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Članek predstavlja priporočila za obravnavo bolnikov z rinitisom v Sloveniji. Predstavljeno je zdravljenje alergijskega in nealergijskega rinitisa ter rinosinuzitisa z nosnimi polipi ali brez njih. Obravnava tudi upravljanje z alergijami, uporabo imunoterapije z alergeni in njen učinek pri zmanjševanju simptomov. Nacionalna priporočila temeljijo na mednarodnih smernicah in priporočilih in ponujajo celovit pregled farmakoloških in nefarmakoloških možnosti zdravljenja teh stanj. Članek poudarja pomen kliničnega odločanja, sodelovanja bolnika in zdravstvenih delavcev na vseh ravneh in rednega spremljanja. Nacionalna priporočila si prizadevajo podpreti strokovnjake na vseh ravneh pri zagotavljanju z dokazi utemeljene oskrbe bolnikov z rinitisom in z njim povezanimi stanji.

Abstract Migraine is a disabling neurovascular disorder among people of all ages, with the highest prevalence in the fertile years, and in women. Migraine impacts the quality of life of affected individuals tremendously and, in addition, it is associated with highly prevalent metabolic diseases, such as obesity, diabetes mellitus and thyroid dysfunction. Also, the clinical response to drugs might be affected in patients with metabolic disease due to body composition and metabolic change. Therefore, the efficacy of antimigraine drugs could be altered in patients with both migraine and metabolic disease. However, knowledge of the pharmacology and the related clinical effects of antimigraine drugs in patients with metabolic disease are limited. Therefore, and given the clinical relevance, this article provides a comprehensive overview of the current research and hypotheses related to the influence of metabolic state and body composition on the action of antimigraine drugs. In addition, the influence of antimigraine drugs on metabolic functioning and, vice versa, the influence of metabolic diseases and its hormonal modulating medication on migraine activity is outlined. Future exploration on personalizing migraine treatment to individual characteristics is necessary to enhance therapeutic strategies, especially given its increasing significance in recent decades.

Abstract Large high pressure die castings (HPDC), recently referred to as mega-castings, can replace plenty of steel metal sheets usually employed for body-in-white (BIW) structures. They can save manufacturing expense and unleash additional lightweight potential thanks to additional design freedom and material properties. The BIW plays a major role in automotive design since it must fulfill numerous structural targets ranging from stiffness for vehicle dynamics, dynamic responses for NVH (noise, vibration, harshness), driving comfort standards and several passive safety requirements. The use of mega-casting structures leads to additional requirements with respect to castability and material quality. Achieving a lightweight design considering requirements related to crash or castability is a challenge on its own, due to the high computational cost of related simulation techniques. Considering multiple requirements simultaneously, therefore often leads to non-weight-optimal structures. To exploit the full lightweight potential, we present a generative multidisciplinary optimization pipeline for the structural design of automotive mega-casting parts in this paper. The approach combines established methods in automotive industry such as topology optimization and response-surface-based (RSM) optimization and enhances the latter by machine learning (ML) based clustering and classification. In a first step topology optimization is employed to derive optimal load-paths for multidisciplinary loading conditions. For this purpose, casting manufacturing constraints as well as more than hundred linearized loads are used to incorporate NVH and passive safety requirements. In a next step the optimal thickness distribution and rib orientation of the structure is achieved using RSM optimization algorithms for the computationally expensive nonlinear crash and casting simulations. Performance indicators are treated by unsupervised learning based on clustering. This enables classification constraints based on simulation field results from hundreds of samples to be included into RSM optimization. It resolves a typical risk of pure scalar, regression-type targets, where supposed optimal results fail when domain experts examine the full field result of the corresponding simulation. It is shown how this approach is superior in achieving a weight-optimal design and turnaround time compared to a design workflow classically used for BIW structures.

Abstract Background Monoclonal antibodies (mAbs) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway are safe and effective treatments for migraine prevention. However, the high cost of these novel therapies has led to reimbursement policies requiring patients to try multiple traditional preventives before access. In Germany, a recent change in insurance policy significantly expanded coverage for the CGRP receptor mAb erenumab, enabling migraine patients who failed just one prior prophylactic medication to receive this mAb. Here, we compare the clinical response to treatment with erenumab in migraine patients treated using the old and new coverage policy. Methods In this retrospective cohort study, we included CGRP-mAb naïve patients with episodic or chronic migraine, who started erenumab at our headache center according to either the old or the new insurance policy and received at least 3 consecutive injections. Headache diaries and electronic documentation were used to evaluate reductions in monthly headache and migraine days (MHD and MMD) and ≥ 50% and ≥ 30% responder rates at month 3 (weeks 9–12) of treatment. Results We included 146 patients who received erenumab according to the old policy and 63 patients that were treated using the new policy. At weeks 9–12 of treatment, 37.7% of the old policy group had a 50% or greater reduction in MHD, compared to 63.5% of the new policy group (P

Spectral imaging allows to analyze optical tissue properties that are invisible to the naked eye. Different spectral setups have been introduced in the last years to allow intraoperative image-guidance. All systems suffer from different disadvantages, such as lack of real-time capability, limited spectral coverage or low resolution. We present a novel approach using two multispectral snapshot cameras covering different spectral ranges as a stereo-system. The proposed method allows for continuous hyperspectral imaging of the surgical scene, while also enabling 3D scene reconstruction. The study demonstrates the feasibility of this approach and its potential applications in real-time monitoring and tissue identification of surgical interventions. The paper also discusses the technical challenges and future directions for improving the imaging system.

Z dokumentom želimo smernice, ki jih predlaga GINA, vključiti v slovenski prostor. Želimo, da bi dokument služil enotnemu in dogovorjenemu pristopu k obravnavi bolnikov z astmo na primarni in specialistični pulmološki ravni.

Calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP mAbs) are increasingly being used as preventive treatments for migraine. Their effectiveness and safety were established through numerous randomized placebo-controlled trials and real-world studies, yet a significant proportion of patients do not respond to this treatment, and currently, there is a lack of accepted predictors of response to guide expectations, as data from studies so far are lacking and inconsistent. We searched Embase and MEDLINE databases for studies reporting on predictors of response to CGRP and/or CGRP-receptor (CGRP-R) mAbs, defined as a 30% or 50% reduction in monthly headache or migraine days at varying durations of follow-up. Quantitative synthesis was performed where applicable. We found 38 real-world studies that investigated the association between various predictors and response rates. Based on these studies, good response to triptans and unilateral pain with or without unilateral autonomic symptoms are predictors of a good response to CGRP(-R) mAbs. Conversely, obesity, interictal allodynia, the presence of daily headaches, a higher number of non-successful previous prophylactic medications, and psychiatric comorbidities including depression are predictive of a poor response to CGRP(-R) mAbs. Future studies should confirm these results and help to generate more tailored treatment strategies in patients with migraine.

Pobudo »Alergijski rinitis in njegov vpliv na astmo« – (angl. Allergic Rhinitis and its Impact on Asthma, ARIA) – so leta 1999 ustanovili na delavnici Svetovne zdravstvene organizacije – World Health Organization (WHO). Njeni prvotni cilji so bili: 1. predlagati novo klasifikacijo alergijskega rinitisa, 2. spodbujati koncept večobolevnosti pri astmi in rinitisu ter 3. skupaj z vsemi deležniki razviti smernice, namenjene globalni uporabi v vseh državah in vsem skupinam bolnikov. Pobuda ARIA se uporablja v 70 državah, trenutno pa se osredinja na uporabo novih tehnologij za individualizirano in napovedno medicino. Mreža MASK – nadzorna mreža MACVIA (Proti kroničnim boleznim za aktivno staranje, franc. – Contre les Maladies Chroniques pour un Vieillissement Actif) in ARIA (angl. ARIA Sentinel NetworK) uporablja mobilno tehnologijo za razvoj klinične poti, ki bi bolnikom, multidisciplinarnim ekipam zdravnikov in raziskovalcem omogočila nadzor rinitisa in astme. Mobilna aplikacija (Android in iOS) je na voljo v 20 državah in 15 jezikih. Uporablja vizualno analogno lestvico za oceno nadzora nad simptomi in oceno delovne zmožnosti in ponuja sistem, ki pomaga pri kliničnem odločanju. Aplikacija omogoča povezovanje z zdravnikom ali drugimi zdravstvenimi delavci. Ta strategija upošteva priporočila Evropskega partnerstva za inovacije za aktivno in zdravo staranje (angl. European Innovation Partnership on Active and Healthy Ageing, EIP on AHA). Cilj novega pristopa pobude ARIA je zagotoviti aktivno in zdravo življenje bolnikov z rinitisom ne glede na njihovo starost, spol ali družbenogospodarski položaj zato, da bi se zmanjšali zdravstvena in družbena neenakost, ki sta posledici te bolezni.

Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.

The Armenian highlands encompasses rugged and environmentally diverse landscapes and is characterized by a mosaic of distinct ecological niches and large temperature gradients. Strong seasonal fluctuations in resource availability along topographic gradients likely prompted Pleistocene hominin groups to adapt by adjusting their mobility strategies. However, the role that elevated landscapes played in hunter-gatherer settlement systems during the Late Pleistocene (Middle Palaeolithic [MP]) remains poorly understood. At 1640 m above sea level, the MP site of Kalavan 2 (Armenia) is ideally positioned for testing hypotheses involving elevation-dependent seasonal mobility and subsistence strategies. Renewed excavations at Kalavan 2 exposed three main occupation horizons and ten additional low densities lithic and faunal assemblages. The results provide a new chronological, stratigraphical, and paleoenvironmental framework for hominin behaviors between ca. 60 to 45 ka. The evidence presented suggests that the stratified occupations at Kalavan 2 locale were repeated ephemerally most likely related to hunting in a high-elevation within the mountainous steppe landscape.

Cytokine signaling is transmitted by cell surface receptors which act as natural biological switches to control cellular functions such as immune reactions. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of green fluorescent protein (GFP)- and mCherry-nanobodies fused to the transmembrane and intracellular domains of cytokine receptors. Following stimulation with homo- and heterodimeric GFP-mCherry fusion proteins, the resulting receptors phenocopied signaling induced by physiologically occurring cytokines. GFP and mCherry fusion proteins were produced in E. coli or CHO-K1 cells, but the overall yield and stability was low. Therefore, we applied two alternative multimerization strategies and achieved immunoglobulin Fc-mediated dimeric and coiled-coil GCN4pII-mediated trimeric assemblies. GFP- and/or mCherry-Fc homodimers activated synthetic gp130 cytokine receptors, which naturally respond to Interleukin 6 family cytokines. Activation of these synthetic gp130 receptors resulted in STAT3 and ERK phosphorylation and subsequent proliferation of Ba/F3-gp130 cells. Half-maximal effective concentrations (EC50) of 8.1 ng/ml and 0.64 ng/ml were determined for dimeric GFP-Fc and mCherry-Fc, respectively. This is well within the expected EC50 range of the native cytokines. Moreover, we generated tetrameric and hexameric GFP-mCherry-Fc fusion proteins, which were also biologically active. This highlighted the importance of close juxtaposition of two cytokine receptors for efficient receptor activation. Finally, we used a trimeric GCN4pII motif to generate homo-trimeric GFP and mCherry complexes. These synthetic cytokines showed improved EC50 values (GFP3: 0.58 ng/ml; mCherrry3: 0.37 ng/ml), over dimeric Fc fused variants. In conclusion, we successfully generated highly effective and stable multimeric synthetic cytokine receptor ligands for activation of synthetic cytokine receptors.

[This corrects the article DOI: 10.1371/journal.pone.0230804.].

The purpose of this paper is to implement the guidelines proposed by GOLD in the Slovenian healthcare system, and to describe the cornerstones of the management of this disease. Te document is meant to serve as an agreed approach to the management of COPD patients.

The purpose of this paper is to implement the guidelines proposed by GINA in the Slovenian healthcare system, and to describe the cornerstones of the management of this disease. The document is meant to serve as an agreed approach to the management of asthma patients.

Background: Medications for asthma and COPD are mainly used in the form of inhalations. A survey was performed to obtain the opinion of experts about the importance of inhalers in inhaled drug therapy.Methods: All members–pulmonologists of the Slovenian Respiratory Society were invited to participate in the survey using a two-stage Delphi method. The result of each response were shown by the median and interquartile range, whereby we calculated the level of consensus.Results: 176 doctors were invited. Most questions were answered by 49 (27.8 %) participants. In the second round 42 doctors responded. As many as 33 out of 41 respondents (80.5 %) felt that in the treatment of asthma and COPD the selection of medicines and inhalers are equally important. When choosing an inhaler, it is crucial that it is simple to instruct the patients about its use. Respondents highly agreed with the statement that patients should receive a prescription for inhaler only after they have been trained on how to use it. As appropriate persons for the training of patients on the use of inhalers the respondents recognized (from most to least suitable) pulmonologists, nurses, general practitioners or pharmacists. 53.8 % of respondents considered that the patient’s skill of the use of inhaler should be checked on every visit to the doctor. Respondents believed that replacing inhalers without consulting the treating doctor may result in incorrect use of the inhaler, poor patient compliance, more exacerbations of the disease and poorer disease control. Some consensus with an indifferent median of 4.5 was reached with regard to the argument that the doctor should prescribe the inhaler that is the cheapest for society.Conclusions: Slovenian pulmonologists believe that any change of inhaler is a critical event, which must be coordinated with the patient and the doctor.

The dynamic exchange of neurotransmitter receptors at synapses relies on their lateral diffusion in the plasma membrane. At synapses located on dendritic spines this process is limited by the geometry of the spine neck that restricts the passage of membrane proteins. Biochemical compartmentalisation of the spine is believed to underlie the input-specificity of excitatory synapses and to set the scale on which functional changes can occur. Synaptopodin is located predominantly in the neck of dendritic spines, and is thus ideally placed to regulate the exchange of synaptic membrane proteins. The central aim of our study was to assess whether the presence of synaptopodin influences the mobility of membrane proteins in the spine neck and to characterise whether this was due to direct molecular interactions or to spatial constraints that are related to the structural organisation of the neck. Using single particle tracking we have identified a specific effect of synaptopodin on the diffusion of metabotropic mGluR5 receptors in the spine neck. However, super-resolution STORM/PALM imaging showed that this was not due to direct interactions between the two proteins, but that the presence of synaptopodin is associated with an altered local organisation of the F-actin cytoskeleton, that in turn could restrict the diffusion of membrane proteins with large intracellular domains through the spine neck. This study contributes new data on the way in which the spine neck compartmentalises excitatory synapses. Our data complement models that consider the impact of the spine neck as a function of its shape, by showing that the internal organisation of the neck imposes additional physical barriers to membrane protein diffusion.

The flux of neurotransmitter receptors in and out of synapses depends on receptor interaction with scaffolding molecules. However, the crowd of transmembrane proteins and the rich cytoskeletal environment may constitute obstacles to the diffusion of receptors within the synapse. To address this question, we studied the membrane diffusion of the γ-aminobutyric acid type A receptor (GABA(A)R) subunits clustered (γ2) or not (α5) at inhibitory synapses in rat hippocampal dissociated neurons. Relative to the extrasynaptic region, γ2 and α5 showed reduced diffusion and increased confinement at both inhibitory and excitatory synapses but they dwelled for a short time at excitatory synapses. In contrast, γ2 was ~3-fold more confined and dwelled ~3-fold longer in inhibitory synapses than α5, indicating faster synaptic escape of α5. Furthermore, using a gephyrin dominant-negative approach, we showed that the increased residency time of γ2 at inhibitory synapses was due to receptor-scaffold interactions. As shown for GABA(A)R, the excitatory glutamate receptor 2 subunit (GluA2) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) had lower mobility in both excitatory and inhibitory synapses but a higher residency time at excitatory synapses. Therefore barriers impose significant diffusion constraints onto receptors at synapses where they accumulate or not. Our data further reveal that the confinement and the dwell time but not the diffusion coefficient report on the synapse specific sorting, trapping and accumulation of receptors.

The activity-dependent modulation of GABA-A receptor (GABA(A)R) clustering at synapses controls inhibitory synaptic transmission. Several lines of evidence suggest that gephyrin, an inhibitory synaptic scaffold protein, is a critical factor in the regulation of GABA(A)R clustering during inhibitory synaptic plasticity induced by neuronal excitation. In this study, we tested this hypothesis by studying relative gephyrin dynamics and GABA(A)R declustering during excitatory activity. Surprisingly, we found that gephyrin dispersal is not essential for GABA(A)R declustering during excitatory activity. In cultured hippocampal neurons, quantitative immunocytochemistry showed that the dispersal of synaptic GABA(A)Rs accompanied with neuronal excitation evoked by 4-aminopyridine (4AP) or N-methyl-D-aspartic acid (NMDA) precedes that of gephyrin. Single-particle tracking of quantum dot labeled-GABA(A)Rs revealed that excitation-induced enhancement of GABA(A)R lateral mobility also occurred before the shrinkage of gephyrin clusters. Physical inhibition of GABA(A)R lateral diffusion on the cell surface and inhibition of a Ca(2+) dependent phosphatase, calcineurin, completely eliminated the 4AP-induced decrease in gephyrin cluster size, but not the NMDA-induced decrease in cluster size, suggesting the existence of two different mechanisms of gephyrin declustering during activity-dependent plasticity, a GABA(A)R-dependent regulatory mechanism and a GABA(A)R-independent one. Our results also indicate that GABA(A)R mobility and clustering after sustained excitatory activity is independent of gephyrin.

Abstract: Bronchoscopy with convex probe ultrasound in combination with transbronchial fine-needle aspiration biopsy is a relatively new, minimally invasive method that can also be used in an outpatient setting. It is indicated for staging of the mediastinal and hilar lymph nodes in patients with lung cancer, for the diagnosis of lung and mediastinal tumors, for the diagnosis of mediastinal lymphadenopaty and for the diagnosis and aspiration of mediastinal cysts. The method has a high diagnostic accuracy, which makes it comparable to more invasive diagnostic methods. At the same time it is less invasive for patients and offers a better safety profile.

The actin cytoskeleton of dendritic spines plays a key role in morphological aspects of synaptic plasticity. The detailed analysis of the spine structure and dynamics in live neurons, however, has been hampered by the diffraction-limited resolution of conventional fluorescence microscopy. The advent of nanoscopic imaging techniques thus holds great promise for the study of these processes. We implemented a strategy for the visualization of morphological changes of dendritic spines over tens of minutes at a lateral resolution of 25 to 65 nm. We have generated a low-affinity photoconvertible probe, capable of reversibly binding to actin and thus allowing long-term photoactivated localization microscopy of the spine cytoskeleton. Using this approach, we resolve structural parameters of spines and record their long-term dynamics at a temporal resolution below one minute. Furthermore, we have determined changes in the spine morphology in response to pharmacologically induced synaptic activity and quantified the actin redistribution underlying these changes. By combining PALM imaging with quantum dot tracking, we could also simultaneously visualize the cytoskeleton and the spine membrane, allowing us to record complementary information on the morphological changes of the spines at super-resolution.

Single Particle Tracking (SPT) is a powerful technique for the analysis of the lateral diffusion of the lipid and protein components of biological membranes. In neurons, SPT allows the study of the real-time dynamics of receptors for neurotransmitters that diffuse continuously in and out synapses. In the simplest case where the membrane is flat and is parallel to the focal plane of the microscope the analysis of diffusion from SPT data is relatively straightforward. However, in most biological samples the membranes are curved, which complicates analysis and may lead to erroneous conclusions as for the mode of lateral diffusion. Here we considered the case of lateral diffusion in tubular membranes, such as axons, dendrites or the neck of dendritic spines. Monte Carlo simulations allowed us to evaluate the error in diffusion coefficient (D) calculation if the curvature is not taken into account. The underestimation is determined by the diameter of the tubular surface, the frequency of image acquisition and the degree of mobility itself. We found that projected trajectories give estimates that are 25 to 50% lower than the real D in case of 2D-SPT over the tubular surface. The use of 3D-SPT improved the measurements if the frequency of image acquisition was fast enough in relation to the mobility of the molecules and the diameter of the tube. Nevertheless, the calculation of D from the components of displacements in the axis of the tubular structure gave accurate estimate of D, free of geometrical artefacts. We show the application of this approach to analyze the diffusion of a lipid on model tubular membranes and of a membrane-bound GFP on neurites from cultured rat hippocampal neurons.

Background: Prognostic factors may help the clinician in treatment decision making. The significance of C-reactive protein (CRP) as a negative prognostic factor has been shown in patients with different malignancies. However, only few studies have analyzed CRP as a prognostic factor in patients with advanced non-small cell lung cancer (NCLCS). The aim of this study was to evaluate the prognostic value of CRP and other prognostic factors in a group of unselected population of patients with advanced NCLSC treated with platinum based chemotherapy. Methods: The retrospective study was conducted by reviewing 53 medical files of advanced NSCLC patients treated with platinum/gemcitabine at the University Clinic Golnik between May 2004 and November 2008. The median age of patients was 65 years, most of them were males (75 %), smokers or ex-smokers (81 %), with performance status 1 ( 64.2 %) and stage IV disease (83 %). The collected data included laboratory characteristics (Hb, platelet count, CRP, LDH) before chemotherapy, information on each individual patient‘s therapy and outcome. The median number of chemotherapy cycles received was 4 (range, 1–6). Results: The median progression free survival (PFS) for the entire group was 4.8 months (range 0–20 months). Patients with elevated CRP levels (≥ 20 mg/l) had inferior PFS compared to those with low pretreatment CRP values (median PFS 8.4 vs 3.6 months, p=0.006). In Cox univariate regression analysis, CRP (p=0.016, HR=1.008, 95 %CI, 1.001–1.014), Hb (p=0.001, HR= 0.96, 95 %CI, 0.95–0.99), and comorbidity (p=0.051, HR=1.2, 95 %CI, 1.00 -1.45) were found to be significant prognostic factors; age, LDH, and platelet count on the other hand were not found to be significant prognostic factors. In multivariate analysis only CRP (p=0.048, HR=0.50, 95 %CI 0.26–0.99) and Hb (p=0.005, HR=0.97, 95 %CI, 0.95 -0.99) retained their independent prognostic value. Conclusion: The survival of patients with advanced NSCLC treated by chemotherapy is significantly influenced by the patient‘s pretreatment CRP and Hb levels, and comorbidity only borderline so. The major advantage of this study is that it was performed on an unselected population of patients, but still uniform with respect to diagnosis, stage and agents used in chemotherapy treatment schedule.

Background: In Slovenia, lung cancer is the second most common cancer among men and the fifth most common cancer among women. Fiveyear survival is 13 %, and at the time of diagnosis, only 16 % of patients have curable disease. Early cancer diagnosis is associated with better prognosis, so reducing the delay time might increase the number of tumours detected at early stages and might improve survival rates. The aim of our study was to measure the delays to diagnosis and treatment and assess whether the duration of delays were acceptable with respect to other similar studies and recommendations. Methods: We identified all patients with suspicious lung lesions, who were referred to a specialised outpatient clinic (the “Tumour clinic”) in a one-year period. The Tumour Clinic was established to speed up lung cancer diagnosing. We also analysed time from the first symptoms to the patient’s first visit to a specialist, the time from the first visit to the final diagnosis, and time from the diagnosis of lung cancer to the beginning of treatment. Results: We examined the records of 159 patients with suspicious lung lesions, who were referred to the outpatient clinic between January and December 2008. The mean age of the patients was 67 years (range 20–88 yrs). Seventy-four (53 male, 21 female) of the patients were diagnosed with malignant disease, including 61 cases of lung cancer. The median time from the onset of symptoms to the first visit was 67 days, and the median time from the first visit until diagnosis was 10 days. Another 12 days (median time) passed from the time of diagnosis to the beginning of treatment. Conclusions: Patients diagnosed with lung cancer wait too long before seeking appropriate medical assistance. When referred to a specialised outpatient clinic, the diagnosis time of lung cancer and the time from diagnosis to the beginning of treatment were acceptable, but there is still room for improvement.

BackgroundEpidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established.Methodology/principal findingsIn this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12(KI) mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12(KI) P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12(KI) microglia overexpress genes for IL1beta, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity.Conclusion/significanceOur results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation.

Background: Bronchoscopic procedures are associated with costs for purchasing and maintaining the equipment. Significant share of bronchoscopy unit budget represent costs of repairs for damaged bronchoscopes which are supposedly higher in the teaching centers. The purpose of the study was to determine frequency, sort and cause of bronchoscope damages as well as costs of repair.Methods: We retrospectively studied frequency, sort, cause and repair costs of bronchoscope damages for 13 new bronchoscopes, which were introduced in a program between August 1, 2001 and December 31, 2006.Results: We registered 47 bronchoscope damages during the study, which represents 1 damage per 141.6 procedures. 6 (12.7 %) damages were potentially preventable with more careful approach. The most frequent wear and tear injury was rubber sheath injury on the distal bending portion of flexible bronchoscope and the most frequent preventable injury was the damage of the working channel of the bronchoscope. Repair costs amounted to 34,950.00 EUR, which means 5.25 EUR per procedure. We could spare mostly 17,781.00 EUR with more attentive work. Application of the bronchoscopes for educational purposes was not associated with higher rate of bronchoscope damages at our institution.Conclusions: Repair costs represent a significant share of bronchoscopy unit budget. We demonstrated that only a smaller number of bronchoscope damages in our unit are potentially preventable, but they still represent an important amount of expenses. Relatively small share of preventable damages during regular program and teaching procedures is attributable to a good bronchoscopy training programme, which is attended future bronchoscopists in our institution.

Background: Strongyloidosis is a parasitosis caused by a nematode Strongyloides stercoralis. It is endemic in tropical and subtropical regions, but rarely encountered in temperate areas. Most patients present with non-specific symptoms or they have no symptoms. The disease evolves into hyperinfection syndrome or disseminated disease in immunocompromised patients characterized by high mortality rates. Early diagnosis and effective treatment are of major importance. Drugs such as mebendazol and albendazol are used in therapy. Antibiotics are used for possible concurrent bacterial infections.Patient and the methods: We present the case of a 73-year-old woman who has chronic obstructive pulmonary disease receiving corticosteroid therapy. She was complaining about chronic abdominal discomfort characterized by intermittent diarrhoea and constipation. Occasionally, she was presenting with red rash. The laboratory findings: eosinophilia, anemia and a positive hematest in a stool specimen. The eggs and larvae of the parasite were identified by the procedures of biopsy and histological examination of duodenal mucosa. The parasite was found in sputum, too – the proof of the invasion into the lungs. Conclusions: The patient was treated with mebendazol and albendazol. The examination of successive stool and sputum specimens after the treatment showed no eggs or larvae.

Background: Conventional transbronchial needle aspiration (TBNA) of enlarged mediastinal lymph nodes is a fairly blind technique. Endobronchial ultrasound (EBUS) guided TBNA resulted in higher success rate. The needle can be inserted safely into the lymph node. We examined the diagnostic yield of EBUS guided TBNA in clinical circumstances.Patients and methods: Patients with enlarged mediastinal lymph nodes, detected on chest X-ray and/or CT scan, underwent bronchoscopy. The exact location of lymph nodes was established by EBUS. 20 MHz ultrasound probe with a balloon catheter was used.Results: Seventy-five patients aged between 20 and 79 years (median age 55 years), underwent EBUS examination followed by TBNA of the target lymph node. Lymph nodes pathology was correctly diagnosed in 65 (87%) of them. In 52 (70%) patients the lymph nodes were infiltrated with malignoma, 13 (17%) had benign diseases and in 10 (13%) patients with non definitive disease the final diagnosis was obtained by surgery or by follow up. No major complication was encountered after EBUS-guided TBNA.Conclusions: Diagnostic yield of EBUS-guided TBNA is high. There were no major complications and the procedure was tolerated well.

Background. Fire-eaters use liquid hydrocarbons for the performance of the flame-blowing and flame swallowing show. Aspiration of hydrocarbon mixture may cause severe lipoid pneumonia. We present two patients who developed severe lipoid pneumonia after an accidental aspiration of petroleum and paraffin during a flame–blowing act.Conclusions. Prolonged treatment with antibiotics and systemic corticosteroids was successful. Radiological resolution occurred three months after the accident

Background. This article presents our three year experience with bronchoscopic management of central bronchial tumours stenosis.Methods. In the years 2000, 2001, and 2002, 52 patients (43 men, 9 women), aged 62.3 ± 10.8 years with central airway obstruction because of primary or secondary malignant tumours in 47 cases (90%) and benign diseases in 5 (10%) were treated. Topical anaesthesia with Lidocaine in all 52 patients where flexible bronchoscopes Olympus were applied was used. Additionally, Fentanyl or Diprivane were used in 25 patients where rigid bronchoscopy (Storz) was performed. Mechanical removal and electrocautery resection (Olympus) were used for tumour resection. In 2 patients Polyflex stent (Rüsch) was introduced into the trachea.Results. We treated 17 (33%) tumours in the trachea, 14 (27%) in the right, 15 (29%) in the left main bronchi and 6 (11%) in more peripheral bronchi. The combination of mechanical removal and electrocautery was applied in 32 (61%), mechanical removal alone in 4 (8%) and electrocautery alone in 16 (31%) of patients. Symptomatic relief was achieved in 41 (79%) patients. In 47 patients with malignant tumours bronchoscopic intervention was applied during the first diagnostic procedure 28 times (60%), after additional surgery, radiotherapy or chemotherapy 14 times (30%) and between additional therapeutic interventions 5 times (10%). The procedure had to be terminated in one patient due to hypoxemia. There was no immediate mortality.Conclusions. Mechanical desobstruction in combination with electrocautery through the flexible and/or rigid bronchoscopes and stent introduction in patients with central airways tumours are efficient and rather safe palliative procedures.

Background. Fluorescence bronchoscopy is more sensitive than white light bronchoscopy in the diagnosis of preneoplastic changes of bronchial mucosa, carcinoma in situ and invasive bronchial cancer.Methods. Thirty-one patients, 22 male, 9 female, age 59 ± 11 years were examined with autofluorescence system Storz 11004BI and D-light/AF with camera SL PDD and Olympus 1T30 or 1T40. Local anaesthesia was applied. Bronchial biopsy was performed 3–5 times on macroscopically suspicious and apparently normal sites of bronchial mucosa. Each biopsy site was classified by white light (WLB), autofluorescence bronchoscopy (AFB) and histologically as normal epithelium, moderate dysplasia, severe dysplasia, and carcinoma in situ or invasive carcinoma. The results of WLB and AFB were compared with histological diagnosis.Results. We confirmed invasive carcinoma in 16, carcinoma in situ in 1 patient, pleural mesothelioma in 1 and benign diseases in 13 patients. Findings were classified as squamous cell (n = 9), small cell (n = 4), adenocarcinoma (n = 3) and unclassifiable (n = 1) carcinoma. Biopsy was performed on 52 sites. Invasive carcinoma was histologically confirmed on 19 biopsy sites. WLB showed invasive carcinoma in 17 cases (89%) and AFB in 18 cases (95%). In the patient with carcinoma in situ WLB found mild dysplastic changes while AFB was positive. WLB sensitivity was 0.85 and AFB 0.95, while specificity of WLB was 0.91 and of AFB was 0.44. Relative sensitivity of WLB + AFB was 1.08 comparing with WLB alone. We observed false positive results because of former biopsies, bleeding, inflammation or scarring in patients with mild dysplasia and normal mucosa with WLB in 1 (3%) and with AFB in 5 (16%) cases.Conclusions. Autofluorescence was more sensitive than white light bronchoscopy in the diagnosis of invasive bronchial carcinoma, carcinoma in situ and dysplasia. False positive results must be considered.

Priporočila prikazujejo, kakšna naj bo obravnava bolnikov s pljučnim rakom v Sloveniji v letu 2002. Predstavljajo osnovne postopke, ki jih želimo zagotoviti bolnikom s to boleznijo. Naslanjajo se na Smernice za internistično obravnavo bolnika s pljučnim rakom (1).

Background. We were interested to study the effectof different ways of administering topical lidocaine and thepossible benefit of using atropine as premedication for flexiblebronchoscopy.Patients and methods. 105 patients were randomised intofour groups. Lidocaine was administered either through thebronchoscope or by transcricoid injection. The use of atropinepremedication was also randomised. The duration of bronchoscopysessions, amount of lidocaine used, symptomes andsigns such as coughing, heart rate and oxygene saturationwere documented. Patients and medical staff graded their perceptionsof the procedure using a four-grade severity scale.Results. The duration of the bronchoscopy was not significantlyprolonged in the group with bronchoscopic lidocaine administrationcompared to the transcricoid group (p = 0.6). The patientswith bronchoscopic lidocaine administration requiredsignificantly more additional lidocaine than in the transcricoidgroup (p = 0.03). No significant difference was found inpatients who received atropine and those without it. Severecoughing recorded by bronchoscopists and nurses was significantlymore frequent in patients without atropine premedication(p = 0.006) but patient did not experience the bronchoscopyto be more unpleasant without atropine.Conclusions. Patients tolerated both variants of topical anaesthesiaequally well but less amount of additional lidocainewas used by transcricoid administration. The use of atropinewas of no benefit, but resulted in more tachycardia events.