Stroke is the third most common cause of death and a leading cause of disability in the United States. The existing treatments of acute ischemic stroke (AIS) involve pharmaceutical thrombolytic therapy and/or mechanical thrombectomy. The Food and Drug Administration (FDA)-approved recombinant tissue plasminogen activator (tPA) administration for treatment of stroke is efficacious, but has a short treatment time window and is associated with a risk of symptomatic hemorrhage. Other than tPA, the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retriever system and the Penumbra Aspiration system are both approved by the FDA for retrieval of thromboemboli in AIS patients. However, the previous clinical studies have shown that the recanalization rate of the MERCI system and the clinical outcome of the Penumbra system are not optimal. To identify the variables which could affect the performance of the thrombectomy devices, much effort has been devoted to evaluate thrombectomy devices in model systems, both in vivo and in vitro, of vascular occlusion. The goal of this study is to establish a physiologically realistic, in vitro model system for the preclinical assessment of mechanical thrombectomy devices. In this study, the model system of cerebrovascular occlusion was mainly composed of a human vascular replica, an embolus analogue (EA), and a simulated physiologic mock circulation system. The human vascular replica represents the geometry of the internal carotid artery (ICA)/middle cerebral artery (MCA) that is derived from image data in a population of patients. The features of the vasculature were characterized in terms of average curvature (AC), diameter, and length, and were used to determine the representative model. A batch manufacturing was developed to prepare the silicone replica. The EA is a much neglected component of model systems currently. To address this limitation, extensive mechanical characterization of commonly used EAs was performed. Importantly, the properties of the EAs were compared to specimens extracted from patients. In the preliminary tests of our model system, we selected a bovine EA with stiffness similar to the thrombi retrieved from the atherosclerotic plaques. This EA was used to create an occlusion in the aforesaid replica. The thrombectomy devices tested included the MERCI L5 Retriever, Penumbra system 054, Enterprise stent, and an ultrasound waveguide device. The primary efficacy endpoint was the amount of blood flow restored, and the primary safety endpoint was an analysis of clot fragments generated and their size distribution. A physiologically realistic model system of cerebrovascular occlusion was successfully built and applied for preclinical evaluation of thrombectomy devices. The recanalization rate of the thrombectomy device was related to the ability of the device to capture the EA during the removal of the device and the geometry of the cerebrovasculature. The risk of the embolic shower was influenced by the mechanical properties of the EA and the design of the thrombectomy device.

Sterile particles underlie the pathogenesis of numerous inflammatory diseases. These diseases can often become chronic and debilitating. Moreover, they are common, and include silicosis (silica), asbestosis (asbestos), gout (monosodium urate), atherosclerosis (cholesterol crystals), and Alzeihmer’s disease (amyloid Aβ). Central to the pathology of these diseases is a repeating cycle of particle-induced cell death and inflammation. Macrophages are the key cellular mediators thought to drive this process, as they are especially sensitive to particle-induced cell death and they are also the dominant producers of the cytokine responsible for much of this inflammation, IL-1β. In response to cytokines or microbial cues, IL-1β is synthesized in an inactive form (pro-IL-1β) and requires an additional signal to be secreted as an active cytokine. Although a multimolecular complex, called the NLRP3 inflammasome, controls the activation/secretion of IL-1β (and has been thought to also control cell death) in response to particles in vitro, the in vivo inflammatory response to particles occurs independently of inflammasomes. Therefore, I sought to better understand the mechanisms governing IL-1β production and cell death in response to particles, focusing specifically on the role of lysosomal cathepsin proteases. Inhibitor studies have suggested that one of these proteases, cathepsin B, plays a role in promoting inflammasome activation subsequent to particle-induced lysosomal damage, however genetic models of cathepsin B deficiency have argued otherwise. Through the use of inhibitors, state-of-the-art biochemical tools, and multi-cathepsin-deficient genetic models, I found that multiple redundant cathepsins promote pro-IL-1β synthesis as well as particle-induced NLRP3 activation and cell death. Importantly, I also found that particle-induced cell death does not depend on inflammasomes, suggesting that this may be why inflammasomes do not contribute to particle-induced inflammation in vivo. Therefore, my observations suggest that cathepsins may be multifaceted therapeutic targets involved in the two key pathological aspects of particle-induced inflammatory disease, IL-1β production and cell death.

Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be due to small subsets of stem-like cancer cells that are able to survive chemotherapy and drive tumor re-growth. A more complete understanding of stem-like cancer cell regulation is required to develop therapies to better target and eliminate these cells. Slow-cycling stem cells are integral components of adult epithelial tissues and may give rise to cancer stem cell populations that share similar characteristics. These slow-cycling adult stem cells are inherently resistant to traditional forms of chemotherapy and transference of this characteristic may help to explain therapy resistance in cancer stem cell populations. Using a novel application for the proliferation marker CFSE, we have identified populations of slow-cycling cancer cells with tumor initiating capabilities. As predicted, slow-cycling cancer cells exhibit a multi-fold increase in chemotherapy resistance and retain the ability to re-enter the cell cycle. Furthermore, we observed consistent over-expression of the CDK5 activator, p35, in slow-cycling cancer cells. Manipulation of p35 expression in cancer cells affects cell cycle distribution and survival when these cells are treated with traditional forms of chemotherapy. Additionally, we demonstrate that alterations in p35 expression affect BCL2 levels, suggesting a mechanism for the survival phenotype. Combined, our data suggest a model whereby slow-cycling stem-like cancer cells utilize the p35/CDK5 complex to slow cell cycling speed and promote resistance to chemotherapy. Future p35 targeting, in combination with traditional forms of chemotherapy, may help eliminate these cells and reduce tumor recurrence rates, increasing long-term patient survival.

Background Obesity is an important risk factor for resistance to insulin-mediated glucose disposal, and is a precursor of type 2 diabetes and other disorders. Objectives To identify molecular pathways in adipose tissue and inflammatory cells that may result in obesity-associated insulin resistance, we exploited the fact that not all obese individuals are prone to insulin resistance. Thus the degree of obesity as a variable was removed by studying obese subjects of similar body mass index (BMI) who are insulin-sensitive (IS) versus insulin-resistant (IR). Methods Combining gene expression profiling with computational approaches, we determined the global gene expression signatures of omental and subcutaneous adipose tissue samples obtained from 10 obese-IR and 10 obese-IS patients undergoing gastric bypass surgery. In a secondary study, we isolated monocytes from 4 obese-IR, 3 obese-IS, and 4 nonobese-IS adolescent and young adult subjects for purposes of assessing differences in expression of inflammatory genes in monocytes using RT-PCR. Results Gene sets related to chemokine activity and chemokine receptor-binding were identified as most highly enriched in the omental tissue from obese-IR compared to obese-IS subjects, independent of BMI. Strikingly, insulin resistance, but not BMI, was associated with increased macrophage infiltration in the omental adipose tissue, as was adipocyte size. In the adolescent and young adult cohort, expression of two cytokine signaling molecules (IL8, SOCS3) and two downstream products of the JNK pathway (JunB, c-Fos) showed increased expression in the obese-IR subjects compared to the obese-IS and nonobese-IS subjects, suggesting the presence of a proinflammatory phenotype in monocytes in obesity, which is exacerbated in the insulin resistant state. Conclusions Our findings demonstrate that inflammation of omental adipose tissue and activation of proinflammatory monocytes is strongly associated with insulin resistance in human obesity. Manipulation of these pathways may result in the prevention of or delay in the onset of obesity-related co-morbidities.

TNFα-induced programmed necrosis is a caspase-independent cell death program that is contingent upon the formation of a multiprotein complex termed the necrosome. The association of two of the components of the necrosome, receptor interacting protein 1 (RIP1) and RIP3, is a critical and signature molecular event during necrosis. Within this complex, both RIP1 and RIP3 are phosphorylated which are consequential for transmission of the pro-necrotic signal. Namely, it has been demonstrated that RIP3 phosphorylation is required for binding to downstream substrates. Nevertheless, the regulatory mechanisms governing necrosome activation remain unclear. Since necrosis is implicated in a variety of different diseases, understanding the biochemical signaling pathway can potentially yield future drug targets. I was interested in identifying other regulators of necrosis in hope of gaining a better understanding of the necrosis signaling pathway and regulators of the necrosome. To address this, I screened a cancer gene siRNA library in a cell line sensitive to necrosis. From this, I independently identified CYLD as a positive regulator of necrosis. Previous studies suggest that deubiquitination of RIP1 in the TNF receptor (TNFR)-1 signaling complex is a prerequisite for transition of RIP1 into the cytosol and assembly of the RIP1-RIP3 necrosome. The deubiquitinase cylindromatosis (CYLD) is presumed to promote programmed necrosis by facilitating RIP1 deubiquitination in this membrane receptor complex. Surprisingly, I found that TNFα could induce RIP1-dependent necrosis in CYLD-/- cells. I show that CYLD does not regulate RIP1 ubiquitination at the receptor complex. Strikingly, assembly of the RIP1-RIP3 necrosome was delayed, but not abolished in the absence of CYLD. In addition to the TNFR-1 complex, I found that RIP1 within the necrosome was also ubiquitinated. In the absence of CYLD, RIP1 ubiquitination in the NP-40 insoluble necrosome was greatly increased. Increased RIP1 ubiquitination correlated with impaired RIP1 and RIP3 phosphorylation, a signature of kinase activation. My results show that CYLD regulates RIP1 ubiquitination in the NP-40 insoluble necrosome, but not in the TNFR-1 signaling complex. Contrary to the current model, CYLD is not essential for necrosome assembly. Rather, it facilitates RIP1 and RIP3 activation within the necrosome and the corollary is enhancement of necrosome functionality and subsequent necrosis. My results therefore indicate that CYLD exerts its pro-necrotic function in the NP-40 insoluble necrosome, and illuminates the mechanism of necrosome activation.

A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed ‘Wallerian degeneration,’ whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wlds) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such as progressive motor neuronopathy), Wlds is able to delay disease onset (for a review, see Coleman, 2005). Wlds has been cloned and was found to be a fusion event of two neighboring genes: Ube4b, which encodes an ubiquitinating enzyme, and NMNAT-1 (nicotinamide mononucleotide adenylyltransferase-1), which encodes a key factor in NAD (nicotinamide adenine dinucleotide) biosynthesis, joined by a 54 nucleotide linker span (Mack et al., 2001). To address the role of Wlds domains in axon protection and to characterize the subcellular localization of Wlds in neurons, our lab developed a novel method to study Wallerian degeneration in Drosophila in vivo (MacDonald et al., 2006). Using this method, we have discovered that mouse Wlds can also protect Drosophila axons for weeks after acute injury, indicating that the molecular mechanisms of Wallerian degeneration are well conserved between mouse and Drosophila. This observation allows us to use an easily manipulated genetic model to move the Wlds field forward; we can readily identify what Wlds domains give the greatest protection after injury and where in the neuron protection occurs. In chapter two of this thesis, I identify the minimal domains of Wlds that are needed for protection of severed Drosophila axons: the first 16 amino acids of Ube4b fused to Nmnat1. Although Nmnat1 and Wlds are nuclear proteins, we find evidence of a non-nuclear role in axonal protection in that a mitochondrial protein, Nmnat3, protects axons as well as Wlds. In chapter 3, I further explore a role for mitochondria in Wlds-mediated severed axon protection and find the first cell biological changes seen in a Wlds-expressing neuron. The mitochondria of Wlds- and Nmnat3-expressing neurons are more motile before injury. We find this motility is necessary for protection as suppressing the motility with miro heterozygous alleles suppresses Wldsmediated axon protection. We also find that Wlds- and Nmnat3- expressing neurons show a decrease in calcium fluorescent reporter, gCaMP3, signal after axotomy. We propose a model whereby Wlds, through production of NAD in the mitochondria, leads to an increase in calcium buffering capacity, which would decrease the amount of calcium in the cytosol, allowing for more motile mitochondria. In the case of injury, the high calcium signal is buffered more quickly and so cannot signal for the axon to die. Finally, in chapter 4 of my thesis, I identify a gene in an EMS-based forward genetic screen which can suppress Wallerian degeneration. This mutant is a loss of function, which, for the first time, definitively demonstrates that Wallerian degeneration is an active process. The mammalian homologue of the gene encodes a mitochondrial protein, which in light of the rest of the work in this thesis, highlights the importance of mitochondria in neuronal health and disease. In conclusion, the work presented in this thesis highlights a role for mitochondria in both Wlds-mediated axon protection and Wallerian degeneration itself. I identified the first cell biological changes seen in Wlds-expressing neurons and show that at least one of these is necessary for its protection of severed axons. I also helped find the first Wallerian degeneration loss-of-function mutant, showing Wallerian degeneration is an active process, mediated by a molecularly distinct axonal degeneration pathway. The future of the axon degeneration field should focus on the mitochondria as a potential therapeutic target.

Background Acute coronary syndromes (ACS) are a major cause of mortality and morbidity in the developed world. By 2020, ACS will be the leading cause of morbidity and mortality worldwide, largely due to substantial increases in ACS burden in developing countries. The developing world has been under-represented in international ACS registries. The Arabian Gulf area is a part of the developing world where little is known about the epidemiology of ACS. The first aim of the dissertation is to compare ACS patient characteristics, current practice patterns, and in-hospital outcomes in the Arabian Gulf area to a large multinational sample. Patients with an ACS suffer numerous clinical complications that worsen their prognosis. Cardiogenic shock (CS) is the most serious complication of ACS and the leading cause of in-hospital death. Despite advances in therapies; CS hospital mortality rates continue to exceed 50%. The second aim of the dissertation is to describe the characteristics of patients presenting with ACS complicated by cardiogenic shock, their management, and outcomes in a large multinational sample. In recent years, ACS has been increasingly affecting younger patients. While marked age-related differences have been observed in the risk of developing as well as the prognosis of ACS, few studies however examined time trends in the epidemiology of ACS in young adult patients. The third aim of the dissertation is to examine trends in frequency rates, patient characteristics, treatment practices, and outcomes in young adults hospitalized with an ACS. Methods Data from two large multinational registries of patients hospitalized with an ACS were used for this investigation. Nearly 65,000 patients were enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, while 6,700 patients participated in the Gulf Registry of Acute Coronary Events (Gulf RACE) in 2007. Results Aim1: Patients in Gulf RACE were significantly younger and were more likely to be male, diabetic, and smoke Compared to GRACE. Patients in Gulf RACE were less likely to receive evidence based therapies. Short-term mortality rates were comparable between the two patient cohorts. Aim2: Compared to patients with no CS, patients with CS were more likely to be older, female, have a history of diabetes, and heart failure. Patients with CS were less likely to receive effective cardiac catheterization and adjunctive cardiac medications. In-hospital case-fatality rate of patients with CS were 59.4%. While in-hospital mortality declines over the study period, incidence rates only showed minor declines. Aim2: Baseline characteristics of patients < 55 years of age did not significantly change, while the use of evidence based therapies increased significantly during the years under study. Rates of short-term adverse outcomes and mortality significantly declined over time. Conclusions We observed marked regional differences in the risk profile, clinical management, and outcomes of patients with an ACS internationally compared to the Arab Middle East. Despite the encouraging trends in the use of evidence based therapies which have likely contributed to the improving trends in the prognosis of ACS, rates of development of ACS, as well as mortality due to ACS complications, remain high.

As more studies accumulate on the impact of diabetes mellitus on the central nervous system, they resound with the same conclusion - diabetes has a detrimental effect on cognition regardless of the presence of comorbidities. Less consistent however, are the specific mental processes wherein these declines are noticeable, and the structural changes that accompany these reductions in mental capacity. From global atrophy to changes in the volume of gray and white matter, to conflicting results regarding the effects of hypo- and hyperglycemic states on the development of the hippocampus, the studies display a variety of results. The goal of this research is to link the structural and compositional changes occurring in the diabetic brain with the clinical and behavioral findings highlighted in the literature, as well as to explore the potential mechanisms behind the pathologic brain state of diabetic encephalopathy. Using diabetic (OVE26) and non-diabetic wild type (FVB) mice as models, differences in the number of hippocampal neurons in the dentate gyrus, and cornu ammonis areas 1,2, and 3 were investigated through Nissl staining. Neurodegeneration was confirmed in those cells determined to be hyperchromatic in the diabetic model through staining with Fluoro-Jade C. Finally, the presence of progenitor cells in the hippocampus was compared in the diabetic and non-diabetic models using Musashi-1 antibodies, to determine whether neurogenesis in these areas is affected by diabetes. These experiments were performed to better understand the effect of DM on learning and memory, and could potentially explain the linkage between diabetes mellitus and the increased prevalence of Alzheimer’s disease, vascular dementia, and depression in this subset of the population.

<p>Akutni respiratorni distres sindrom (ARDS) predstavlja klinički sindrom koji se manifestuje te&scaron;kom respiratornom insuficijencijom sa razvojem akutnog edema pluća u odsustvu znakova popu&scaron;tanja leve polovine srca. S obzirom da ovaj sindrom ima heterogenu etiologiju, progresivan tok i visoku stopu mortaliteta, pravovremena i tačna dijagnoza esencijalna je u primeni efektivne i rane terapije, a samim tim i u pobolj&scaron;anju prognoze bolesti. Cilj ove doktorske disertacije bio je da se ispita povezanost kliničke i patohistolo&scaron;ke dijagnoze ovog sindroma, kao i da se analiziraju i uporede vrednosti kliničkih parametara neophodnih za postavljanje dijagnoze ARDS-a sa patohistolo&scaron;kim parametrima o&scaron;tećenja plućnog tkiva. Studija je obuhvatila 67 pacijenata Instituta za plućne bolesti Vojvodine koji su umrli pod kliničkom slikom ARDS-a i/ili kod kojih je na obdukciji patohistolo&scaron;ki dokazan ARDS. Za postavljanje kliničke dijagnoze ARDS-a kori&scaron;ćeni su kriterijumi The American-European Consensus Conference iz 1994. Nakon semikvantitativne analize patohistolo&scaron;kih parametara difuznog alveolarnog o&scaron;tećenja određivan je histolo&scaron;ki stadijum ARDS-a i svi pacijenti podeljeni su u dve grupe: I grupa - pacijenti u eksudativnoj fazi i II grupa - pacijenti u proliferativnoj fazi difuznog alveolarnog o&scaron;tećenja. Formirane grupe pacijenata upoređivane su u odnosu na vrednosti kliničkih parametara 12h pre smrtnog ishoda. U cilju procene prisustva komorbiditeta analizirani su indeks telesne mase (engl. body mass index- BMI) i podaci o prethodno dijagnostikovanoj arterijskoj hipertenziji. Kod svih pacijenata uključenih u studiju upoređivane su kliničke dijagnoze sa obdukcionim nalazom. Za klasifikaciju autopsijskih dijagnoza kori&scaron;ćena je Goldman-ova klasifikacija. Na osnovu provedenog istraživanja, do&scaron;lo se do zaključka da slaganje klinički dijagnostikovanih i patohistolo&scaron;ki potvrđenih slučajeva ARDS-a iznosi 68%. Senzitivnost kliničke dijagnoze ARDS-a iznosi 82%, a pozitivna prediktivna vrednost 80%. Pacijenti sa nalazom eksudativne faze DAD-a u plućnom tkivu su u najvećem procentu imali klinički težak ARDS, dok su se pacijenti sa nalazom proliferativne faze sindroma če&scaron;će manifestovali pod kliničkom slikom srednje te&scaron;kog ARDS-a, odnosno utvrđeno je da postoji statistička povezanost između nižih vrednosti PaO2/FiO2 i teže faze ARDSa. Patohistolo&scaron;kom analizom promena u plućnom tkivu nađeno je da najvažnija obeležja eksudativne faze ARDS-a predstavljaju: hijaline membrane, edem i krvarenje, dok su se kao najvažnija obeležja proliferativne faze ARDS-a izdvojili: proliferacija pneumocita tipa II, intersticijalna i mutilantna fibroza i organizirajuća pneumonija. Kod pacijenata sa kliničkom dijagnozom ARDS-a kod kojih ARDS nije i patohistolo&scaron;ki dokazan, najče&scaron;ći nalaz na plućima bila je fibrinozno-purulentna bronhopneumonija. Analizom etiolo&scaron;kih faktora koji doprinose razvoju ovog sindroma otkriveno je da je ARDS najče&scaron;će nastao kao posledica delovanja direktnih/pulmonalnih činilaca: pneumonije i virusa gripa H1N1. Najzastupljeniji komorbiditeti prisutni kod pacijenata sa ARDS-om bili su sistemska hipertenzija i gojaznost. Najzad, kod svih pacijenata uključenih u istraživanje upoređivane su kliničke dijagnoze sa obdukcionim nalazom i na osnovu Goldman-ove klasifikacije kliničke dijagnoze i obdukcioni nalaz slažu se u 72% slučajeva. Rezultati ove studije mogli bi se upotrebiti u daljim istraživanjima kako bi omogućili bolji dijagnostički pristup ovom problemu, a samim tim i bolji terapijski pristup i smanjivanje stope mortaliteta.</p> / <p>Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by severe respiratory failure with development of acute pulmonary edema in the absence of left heart failure signs. Since this syndrome has a heterogeneous etiology, progressive course and high mortality, timely and accurate diagnosis is essential in the implementation of effective and early treatment, and therefore in improving the prognosis of the disease. The aim of this PhD thesis was to examine the association between clinical and pathohistological diagnosis of this syndrome, as well as to analyze and compare the values of clinical parameters necessary for the diagnosis of ARDS with pathohistological parameters of diffuse alveolar damage. The study included 67 patients of the Institute for Lung Diseases who died under clinical picture of ARDS and / or in which, at the autopsy, pathohistological diagnosis of ARDS was set. To set up a clinical diagnosis of ARDS the criteria of the American-European Consensus Conference in 1994 were used. After a semi-quantitative analysis of histopathological parameters of diffuse alveolar damage, all patients were divided into two groups: Group I - patients in the exudative stage and Group II - patients in the proliferative phase of diffuse alveolar damage. Formed groups of patients were compared with respect to clinical parameters values 12 h before death. In order to assess the presence of comorbidities body mass index (BMI) and data on previously diagnosed arterial hypertension were analyzed. In all patients included in the study the clinical diagnosis were compared with autopsy findings according to Goldman&#39;s classification. According to this study, agreement of clinically diagnosed and histologically confirmed cases of ARDS is 68%. The sensitivity of clinical diagnosis of ARDS is 82%, and positive predictive value is 80%. Patients with exudative phase of DAD most frequently had a severe form of ARDS, whereas patients with proliferative phase often manifested with moderate form of ARDS, ie it was found that there is a statistical association between lower values PaO2 / FiO2 and more severe phase of ARDS. Pathological analysis of changes in lung tissue revealed that the most important characteristics of exudative phase of ARDS are: hyaline membrane, edema and bleeding, while the most important features of the proliferative phase of ARDS are: the proliferation of type II pneumocytes, interstitial fibrosis and mutilating and organizing pneumonia. In patients with a clinical diagnosis of ARDS in which ARDS was not pathohistologically proven, the most common finding in the lungs was fibrinous-purulent bronchopneumonia. The analysis of etiological factors that contribute to the development of this syndrome discovered that ARDS usually develop as a result of pulmonary factors: pneumonia and influenza virus H1N1. The most common comorbidities present in patients with ARDS were systemic hypertension and obesity. Finally, in all patients included in the study clinical diagnosis and autopsy findings were compared and based on Goldman&#39;s classification clinical diagnosis and autopsy findings are in agreement in 72% of cases. The results of this study could be used in further research to enable better diagnostic approach to this problem, and therefore a better therapeutic approach and reducing mortality rates.</p>

<p>Увод: Астма као хронично оболење представља велики здравствени, социјални и економски проблем широм света Ово оболење једно је од најчешћих хроничних оболења код деце и најчешћи узрок повећаног броја хоспитализација код деце млађе од 15 година. Резултати досадашњих студија говоре у прилог пораста преваленције астме и алергијских болести код деце у последњих десетак година. Епидемиолошка испитивања су значајна за разумевање природе астме, као и откривања могућих фактора за тренд пораста учесталости астме код деце. Разлика у географској дистрибуцији учесталости симптома астме унутар исте земље сугерише да фактори средине, више него можда генетски фактори, утичу на дистрибуцију преваленције симптома астме. У литератури се као најзначајнији фактори средине истичу загађење животне средине и климатски фактора. Доступне студије показују да постоји узрочна повезаност између повећане изложености загађењу животне средине и акутних респираторних симптома. Процењено је да је у Европи током 2000. године дошло до губитка 3,6 милиона година живота услед повећања концентрације респирабилних честица. И новије препоруке Светске здравствене организације одлучно предлажу смањење изложености деце загађујућим материјама. Резултати доступних студија сугеришу да ефекти загрејавања и топлотних таласа, као и ниских темепратура, утичу на морбидитет и учесталост хоспитализација деце са астмом. Циљеви истраживања били су одредити преваленцију симптома астме код деце узраста од 6 до 15 година на територији Републике Српске, затим одредити утицај загађујућих материја животне средине и климатских фактора на преваленцију симптома астме код деце узраста од 6 до 15 година на територији Републике Српске. Материјал и методе: Истраживање је проведено у облику студије пресека и обухватало је 3000 деце узраста од 6 до 15 година из 13 основних школа на територији Републике Српске. Преваленција симптома астме код деце узраста од 6 до 15 година одређивала се путем упитника Интернационалне студије за астму и алергије код деце (The International Study of Asthma and Allergies in Childhood &ndash; ISAAC). Овај упитник дизајниран је за потребе мултицентричне студије о преваленцији астме, алергијског ринитиса и екцема код деце. Мерење квалитета ваздуха обухватало је следеће параметре: сумпoр диoксид SO2 (&mu;g/m3), угљен мoнoксид CO (mg/m3), азот диоксид NO2 (&mu;g/m3), oзoн O3 (&mu;g/m3) и респирабилне честице PM10 (&mu;g/m3). Континуирана мерења компоненти загађености ваздуха вршила су се на метеоролошком опсерваторију гдје су се континуирано мерили имисионе концентрације стационарним еколошким лабораторијем. Мерења климатских фактора на станицама Републичког хидрометеоролошког завода Републике Српске вршила су се према стандардима Светске метеоролошке организације (WMO). Мерења су се вршила у оквиру метеорoлошког круга који се налази на отвореном простору да би се избегао вештачки утицај околине и у одређеним терминима у зависности од ранга станице. Подаци су анализирани уз помоћ статистичког софтвера IBM SPSS Statistics 21. Резултати: Визинг у последњих 12 месеци имало је 7,9% деце укључене у студију. Дијагнозу астме икада имало је постављено 3,5% испитаника. Статистички значајну учесталост недијагностиковане астме имала су деца са блажим симптомима астме у последњих 12 месеци. Сув кашаљ ноћу био регистрован је код 14,8% испитаника. Код дечака је била значајно виша преваленција визинга у последњих 12 месеци и сувог кашља него код девојчица. Код превремено рођене деце статистички значајно је виша преваленција свих симптома астме. Регистрована је и значајна релација између пушења међу укућанима и појаве визинга у последњих 12 месеци (&chi;2 (1, N=1956) = 5,13, p=0,02). Код испитаника чији укућани су пушачи била је виша преваленција овог симптома (9,6%) у односу на децу чији укућани не пуше (6,7%). Пушење мајки у трудноћи статистички значајно је утицало на преваленцију свих симптома астме код деце. Концентрација азот оксида и PM10 је статистички значајно повезана са преваленцијом визинга и сувог кашља у последњих 12 месеци, док је повезаност са преваленцијом дијагнозе астме код деце на маргини статистичке значајности. Концентрација сумпор диоксида и озона је статистички значајно повезана са преваленцијом визинга у последњих 12 месеци. Преваленција астме у планинској регији је 7,3%, у умерено-континенталној регији је 8,0% и медитеранској регији 8,4%. Просечна годишња температура даје статистички значајан допринос предвиђању појаве визинга у последњих 12 месеци међу децом која су икада имали визинг у току живота. Са порастом просечне годишње температуре за 1 степен вероватноћа појаве визинга у последњих 12 месеци је 1,98 пута већа међу децом која су икада имала визинг. Пораст максималне просечне дневне температуре статистички значајно утиче на појаву визинга у току живота и сувог кашља у последњих 12 месеци. Постоји статистички значајна повезаност између минималне просечне дневне температуре и појаве визинга толико тешког да дете није у могућности изговорити неколико речи између два удаха. Закључак: Мушки пол, рођење пре термина, изложеност дуванском диму и пушење мајке током трудноће представљају статистички значајане ризике за развој астме код детета. Дечаци, деца млађег узраста, превремено рођена деца и деца храњена млечним формулама у првих 6 месеци живота имају статистичи значајан ризик за развој сувог кашља. Статистички значајну повезаност са преваленцијом астме код деце имају следеће мерене загађујуће материје: SO2, O3, азот оксиди и PM10. Статистички значајну повезаност са преваленцијом астме код деце има пораст просечне годишње температуре и више вредности максималне просечне дневне температуре.</p> / <p>Uvod: Astma kao hronično obolenje predstavlja veliki zdravstveni, socijalni i ekonomski problem širom sveta Ovo obolenje jedno je od najčešćih hroničnih obolenja kod dece i najčešći uzrok povećanog broja hospitalizacija kod dece mlađe od 15 godina. Rezultati dosadašnjih studija govore u prilog porasta prevalencije astme i alergijskih bolesti kod dece u poslednjih desetak godina. Epidemiološka ispitivanja su značajna za razumevanje prirode astme, kao i otkrivanja mogućih faktora za trend porasta učestalosti astme kod dece. Razlika u geografskoj distribuciji učestalosti simptoma astme unutar iste zemlje sugeriše da faktori sredine, više nego možda genetski faktori, utiču na distribuciju prevalencije simptoma astme. U literaturi se kao najznačajniji faktori sredine ističu zagađenje životne sredine i klimatski faktora. Dostupne studije pokazuju da postoji uzročna povezanost između povećane izloženosti zagađenju životne sredine i akutnih respiratornih simptoma. Procenjeno je da je u Evropi tokom 2000. godine došlo do gubitka 3,6 miliona godina života usled povećanja koncentracije respirabilnih čestica. I novije preporuke Svetske zdravstvene organizacije odlučno predlažu smanjenje izloženosti dece zagađujućim materijama. Rezultati dostupnih studija sugerišu da efekti zagrejavanja i toplotnih talasa, kao i niskih temepratura, utiču na morbiditet i učestalost hospitalizacija dece sa astmom. Ciljevi istraživanja bili su odrediti prevalenciju simptoma astme kod dece uzrasta od 6 do 15 godina na teritoriji Republike Srpske, zatim odrediti uticaj zagađujućih materija životne sredine i klimatskih faktora na prevalenciju simptoma astme kod dece uzrasta od 6 do 15 godina na teritoriji Republike Srpske. Materijal i metode: Istraživanje je provedeno u obliku studije preseka i obuhvatalo je 3000 dece uzrasta od 6 do 15 godina iz 13 osnovnih škola na teritoriji Republike Srpske. Prevalencija simptoma astme kod dece uzrasta od 6 do 15 godina određivala se putem upitnika Internacionalne studije za astmu i alergije kod dece (The International Study of Asthma and Allergies in Childhood &ndash; ISAAC). Ovaj upitnik dizajniran je za potrebe multicentrične studije o prevalenciji astme, alergijskog rinitisa i ekcema kod dece. Merenje kvaliteta vazduha obuhvatalo je sledeće parametre: sumpor dioksid SO2 (&mu;g/m3), ugljen monoksid CO (mg/m3), azot dioksid NO2 (&mu;g/m3), ozon O3 (&mu;g/m3) i respirabilne čestice PM10 (&mu;g/m3). Kontinuirana merenja komponenti zagađenosti vazduha vršila su se na meteorološkom opservatoriju gdje su se kontinuirano merili imisione koncentracije stacionarnim ekološkim laboratorijem. Merenja klimatskih faktora na stanicama Republičkog hidrometeorološkog zavoda Republike Srpske vršila su se prema standardima Svetske meteorološke organizacije (WMO). Merenja su se vršila u okviru meteorološkog kruga koji se nalazi na otvorenom prostoru da bi se izbegao veštački uticaj okoline i u određenim terminima u zavisnosti od ranga stanice. Podaci su analizirani uz pomoć statističkog softvera IBM SPSS Statistics 21. Rezultati: Vizing u poslednjih 12 meseci imalo je 7,9% dece uključene u studiju. Dijagnozu astme ikada imalo je postavljeno 3,5% ispitanika. Statistički značajnu učestalost nedijagnostikovane astme imala su deca sa blažim simptomima astme u poslednjih 12 meseci. Suv kašalj noću bio registrovan je kod 14,8% ispitanika. Kod dečaka je bila značajno viša prevalencija vizinga u poslednjih 12 meseci i suvog kašlja nego kod devojčica. Kod prevremeno rođene dece statistički značajno je viša prevalencija svih simptoma astme. Registrovana je i značajna relacija između pušenja među ukućanima i pojave vizinga u poslednjih 12 meseci (&chi;2 (1, N=1956) = 5,13, p=0,02). Kod ispitanika čiji ukućani su pušači bila je viša prevalencija ovog simptoma (9,6%) u odnosu na decu čiji ukućani ne puše (6,7%). Pušenje majki u trudnoći statistički značajno je uticalo na prevalenciju svih simptoma astme kod dece. Koncentracija azot oksida i PM10 je statistički značajno povezana sa prevalencijom vizinga i suvog kašlja u poslednjih 12 meseci, dok je povezanost sa prevalencijom dijagnoze astme kod dece na margini statističke značajnosti. Koncentracija sumpor dioksida i ozona je statistički značajno povezana sa prevalencijom vizinga u poslednjih 12 meseci. Prevalencija astme u planinskoj regiji je 7,3%, u umereno-kontinentalnoj regiji je 8,0% i mediteranskoj regiji 8,4%. Prosečna godišnja temperatura daje statistički značajan doprinos predviđanju pojave vizinga u poslednjih 12 meseci među decom koja su ikada imali vizing u toku života. Sa porastom prosečne godišnje temperature za 1 stepen verovatnoća pojave vizinga u poslednjih 12 meseci je 1,98 puta veća među decom koja su ikada imala vizing. Porast maksimalne prosečne dnevne temperature statistički značajno utiče na pojavu vizinga u toku života i suvog kašlja u poslednjih 12 meseci. Postoji statistički značajna povezanost između minimalne prosečne dnevne temperature i pojave vizinga toliko teškog da dete nije u mogućnosti izgovoriti nekoliko reči između dva udaha. Zaključak: Muški pol, rođenje pre termina, izloženost duvanskom dimu i pušenje majke tokom trudnoće predstavljaju statistički značajane rizike za razvoj astme kod deteta. Dečaci, deca mlađeg uzrasta, prevremeno rođena deca i deca hranjena mlečnim formulama u prvih 6 meseci života imaju statističi značajan rizik za razvoj suvog kašlja. Statistički značajnu povezanost sa prevalencijom astme kod dece imaju sledeće merene zagađujuće materije: SO2, O3, azot oksidi i PM10. Statistički značajnu povezanost sa prevalencijom astme kod dece ima porast prosečne godišnje temperature i više vrednosti maksimalne prosečne dnevne temperature.</p> / <p>Introduction: Asthma аs a chronic diseases is a major health, social and economic problem worldwide. It is one of the most common chronic diseases in children and the most common cause of an increased number of hospitalizations in children under the age of 15 years. The results of previous studies show an increase in the prevalence of asthma and allergic diseases in children in the last ten years. Epidemiological studies are important for understanding the nature of asthma, as well as for discovering of possible factors for the increasing trend of the prevalence of asthma in children. The difference in the geographical distribution of the prevalence of asthma symptoms within the same country suggests that environmental factors, rather than genetic factors may influence the distribution of the prevalence of asthma symptoms. Air pollution and climatic factors highlight as the most important environmental factors in the literature. Available studies indicate that there is a causal link between increased exposure to air pollution and acute respiratory symptoms. It is estimated that was a loss of 3.6 million years of life due to increased concentrations of respirable particles in Europe during 2000. year. Also, the recent recommendations of the World Health Organization strongly suggest reducing children&#39;s exposure to air pollutants. The results of the available studies suggest that the effects of warming and heat waves, as well as low temperatures, influence on the incidence of morbidity and hospitalization in children with asthma. The aims of this research were to determine the prevalence of asthma symptoms in children aged 6 to 15 years on the territory of Republic of Srpska, to determine the impact of air pollutants and climatic factors on the prevalence of asthma symptoms in children aged 6 to 15 years on the territory of Republic of Srpska. Materials and Methods: The study was conducted in the form of cross-sectional study and included 3,000 children aged 6 to 15 years from 13 primary schools in Republic of Srpska. The prevalence of asthma symptoms in children aged 6 to 15 years is determined through a questionnaire of the International Study of Asthma and Allergies in Children (ISAAC). This questionnaire has been designed for the needs of a multi-center study of the prevalence of asthma, allergic rhinitis and eczema in children. Measuring air quality included the following parameters: sulfur dioxide SO2 (mg/m3), carbon monoxide CO (mg/m3), nitrogen dioxide NO2 (mg/m3), ozone O3 (g/m3) and respirable particles PM10 (mg/m3). Air quality monitoring is performed using the meteorological observatory, where we continuously measured the emission concentration by a stationary ecological laboratory. Measurements of climate factors in stations of the Republic Hydrometeorological Service of Republic of Srpska were done according to the standards of the World Meteorological Organization (WMO). Measurements were made in certain periods depending on the station rank in the space of the meteorological circle which was located in the open space in order to avoid artificially influence the environment. Data were analyzed using statistical software IBM SPSS Statistics 21. Results: The prevalence of wheezing in the past 12 months was 7.9%, while the prevalence of diagnosed asthma ever was 3.5%. Children with symptoms of mild asthma in the past 12 months had statistically significant prevalence of undiagnosed asthma. A dry cough at night was registered in 14.8% of participants. Boys have significantly higher prevalence of wheezing in the past 12 months and a dry cough than girls. Premature infants have significantly higher prevalence of all asthma symptoms. It was registered significant relationship between smoking among family members and the occurrence of wheezing in the past 12 months (&chi;2 (1, N = 1956) = 5.13, p = 0.02). Prevalence of these symptoms was higher for participants who lived with smokers (9.6%) compared to children whose family members do not smoke (6.7%). Maternal smoking during pregnancy significantly influenced the prevalence of asthma symptoms in children. The concentration of nitrogen oxides and PM10 was significantly associated with the prevalence of wheezing and dry cough in the past 12 months. The concentration of sulfur dioxide and ozone was significantly associated with the prevalence of wheezing in the past 12 months. The prevalence of asthma in the highland climate regions was 7.3%, in the continental regions was 8.0% and 8.4% in the mediterranean regions. The average annual temperature gives a statistically significant contribution to predicting the occurrence of wheezing in the past 12 months among children who have ever had wheezing during their lifetime. The likelihood of wheezing in the past 12 months was 1.98 times higher for each degree of average annual temperature rise among children who ever had wheezing. The increase of average daily maximum temperature significantly affects the occurrence of wheezing ever and dry cough in the past 12 months. There is a statistically significant correlation between the average daily minimum temperature and the occurrence of severe wheezing that the child is not able to say a few words between breaths. Conclusion: Male gender, preterm birth, exposure to environmental tobacco smoke and maternal smoking during pregnancy are a statistically significant risk for the development of asthma in children. Boys, younger children, premature babies and children formulas fed during first 6 months of life have a statistically significant risk for the development of a dry cough. Statistically significant association with the prevalence of asthma in children showed following air pollutants: SO2, O3, nitrogen oxides and PM10. Statistically significant association with the prevalence of asthma in children has rise of the average annual temperature and higher value of the maximum average daily temperature.</p>