (inhalation therapy with bronchodilators and inhaled corticosteroids in asthmatic patients, systemic antibiotics and pancreatic enzyme replacement therapy in CF patients), medication administration technique and nutritional habits. Children with CRD may have higher prevalence of oral diseases. Patients and their parents, but also general paediatricians and pulmonologists, should be aware of importance of good oral health. Dental practitioners should be more informed about risk factors and specificities of oral health in these patients. Preventive measures, early diagnosis and effective treatment strategies in children with CRD can reduce occurrence of oral diseases and improve patient's quality of life.

Primarna cilijarna diskinezija (PCD) predstavlja retku bolest koja se nasleđuje na autozomno recesivan način ili je nasleđivanje vezano za hromozom X, i predominantno utiče na funkcionisanje pluća, reproduktivnih organa i na lateralnost unutrašnjih organa. PCD je klinički i genetički veoma heterogen poremećaj koji se javlja odmah po rođenju, a karakteriše se promenama na motornim cilijama koje su posledica patogenih varijanti u genima koji kodiraju za proteine koji su neophodni za pravilnu strukturu i funkciju ovih organela. Do sada je opisano 38 gena uzročnika bolesti koje su odgovorne za nastanak PCD-a, a smatra se da je taj broj mnogo veći s obzirom da 2500 proteina učestvuje u izgradnji i pravilnom funkcionisanju cilija. Velika raznolikost kliničke slike PCD pacijenata često dovodi do odloženog uspostavljanja precizne dijagnoze ove bolesti, a nije retkost i da pacijenti sa drugim bolestima pluća budu okarakterisani kao PCD pacijenti. Genetički profil ove bolesti kod pacijenata sa teritorije Srbije do sada nije utvrđen, pa je identifikacija gena uzročnika neophodna. Stoga je u okviru ove teze urađeno genomsko profilisanje pacijenata sa primarnom cilijarnom diskinezijom u cilju razvoja genetičkog algoritma koji bi, osim opisanih patogenih genetičkih varijanti i gena uzročnika, obuhvatio i novootkrivene varijante u kodirajućim regionima gena uzročnika PCD-a i gena kandidata za PCD. Sve ovo omogućava razvoj strategije za diferencijalnu dijagnozu PCD-a i drugih bolesti pluća suspektnih na ciliopatije koji se klinički manifestuju kao PCD. Takođe, pristupljeno je funkcionalnoj karakterizaciji novootkrivenih patogenih varijanti u već poznatim genima koji su odgovorni za razvoj PCD-a i/ili u genima koji do sada nisu asocirani sa PCD-om, a koji bi mogli da dovedu do karakterističnog fenotipa kod pacijenta. Jedna od glavnih odlika PCD pacijenata je strukturna i/ili funkcionalna promena na cilijama, pa su one nepokretne, slabo pokretne, promenjen im je obrazac kretanja ili, Primary ciliary dyskinesia (PCD) is a rare disease that is inherited in autosomal recessive manner or the inheritance is X-linked, and predominantly affects the functioning of the lungs, reproductive organs and the laterality of the internal organs. PCD is clinically and genetically very heterogeneous disorder that occurs immediately after birth, and is characterized by alterations in motor cilia due to pathogenic variants in genes encoding proteins that are necessary for the proper structure and function of these organelles. So far, there have been described 38 PCD-causative genes, and this number is considered to be much higher given that 2500 proteins participate in the formation and functioning of the cilia. Clinical heterogeneity of PCD patients often leads to the delayed establishment of a precise diagnosis of the disease, and it is not unusual that patients with other lung diseases are classified as PCD patients. The genetic background of the disease in patients with Serbian descent has not been established so far, so the mutational profile involved in the pathogenesis of PCD is necessary. Therefore, within this thesis, genomic profiling of patients with primary ciliary dyskinesia was performed in order to develop a genetic algorithm that, in addition to the described disease-causing pathogenic genetic variants and genes, would include novel variants in the coding regions of PCD-causative and candidate genes. This approach allows the establishment of a strategy for the differential diagnosis of PCD and other lung diseases suspected to ciliopathies that are clinically manifested as PCD. Functional characterization of a novel potentially pathogenic variant in PCD disease-causing genes and genes that have not been associated with PCD so far, but could be associated with the characteristic phenotype of PCD, was performed. One of the main features of PCD is ultrastructural defects of cilia leading to ciliary immotility, abnormal motility, or their absence...

Uvod/Cilj Izmenjena funkcija aksonemalne strukture dovodi do ciliopatija (motornih i senzornih), koje su do sada povezane sa brojnim pedijatrijskim poremećajima, uključujući i respiratorne. Primarna cilijarna diskinezija (PCD) najčešća je ciliopatija, koja nastaje kao posledica poremećaja u motornim cilijama. Promenjena struktura i/ ili funkcija motornih cilija dovodi do neonatalnog respiratornog distresa, hroničnog vlažnog kašlja, simptoma nazalne sekrecije, bronhoektazija, hronične upale sinusa i uha, a 50% bolesnika ima i situs inversus. Ovi simptomi su prilično uobičajeni kod male dece i u drugim stanjima; stoga je uspostavljanje precizne dijagnoze otežano. Cilj ovog istraživanja je ukazivanje na značaj genomskog profilisanja bolesnika i dizajniranje strategije za genetičku analizu podataka kod bolesnika suspektnih na ciliopatije sa kliničkom slikom sličnom drugim bolestima pluća. Metode Sproveli smo bioinformatičku analizu podataka dobijenih metodom sekvenciranja nove generacije 21 bolesnika sa potvrđenom ili suspektnom dijagnozom PCD-a. Analizirano je 93 gena: 29 PCD gena, 45 gena asociranih sa pojedinačnim simptomima plućnih bolesti i 19 gena asociranih sa senzornim ciliopatijama. Rezultati Dizajnirani algoritam za genetičku analizu NAM je omogućio da potvrdimo kliničku i uspostavimo genetičku dijagnozu kod 17/21 (80,95%) bolesnika, među kojima je 11/21 (52,38%) PCD bolesnika. Kod 3/21 (14,28%) bolesnika detektovane su monoalelske varijante u PCD genima, kod 6/21 (28,57%) bolesnika detektovane su varijante u genima relevantnim za druga plućna oboljenja, dok je kod 1/21 (4,76%) bolesnika genetička osnovna bolesti ostala nerazjašnjena. Zaključak Dizajniranje strategije za lakše i brže uspostavljanje konačne dijagnoze ciliopatija je obavezno i uključuje i kliničku i genetičku potvrdu bolesti., Introduction/Objective Dysfunction of the axonemal structure leads to ciliopathies. Sensory and mo-tile ciliopathies have been associated with numerous pediatric diseases, including respiratory diseases. Primary ciliary dyskinesia (PCD) is ciliopathy linked to the dysfunction of motile cilia. Motile ciliary dys-function in childhood leads to chronic rhinosinusitis, persistent cough, neonatal respiratory distress, bronchiectasis, and situs inversus (SI) have 50% of patients. These symptoms are common among pediatric lung diseases, which additionally makes it difficult to establish the accurate diagnosis. The aim of the study was to point out the significance of genomic profiling for patients with suspected ciliopathies and to design a strategy for genomic analysis relevant for differential diagnosis of lung disease patients with suspected ciliopathies. Methods We conducted a bioinformatic analysis of data generated by New Generation Sequencing (NGS) approach of 21 patients with final or suspected diagnosis of PCD. It was analyzed 93 genes: 29 PCD genes, 45 genes related to individual symptoms of lung diseases, and 19 genes related to sensory ciliopathies. Results the algorithm we have designed, enabled us to establish the clinical and genetic diagnosis for 17/21 (80.95%) patients, among which 11/21 (52.38%) were PCD patients. In 3/21 (14.28%) patients we detected monoallelic variants in PCD disease-causing genes. In 6/21 (28.57%) patients, variants in genes for other pulmonary diseases were detected, and for one patient, genetic background of disease remained unclear. Conclusion an improved strategy for easier and faster establishment of final diagnosis of ciliopathies is mandatory and includes both, clinical and genetic confirmation of disease.

Astma kao jedna od najčešćih hroničnih bolesti utiče ne samo na fizičko nego i na mentalno zdravlje pacijenta. U mlađoj populaciji, uključujući i studente univerziteta, astma je od posebnog značaja, zbog više prevalencije u poređenju sa drugim hroničnim bolestima. Adolescenti sa astmom su u dva puta većem riziku za psihološke poremećaje kao što su anksioznost i depresija i u povećanom riziku za smrtni ishod zbod nje. Anksioznost i depresivnost su nezavisni faktori rizika za lošu kontrolu astme. Uloga aleksitimije, kao posebne specifične psihološke karakteristike opisane kao smanjene mogućnosti u prepoznavanju i opisivanju emocija, i povezanost sa nivoom anksioznosti i depresivnosti u astmi, takođe je prepoznata. Prevalencija aleksitimije je procenjena na 8-19% u opštoj populaciji, ali je primećena i kod obolelih od hroničnih bolesti. Aleksitimija može biti povezana sa rekurentnim veoma teškim egzacerbacijama kod obolelih od astme. Postoji mali broj istraživanja koja su pratila specifičnu ulogu aleksitimije u populaciji univerzitetskih studenta sa astmom. Cilj ove studije je bio da se odredi prevalencija aleksitimije kod studenata sa astmom, i njena relacija sa plućnom fumkcijom, anksioznošću i depresivnošću. Takođe, cilj je bio i validacija srpske verzije testa za kontrolu astme (ACT) kod obolelih od astme. Metod. Studija preseka je sprovedena u Zavodu za zdravstvenu zaštitu studenata u Beogradu, Srbija, i uključila je 210 studenata univerziteta sa astmom i 201 zdravog studenta kao kontrolnu grupu. Toronto aleksitimija skala (TAS-20) je korišćena za procenu aleksitimije i poređenje skorova tri glavna faktora aleksitimije: teškoće u prepoznavanju osećanja (Faktor 1), teškoće u opisivanju osećanja (Faktor 2) i eksterno orijentisano mišljenje (Faktor 3). Svi ispitanici su podvrgnuti spirometrijskom testiranju, procenjena im je kontrola astme korišćenjem Testa za kontrolu astme i na osnovu preporuka Globalne inicijative za astmu (GINE) i psihometrijski parametri su prez, Asthma as one of the most prevalent chronic disease has impact not only on physical but also on mental health of the patient. In younger population, including university students, asthma is of special importance, having higher prevalence compared to other chronic diseases. Adolescents with asthma are at two-fold higher risk of psychological disorders such as anxiety and depression and are at increased risk for asthma death as well. Anxiety and depression are independant risk factors for poor asthma control. The role of alexithymia, as separate specific psychological feature described as lack of capability to identify and verbalize emotions, and association with levels of anxiety and depression in asthma has also been recognized. Prevalence of alexithymia is estimated to be 8-19% in general population, observed also in chronic diseases. Alexithymia may be related to recurrent very severe asthma exacerbations in patients with asthma. Limited research was published specifically at the role of alexithymia in university student population with asthma. The aim of this study was to determine prevalence of alexithymia in students with asthma, and its relationship with pulmonary function, anxiety and depression. Also, the aim was to validate Serbian version of the Asthma control test (ACT) in patients with athma. Method. The cross-section study was conducted in the Institute for Students Health Care in Belgrade, Serbia, including 210 university students diagnosed with asthma and 201 healthy students as control group. Toronto Alexithymia Scale (TAS-20) was used for alexithymia assessment and compared with scores for the three main alexithymia factors: difficulty identifying feelings (Factor 1), difficulty describing feelings (Factor 2) and externally-oriented thinking (Factor 3). All subjects underwent spirometry. Asthma control was assessed by Asthma Control test (ACT) score and Global Initiative for Asthma (GINA) guidelines and psychometric parameters presented by Beck’s De

Primary ciliary dyskinesia (PCD) is a rare inherited autosomal recessive or X-linked disorder that mainly affects lungs. Dysfunction of respiratory cilia causes symptoms such as chronic rhinosinusitis, coughing, rhinitis, conductive hearing loss and recurrent lung infections with bronchiectasis. It is now well known that pathogenic genetic changes lead to ciliary dysfunction. Here we report usage of clinical-exome based NGS approach in order to reveal underlying genetic causes in cohort of 21 patient with diagnosis of PCD. By detecting 18 (12 novel) potentially pathogenic genetic variants, we established the genetic cause of 11 (9 unrelated) patients. Genetic variants were detected in six PCD disease-causing genes, as well as in SPAG16 and SPAG17 genes, that were not detected in PCD patients so far, but were related to some symptoms of PCD. The most frequently mutated gene in our cohort was DNAH5 (27.77%). Identified variants were in homozygous, compound heterozygous and trans-heterozygous state. For detailed characterization of one novel homozygous genetic variant in DNAI1 gene (c. 947_948insG, p. Thr318TyrfsTer11), RT-qPCR and Western Blot analysis were performed. Molecular diagnostic approach applied in this study enables analysis of 29 PCD disease-causing and related genes. It resulted in mutation detection rate of 50% and enabled discovery of twelve novel mutations and pointed two possible novel PCD candidate genes.

The Burkholderia cepacia complex (Bcc) organisms remain significant pathogens in patients with cystic fibrosis (CF). This study was performed to evaluate the prevalence, epidemiological characteristics, and presence of molecular markers associated with virulence and transmissibility of the Bcc strains in the National CF Centre in Belgrade, Serbia. The Bcc isolates collected during the four-year study period (2010-2013) were further examined by 16 s rRNA gene, pulsed-field gel electrophoresis of genomic DNA, multilocus sequence typing analysis, and phylogenetic analysis based on concatenated sequence of seven alleles. Fifty out of 184 patients (27.2 %) were colonized with two Bcc species, B. cenocepacia (n = 49) and B. stabilis (n = 1). Thirty-four patients (18.5 %) had chronic colonization. Typing methods revealed a high level of similarity among Bcc isolates, indicating a person-to-person transmission or acquisition from a common source. New sequence types (STs) were identified, and none of the STs with an international distribution were found. One centre-specific ST, B. cenocepacia ST856, was highly dominant and shared by 48/50 (96 %) patients colonized by Bcc. This clone was characterized by PCR positivity for both the B. cepacia epidemic strain marker and cable pilin, and showed close genetic relatedness to the epidemic strain CZ1 (ST32). These results indicate that the impact of Bcc on airway colonization in the Serbian CF population is high and virtually exclusively limited to a single clone of B. cenocepacia. The presence of a highly transmissible clone and probable patient-to-patient spread was observed.

Gljive su poslednjih decenija postale jedan od vodećih uzročnika bolesti kod ljudi. Obzirom na opšteprisutnost u vazduhu i životnom prostoru (indoor i outdoor), gljive su česti izazivači gljivičnih oboljenja gornjih i donjih partija respiratornog trakta (RT) gde dovode do hroničnih oboljenja. Gljive prisutne u prašini i vazduhu bolesničkih soba, klima uređajima, vodovodnim cevima i vlažnim zidovima kupatila, predstavljaju važan rezervoar infekcije. Lako se šire putem vazduha i imaju sposobnost da prodru do najnižih delova donjih partija RT, ili da se zadrže u sinusnim šupljinama. Gljivične spore dimenzija 10 do 100 μm bivaju zaustavljene u sinusima, nosnom kavumu, farinksu i larinksu i na ovim mestima stvaraju depozite. U RT vladaju tamni, topli i vlažni uslovi koji predstavljaju idealne uslove za razmnožavanje plesni u plućima. Najčešći "outdoor" izolati gljiva su vrste roda Aspergillus, Penicillium i Cladosporium, dok su najčešći "indoor" izolati gljiva vrste roda Stachybotris, Fusarium i Rhodotorula. Izloženost ljudi "indoor" i "outdoor" gljivičnim sporama u vazduhu je neizbežna, a inhalacija spora gljiva je jedan od „okidača“ za nastanak imunopatoloških procesa u RT, koji može biti u vidu alergijske reakcije ili infekcije. Gljive koje uzrokuju oboljenja ljudi se mogu podeliti na dve kategorije prema patogenom potencijalu: oportunističke i striktno patogene. Najčešći izazivači gljivičnih infekcija (GI) RT su oportunističke plesni. Brzo i tačno dokazivanje prisustva gljiva u donjim i gornjim partijama RT je veoma važno zbog pravovremene primene terapije, skraćenja trajanja bolesti, snižavanja procenta nastanka komplikacija i sprečavanja razvoja invazivnih GI (IGI). Dijagnoza GI RT zavisi od brojnih faktora kao što su stručnost kliničara da pravovremeno posumnja na GI, pravilno odabran i uzorkovan klinički materijal, vreme potrebno od uzorkovanja do rezultata i senzitivnosti (Sn) i specifičnosti (Sp) postojećih dijagnostičkih testova. Kultivacija kliničkih uzoraka, In recent decades fungi become one of the leading causes of disease in humans. Given fungi are widespread in the air and in the living space (indoor and outdoor), fungi are commonly cause fungal infections (FI) of the upper and lower respiratory tract (RT) which lead to chronic infection. Fungi are present in dust and air of hospital rooms, air conditioning and damp walls bathrooms, represent an important reservoir of infection. It is easily spread through the air and have the ability to penetrate to the lowest parts of the RT, or to be kept in the sinus cavities. Spore sized 10 to 100 microns are stopped in the sinuses, nasal cavity, pharynx and larynx and in these places create deposits. The RT ruled dark, warm and moist conditions that are ideal for the propagation of fungi in the lungs. The most common outdoor isolates of fungi are Aspergillus, Penicillium and Cladosporium, whereas the most common outdoor isolates are Stachybotris, Fusarium and Rhodotorula. Human exposure to indoor and outdoor fungal spores in the air is inevitable and the inhalation of fungal spores is one of the "trigger" for the development of immunopathological processes in the RT, which can be in the form of allergic reactions or infection. Fungi that cause diseases in humans can be divided into two categories according to the pathogenic potential: opportunistic and strict pathogens. The most frequent causes of FI of RT are opportunistic molds. Detection of fungi in RT is crucial for timely initiation of therapy and positive outcome. Diagnosis of FI in RT depends on numerous factors such as the expertise of clinicians to make timely suspects FI, properly selected and sampled clinical material, the time required from sampling to results and sensitivity (Sn) and specificity (Sp) of existing diagnostic tests. Cultivation of clinical samples from the upper and lower parts of the RT is the "gold standard" for diagnosis of FI. Sn of mycological methods for the detection of fungus varies with the

Introduction It has been suggested that asthmatic patients may have a higher risk for oral diseases, both as a result of the medical condition and effects of medications. Objective The aim of the study was to determine the oral health status of children with asthma and to evaluate the oral health parameters according to the medications and severity of the disease. Methods The study group consisted of 158 children with asthma and 100 healthy control subjects aged 2-18 years. The diagnosis of dental caries was performed using the Decayed, Missing, and Filled Teeth (DMFT/dmft) criteria. The oral hygiene, periodontal status and gingival health were assessed with the Simplified Oral Hygiene Index (Greene-Vermillion), Community Periodontal Index of Treatment Needs and Gingival Index (Loe-Silness), respectively. Results Thirty (19%) patients with asthma and 43 (43%) healthy children were caries-free (p lt 0.001). There were no significant differences between asthmatic and control children in caries experience (for children with asthma mean DMFT=2.1±}1.8, mean dmft=4.2±}3.3; for healthy children mean DMFT=2.5±}0.9, mean dmft=5.2±}1.3). Level of asthma control did not have influence on dental health, while dose of inhaled corticosteroid had impact on primary dentition. Periodontal status and gingival health did not differ between asthmatic and control children. However, children with asthma had poorer oral hygiene (p lt 0.001). Conclusion Results of the study do not show a relationship between asthma and oral diseases. However, further improvement could be made in educating children and parents on the importance of good oral hygiene and prevention of oral diseases., Uvod Stavovi o oralnom zdravlju dece obolele od astme još nisu usaglašeni, a mogući nepovoljni uticaji lekova koji se koriste u lečenju nisu potpuno definisani. Cilj rada Cilj rada je bio da se utvrdi stanje oralnog zdravlja dece obolele od astme i ispita povezanost primene lekova i stepena kontrole bolesti na pojavu oralnih oboljenja kod ove dece. Metode rada U istraživanje je uključeno 158 dece obolele od astme i 100 zdrave dece uzrasta 2-18 godina kod koje je analizirano stanje oralnog zdravlja. Ispitani su: zastupljenost oboljenja zuba (indeks KEP/kep), stanje gingive (Loe-Silnesov gingivalni indeks), zastupljenost parodontalnih oboljenja (zajednički parodontalni indeks) i nivo oralne higijene (Grin-Vermilionov indeks). Rezultati Tridesetoro dece obolele od astme (19,0%) i 43 zdrave dece (43,0%) imalo je sve zdrave zube (p lt 0,001). Prosečna zastupljenost karijesa kod zdravih ispitanika(prosečna vrednost indeksa KEP bila je 2,5±}0,9, a indeksa kep 5,2±}1,3) i dece obolele od astme (prosečna vrednost indeksa KEP bila je 2,1±}1,8, a indeksa kep 4,2±}3,3) bila je bez značajne razlike. Stepen kontrole astme nije uticao na zdravlje zuba, dok je doza inhalacionih kortikosteroida pokazala uticaj u mlečnoj denticiji. Parodontalni status i zdravlje gingive nisu se razlikovali između dece obolele od astme i zdravih ispitanika. Deca obolela od astme imala su značajno lošiju higijenu usta i zuba (p lt 0,001). Zaključak Rezultati istraživanja ne ukazuju na povezanost astme i oralnih oboljenja kod dece. Loša higijena usta i zuba kod dece obolele od astme ukazuje na potrebu dodatne edukacije i primene posebnih programa prevencije, kako bi se rizici za nastanak ovih oboljenja sveli na najmanju meru.

Retov sindrom (RTT) je teţak neurorazvojni poremećaj koji se uglavnom susreće kod osoba ţenskog pola. U različitim delovima sveta RTT ima prevalenciju od 0,4-2,23:10000 devojčica. Kod većine bolesnika nastaje usled mutacija MECP2 gena. Ciljevi rada: ispitavanje epidemioloških i kliničkih karakteristika RTT u populaciji Srbije; ispitivanje genotipsko-fenotipske korelacije u našoj sredini, te prognostičkog značaja odabranih demografskih, kliničkih i genetičkih varijabli; ispitivanje depresivnosti i kvaliteta ţivota majki koje se staraju o deci sa RTT. Materijal i metode: Studija je obuhvatila 102 bolesnice kod kojih je RTT dijagnostikovan izmeĎu 1987. i 2011. godine. Za utvrĎivanje epidemioloških parametara (incidencije i prevalencije) korišćeni su podaci o vitalnoj statistici Republičkog zavoda za statistiku Srbije. Korišćena je medicinska dokumentacija Instituta za zdravstvenu zaštitu majke i deteta Srbije i rezultati molekularnih analiza učinjenih u laboratoriji Biološkog fakulteta u Beogradu. Za analizu rezultata korišćene su deskriptivne i analitičke statističke metode. Rezultati: Incidencija RTT u Srbiji iznosi 0,586:10000 ţivoroĎene ţenske dece. Većina bolesnica (86%) ima klasični oblik RTT. Najčešće mutacije u MECP2 genu u populaciji bolesnica sa RTT u Srbiji su T158M, R255X i R168X. Epilepsija je prisutna kod 70,5% obolelih u ispitivanoj grupi. Prema rezultatima Kaplan-Meierove funkcije preţivljavanja, bolesnice sa RTT u Srbiji imaju veći rizik za rani smrtni ishod nego što pokazuju studije iz razvijenih sredina. Najčešći uzrok smrti ovih bolesnica u Srbiji bila je pneumonija. Klinički skor teţine bolesti (Clinical Severity Score, CSS) je bio najsnaţniji prediktor smrtnog ishoda kod RTT. Pokazana je visoka prevalencija teške depresije od 30,6% meĎu majkama koje se staraju o deci sa RTT. Zaključak: Incidencija RTT u Srbiji odgovara nalazima velikih studija iz drugih zemalja. Postoji genotipsko-fenotipska korelacija za više kliničkih aspekata RTT. PotvrĎena je, Introduction: Rett Syndrome (RTT) is severe neurodevelopmental disorder which mainly affects females. Prevalence of RTT ranges from 0,4-2,23:10000 girls in different populations worldwide. Majority of cases are caused by mutations in MECP2 gene. Objectives: investigation of epidemiological and clinical features of RTT in population of Serbia; investigation of genotype-phenotype correlation and evaluation of prognostic value of selected demographic, clinical and genetic factors; investigation of depression and health-related quality of life in mothers giving care to children with RTT. Matherial and methods: Study included 102 female patients with RTT diagnosed between 1987. and 2011. Estimation of epidemiological parameters (incidence i prevalence) was based on vital statistics provided by Statistical Office of the Republic of Serbia. Medical documentation of Mother and Child Health Institute of Serbia was used, as well as genetic diagnosis reports from Biological Faculty in Belgrade. Data analysis included descriptive and analytical statistical methods. Results: Incidence of RTT in Serbia is estimated at 0,586:10000 live female births. Majority of patients (86%) have classical type of RTT. Most common mutations in Serbian population with RTT were T158M, R255X and R168X. Epilepsy was present in 70,5% of our group. According to Kaplan-Meier survival analysis, Serbian RTT patients had higher risk for earlier mortality than shown in studies from developed countries. Pneumonia was the most frequent cause of death in our RTT group. Clinical Severity Score (CSS) was the strongest single predictor of lethal outcome in RTT patients. High prevalence of severe depression (30,6%) was noted in mothers giving care to children with RTT. Conclusion: Incidence of RTT in Serbia corresponds to findings of major epidemiological studies. The genotype-phenotype correlation is present regarding certain clinical aspects of RTT. Value of CSS in evaluating severity of the RTT and predicting

Uvod: Cistična fibroza (CF) je najčešća nasledna monogenetska bolest u našoj populaciji. Učinjenim istraživanjem omogućeno je razumevanje mehanizama ventilatornog ograničenja i intolerancije napora kod obolelih od CF. Ciljevi istraživanja: U toku istraživanja procenjivan je aerobni kapacitet i indeks disajne rezerve obolelih od CF s različitim stepenom poremećaja funkcije pluća. Ispitivana je povezanost stanja uhranjenosti, snage disajnih mišića i radiografskih promena na plućima na rezultate ergospirometrijskih ispitivanja. Metodologija: Spirometrija je merena na pneumotahografskom sistemu, a telesna pletizmografija po principu konstantnog volumena. Ergospirometrija je učinjena na ergobiciklu po „ramp” protokolu, uz predhodnu kanilaciju arterijskog krvnog suda zbog dobijanja uzoraka krvi za određivanje sadržaja respiracijskih gasova i koncentracije laktata. Snaga disajnih mišića merena je posebnim instrumentom i izražavana vrednostima maksimalnih inspirijumskih i ekspirijumskih pritisaka. Učinjena je standardna radiografija grudnog koša u dva pravca, a snimci su potom ocenjivani prema radiografskom skoru po Chrispin i Normanu. Rezultati istraživanja: U istraživanje su uključena 64 obolela od CF (32 muškog i 32 ženskog pola, prosečnog uzrasta 17,1 godinu). Pokazana je značajna pozitivna korelacija parametara plućne funkcije s vršnim opterećenjem i aerobnim kapacitetom u toku ergospirometrije. Odnos rezidualnog volumena i totalnog plućnog kapaciteta – RV/TLC, je najznačajniji prediktivni činilac tolerancije napora. Vrednosti forsiranog ekspirijumskog volumena u prvoj sekundi (FEV1) je najvažniji prediktivni činilac ventilatornog ograničenja. Hipoksemija i desaturacija hemoglobina kiseonikom <90% prisutni su kod bolesnika s malnutricijom i najtežim poremećajem plućne funkcije. Nije utvrđen uticaj snage disajnih mišića na vrednosti vršnog opterećenja, aerobnog kapaciteta i indeksa disajne rezerve. Bolesnici s visokim vrednostima radiografskog skora, dostižu najniže vrš, Introduction: Cystic fibrosis (CF) is the most frequent monogenic inherited disease in Caucasians. Structural changes and decrease in lung function are important mechanisms of ventilatory limitation and exercise intolerance in patients with CF. Aims and goals: The primary goal was to assess the aerobic capacity and breathing reserve index during cardiopulmonary exercise testing (CPET) in patients with CF. The influences of lung function, nutritional status, respiratory muscle strength and changes on chest radiography were also evaluated. Methodology: Patients older than 8 years with CF were recruited in the study. Spirometry and whole body plethysmography were performed before CPET on pneumotach system and using a volume-constant method. Patients performed progressive CPET on an electrically braked cycle ergometer, using a ramp protocol to maximum effort. A catheter was placed either in the brachial or radial artery to draw blood for blood gas analyses and determine lactate concentrations during CPET. Respiratory muscle strength was expressed as maximal inspiratory and expiratory pressure values. Standard chest radiographies were scored according to Chrispin-Norman score. Results: Data collected from 64 patients with CF (32 male, 32 female, mean age 17.1 years) were included in this analysis. Forced expiratory volume in 1 second (FEV1) significantly correlates with peak exercise capacity and aerobic capacity in patients with CF. The relationship between residual volume and total lung capacity (RV/TLC) is the most significant predictive factor of ventilatory limitation. Hypoxemia and oxygen desaturation <90% are present in patients with decreased lung function and malnutrition. The influence of respiratory muscle strength on peak exercise, aerobic capacity and breathing reserve index was not shown. Patients with highest values of Cripsin-norman score have the most prominent exercise limitation during progressive CPET. Conclusion: Aerobic capacity and breathing reserv