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Aims: Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases., Methods: MASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients., Stakeholders: Include patients, health care professionals (pharmacists and physicians), authorities, patient's associations, private and public sectors., Results: MASK is deployed in 23 countries and 17 languages. 26,000 users have registered., Eu Grants 2018: MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour)., Lessons Learnt: (i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases.

Introduction: Ambulatory sleep testing is nowadays an available diagnostic method, measuring air flow and blood oxygen saturation in patients with a suspicion of obstructive sleep apnoea syndrome (OSAS). It can be performed by either a general practitioner or an ambulatory specialist in various fields. Using this simple screening method it is possible to exclude subjects without OSAS, who therefore do not require further sleep testing at a sleep laboratory. There is no published data regarding the use of ambulatory sleep testing by sleep laboratories in the Czech Republic. The aim of this study was to evaluate the proportion of patients examined by ambulatory sleep testing and to determine the factors influencing its indication., Material and Methods: The study involved 497 patients (363 males) with an average age of 55.5 ± 12.3 years. These patients were tested by the sleep laboratory at University Hospital Olomouc with a suspicion of OSAS. The clinical complaints of the patients were evaluated (e.g. excessive daytime sleepiness, microsleeps, etc.) along with a basic examination, including anthropometric parameter measurements, on admission to the ward. Whilst admitted, night sleep testing using respiratory polygraphy or videopolysomnography was performed in all patients. Furthermore, the number of patients that underwent ambulatory sleep testing prior to admission to the sleep laboratory and the number of patients with an indication for positive airway pressure therapy (PAP) (apnoea-hypopnea index > 15) was assessed. The results were processed using the software IBM SPSS Statistics v22., Results: Ambulatory sleep testing was performed in only 96 patients (19.3 %). Among these patients, 76 (79.0 %) were diagnosed with OSAS with an indication for PAP. In the 401 patients who did not undergo ambulatory sleep tests, 227 (53.9 %) were diagnosed with OSAS with an indication for PAP. Patients who underwent ambulatory sleep tests and those who did not differed only in age (p = 0.03). There were no significant differences in other parameters (sex, height, weight, BMI, circumference of neck, waist and hips, ESS), including sleepiness (p = 0.605) and microsleeps (p = 0.74)., Conclusion: Ambulatory sleep testing is performed in only a small proportion of patients. Its use can reduce healthcare costs as well as waiting times for sleep laboratory tests.

The increase of antimicrobial resistance necessitates the renewal and strong research involvement in antibacterial drug design. In the following work, we comment on the key approaches used in development of new antibacterials, focusing on intracellular therapeutic targets that have been so far mostly underexplored: the enzymes of the Mur pathway MurA to MurF. We identify common obstacles observed during research on MurA, MurB, and Mur ligases inhibitors and their development into potential antibacterial compounds, and discern several approaches and solutions to tackle the whole-cell activity of designed compounds. Furthermore, we consolidate recent literature reports and encourage the further research on Mur enzymes., (© 2018 Wiley Periodicals, Inc.)

We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of bacterial cell wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis -double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antibacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC 50 = 25 μM) and good antibacterial activity against E. coli BW25113 Δ tolC strain (MIC = 0.5 μg/mL).

Introduction: Neurogenic pulmonary oedema (NPE) is avery rare complication of epileptic seizures, which could potentially increase mortality., Material and Methods: The case of a66-year-old male patient with NPE caused by repeated epileptic seizures is reported. Rapid resolution of pulmonary oedema is well documented by X-ray and computed tomography images., Conclusions: Neurogenic pulmonary oedema could potentially increase mortality, and thus, it is important to perform achest X-ray in all patients presenting with seizures and dyspnoea.

Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) are commonly interconnected, and this coincidence negatively influences patients' mortality and morbidity. On the basis of the current available data originating mainly from cardiovascular studies epicardial fat (EF) has been proposed as a marker of cardiovascular risk. This review is focused on a potential role of epicardial fat as a new biomarker for risk stratification of COPD patients. Epicardial fat may present an important link between chronic obstructive pulmonary disease and cardiovascular diseases, mainly coronary artery disease.

Objective: It is well recognized that the most effective treatment for obstructive sleep apnea (OSA) is continuous positive airway pressure (CPAP). Different treatment possibilities comprise surgery, mandibular advancement, pulmonary rehabilitation, and oropharyngeal and facial exercises (PR program). However, these treatments showed inconsistent results. The purpose of the study was to compare the short-term effects of CPAP and the combination of PR program with CPAP on OSA severity, ventilatory functions, and changes in body characteristics in a newly diagnosed patient., Methods: This study was a single-center, two-arm, parallel, randomized, controlled, open-label trial. Forty patients with OSA (20 men, 20 women, aged 54.2 ± 6.8 years) with moderate to severe obstructive sleep apnea were randomized to CPAP and CPAP + PR. The PR group underwent six weeks of 60-min twice-weekly individual PR programs. The primary outcome measure was apnea/hypopnea index, oxygen desaturation index, and Epworth Sleepiness Scale. The secondary outcome measures were a percentage of total sleep time with oxygen saturation below 90%, body mass index (BMI), vital capacity and forced expiratory volume in 1 s (% of predicted), neck, waist, and hip circumferences., Results: Five patients with OSA did not complete the program. The comparison between baseline and final assessment was made in 15 patients in the CPAP + PR group and 20 patients in the control group with CPAP only. Although OSA severity was controlled with CPAP treatment in both groups, a significant reduction of neck, waist, and hip circumferences, BMI, and improvement of pulmonary function were confirmed only in the CPAP + PR group after treatment., Conclusion: Treatment with CPAP combined with the PR program improved OSA patients to a greater extent than only CPAP., (Copyright © 2018 Elsevier B.V. All rights reserved.)

mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app ( the Allergy Diary , Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary .

Objectives: Adjuvant chemotherapy (AC) in non-small cell lung cancer (NSCLC) has become a standard of care in patients with stages IIA, IIB, and IIIA after complete tumor resection. Utilization and outcome of AC in routine practice is described in a few studies, with non-conclusive results., Materials and Methods: This retrospective study included consecutive patients with NSCLC who underwent curative-intent surgery. Data of AC uptake in stages IB (tumor of ≥4 cm in diameter), II, and IIIA, and reasons of AC omission were evaluated according to medical records. Mortality risk among patients treated with surgery (only) and different types of AC in routine practice was compared., Results: AC was applied to 79% of patients with stages IB (tumor of ≥4 cm in diameter), II, and IIIA, and was associated with an improved median of overall survival (HR = 0.69; 95% CI = 0.44-1.06). Significantly longer survival was achieved in the sub-group treated with platinum and oral vinorelbine (HR = 0.575, 95% CI = 0.339-0.974), and the longest survival was among patients treated with oral vinorelbine and cisplatin (HR = 0.371, 95% CI = 0.168-0.820)., Conclusions: AC utilization should be based on co-operation between surgeons, pneumo-oncologists, and patients. Rational use of AC offers better survival in routine practice.

The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki = 1.09 ± 0.12 nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu 2+ ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Aβ 1-42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Epicardial fat (EPI) plays important role in development of metabolic and cardiovascular diseases. According to population studies EPI represents independent risk factor of cardiovascular diseases (CVD) and also for neoplasms. Osteoprotegerin (OPG) is a glycoprotein which have role in regulation of immune and cardiovascular systems. High serum levels of OPG are connected with high cardiovascular risk. The aim of our study was to evaluate possible correlation between EPI and OPG level in asymptomatic relatives of patients with CVD., Material and Methods: 53 asymptomatic relatives (37 male) (median age 53 years) of patients with CVD (ischemic heart disease, cerebrovascular disease) were included. Physical examination and biochemistry analysis were performed. GE Vivid 7 (GE Medical) was used for echocardiography. EPI was measured according to guidelines using parasternal long axis in diastole as a space in front of right ventricle., Results: EPI was present in 46 subjects (86.8 %) with mean value of 2.91 mm. In 10 subjects was the amount of EPI > 5 mm. Spearmann correlation analysis found statistically significant correlation between EPI and OPG (r = 0.271; p = 0.05) and age (r = 0.500; p < 0.0001). We have not found correlation between EPI, glycaemia and level of insulin, glycated Hb, total, LDL, HDL cholesterol and triglycerides., Conclusion: We have found positive correlation between EPI and OPG. More studies are needed to confirm applicability of this correlation in risk stratification.Key words: cardiovascular risk - epicardial fat - osteoprotegerin.

MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure-activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC 50 of 8µM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1µg/mL to 8µg/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Adipocyte fatty acid-binding protein (A-FABP) is a promising link between metabolic syndrome and atherosclerosis. Epicardial fat (EPI) is an independent risk factor for cardiovascular disease (CVD)., Objective: The aim of this pilot study was to evaluate the correlation between EPI and A-FABP in asymptomatic patients with a family history of CVD., Methods: 59 subjects (39 males) (median = 54 years old) were enrolled in the study and their EPI thickness and A-FABP levels were assessed., Results: EPI was found in 46 patients (77.9%). There were positive correlations between EPI and A-FABP (r=0.336; P=0.010), age (r=0.526; P<0.001), fibrinogen (r=0.304; P=0.023) and systolic blood pressure (r=0.279; P=0.034). A positive correlation was found between EPI and A-FABP in a subgroup of overweight and obese patients (0.389; P=0.041, 0.407; P=0.004) and in the subgroup of patients with excluded CVD (r=0.368; P=0.006)., Conclusions: We found a positive correlation between EPI and A-FABP in a group of patients with a family history of CVD and in subgroups of overweight and obese patients.

Accumulating evidence indicates a solid relationship between several enzymes and Alzheimer's disease. Cholinesterases and monoamine oxidases are closely associated with the disease symptomatology and progression and have been tackled simultaneously using several multifunctional ligands. This design strategy offers great chances to alter the course of Alzheimer's disease, in addition to alleviation of the symptoms. More than 15 years of research has led to the identification of various dual cholinesterase/monoamine oxidase inhibitors, while some showing positive outcomes in clinical trials, thus giving rise to additional research efforts in the field. The aim of this review is to provide an update on the novel dual inhibitors identified recently and to shed light on their therapeutic potential.

We report on the successful application of ProBiS-CHARMMing web server in the discovery of new inhibitors of MurA, an enzyme that catalyzes the first committed cytoplasmic step of bacterial peptidoglycan synthesis. The available crystal structures of Escherichia coli MurA in the Protein Data Bank have binding sites whose small volume does not permit the docking of drug-like molecules. To prepare the binding site for docking, the ProBiS-CHARMMing web server was used to simulate the induced-fit effect upon ligand binding to MurA, resulting in a larger, more holo-like binding site. The docking of a filtered ZINC compound library to this enlarged binding site was then performed and resulted in three compounds with promising inhibitory potencies against MurA. Compound 1 displayed significant inhibitory potency with IC 50 value of 1μM. All three compounds have novel chemical structures, which could be used for further optimization of small-molecule MurA inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This general article discusses the problems of beta-blockers use in patients with chronic obstructive pulmonary disease (COPD). Its aim is to refute exaggerated concerns of physicians over possible undesirable effects of beta-blockers on the patient respiratory functions and present new data on the effects of beta-blockers on the extent of COPD exacerbations, bronchial reactivity and mortality of patients.

Background: Toll-like receptor 4 (TLR4) has been associated with several inflammatory diseases, such as sepsis, atherosclerosis and chronic pain., Objective: The aim of the present study was to develop an efficient and straightforward synthetic approach for the preparation of small-molecule antagonists Naryl- N'-(5-(2-hydroxybenzoyl)pyrimidin-2-yl)guanidines in order to evaluate these for TLR4 antagonist activity and to obtain useful information about their structure-activity relationships., Methods: The present work have designed and optimized a three-step synthetic route for derivatives of a previously demonstrated antagonist of TLR4: 1-(4- fluorophenyl)-2-(5-(2-hydroxy-5-methoxybenzoyl)pyrimidin-2-yl)guanidine. The antagonist activities of eight novel synthesized compounds were evaluated on cells which selectively express TLR4., Results: Three guanidine derivatives showed promising antagonist activities, with IC50 values in the low micromolar range., Conclusion: Our findings represent an important starting point for further studies of small-molecule agents targeting Toll-like receptors.

Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions.

Sarcosine was discovered to be an excellent ligand for cobalt-catalyzed carbon-carbon cross-coupling of Grignard reagents with allylic and vinylic bromides. The Co(II)/sarcosine catalytic system is shown to perform efficiently when phenyl and benzyl Grignards are coupled with alkenyl bromides. Notably, previously unachievable Co-catalyzed coupling of allylic bromides with Grignards to linearly coupled α-products was also realized with Co(II)/sarcosine catalyst. This method was used for efficient preparation of the key intermediate in an alternative synthesis of the antihyperglycemic drug sitagliptin.

Previously, we identified CYP53 as a fungal-specific target of natural phenolic antifungal compounds and discovered several inhibitors with antifungal properties. In this study, we performed similarity-based virtual screening and synthesis to obtain benzoic acid-derived compounds and assessed their antifungal activity against Cochliobolus lunatus, Aspergillus niger and Pleurotus ostreatus. In addition, we generated structural models of CYP53 enzyme and used them in docking trials with 40 selected compounds. Finally, we explored CYP53-ligand interactions and identified structural elements conferring increased antifungal activity to facilitate the development of potential new antifungal agents that specifically target CYP53 enzymes of animal and plant pathogenic fungi., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Aim: Obstructive sleep apnea (OSA) is a common cause of secondary arterial hypertension. Masked hypertension (MH) is defined as normal office blood pressure and abnormal results in 24 h ambulatory blood pressure monitoring (ABPM). The aim of this study was to evaluate the effect of CPAP therapy on the prevalence of MH in patients with OSA., Methods: 43 patients (40 men) were included, average age 54.2±10.5 years. All underwent sleep study (PG or PSG) with a diagnosis of OSA indicated for CPAP treatment, average apnea-hypopnea index (AHI) 60.6±23.6. Patients were treated with CPAP for one year. Ambulatory blood pressure monitoring was performed before and after one year of treatment., Results: Masked hypertension was initially present in 25 (58.1%) and in 26 (60.5%) patients after one year of CPAP therapy. However, there was a statistically significant improvement in BP for all evaluated intervals of ABPM with the exception of systolic pressure during the daytime., Conclusions: Masked hypertension was very prevalent in these patients with OSA. The CPAP treatment for one year however had no affect on prevalence of masked hypertension although there was a positive effect of CPAP treatment on blood pressure for all assessed intervals of ABPM with the exception of systolic BP during daytime.

This paper is discussing recent findings about links between obstructive sleep apnea syndrome and arterial hypertension. It describes diagnostic approaches and also therapy of patients. It is describing options of pharmacological treatment and the influence of continuous positive airway pressure therapy on blood pressure level.

Unlabelled: Hydrocephalus is a disorder of abnormal accumulation of cerebrospinal fluid in the intracranial space, usually in the cerebral ventricles. The number of patients reaching reproductive age and intending to become pregnant has increased in recent years because of treatment advances. An implanted shunt is usually introduced into the abdominal cavity (ventriculoperitoneal shunt). Numerous changes occur during pregnancy, mainly increased accumulation of water, increased intracranial cerebrospinal fluid volume and increased intra-abdominal pressure as a result of the growing uterus. These changes contribute to increased incidence of complications during pregnancy and childbirth. Therefore, it is necessary to make a preconception exam and specify pregnancy management, a suitable method of childbirth and dealing with potential complications. Multidisciplinary care is mandatory with the dominant cooperation of obstetricians and neurosurgeons who should be also available during the delivery when needed. Possible shunt malfunction is necessary to diagnose properly and in time and solve it individually, taking into account the overall and neurological status of the patient and gestational age. The presence of a shunt does not affect pregnancy and vaginal delivery is considered by most authors as the first option. Primary cesarean section is preffered in patients with obstructive hydrocephalus or rapid deterioration in the case of shunt malfunction. Epidural anesthesia or general, eventually spinal anesthesia are recommended., Keywords: hydrocephalus, shunt, ventriculoperitoneal shunt, ventriculoatrial shunt, endoscopy, endoscopic third ventriculostomy, pregnancy.

Cinnamic acid derivatives can be found in plant material, and they possess a remarkable variety of biological effects. In the present study, we have investigated the cytotoxic effects of representative cinnamic acid esters and amides. The cytotoxicity was determined by MTT test on human cervix adenocarcinoma (HeLa), myelogenous leukemia (K562), malignant melanoma (Fem-x), and estrogen-receptor-positive breast cancer (MCF-7) cells, versus peripheral blood mononuclear cells (PBMCs) without or with the addition of the plant lectin phytohemaglutinin (PHA). The compounds tested showed significant cytotoxicity (IC50s between 42 and 166 µM) and furthermore selectivity of these cytotoxic effects on the malignant cell lines versus the PBMCs was also seen, especially when electron-withdrawing groups, such as a cyano group (compound 5), were present on the aromatic rings of the alcohol or amine parts of the cinnamic acid derivatives. The additional study on cell cycle phase distribution indicated that novel cinnamic acid derivatives inhibit cell growth by induction of cell death. Thus, cinnamic acids derivatives represent important lead compounds for further development of antineoplastic agents.

Unlabelled: The objective of our study was to determine a correlation between the level of adipocyte fatty acid-binding protein (A-FABP) (as a possible link between metabolic syndrome and atherosclerosis), the calcium score (CS) and laboratory parameters, including insulin resistance indices in asymptomatic first degree relatives of patients with cardiovascular diseases. SET AND METHODOLOGY: Examination was conducted in 82 persons (53 male) with the average age of 52.79 ± 9.6. The examinations consisted of anthropometric and physical tests (determination of body weight, height, body mass index - BMI and casual blood pressure measurement), laboratory analysis (uric acid, creatinine, lipid panel, insulin, glucose, C-reactive protein, fibrinogen, glycated hemoglobin, adipocyte fatty acid-binding protein - A-FABP) and determination of insulin resistance indices HOMA and QUICKI. Total calcium score (CS) was determined by the Agatston method without the need to administer a contrast agent., Results: The value of the A-FABP level does not show a statistically significant dependence on the categorised CS or on non-categorised CS values. There is a statistically significant positive dependence of the level of A-FABP on the HOMA index (p = 0.00688) and a statistically significant negative dependence on the QUICKI index (p = 0.0068). The A-FABP level is statistically significantly higher in women (p = 0.048), in elder persons (p = 0.043), and in persons with higher BMI values (p = 0.029). Among continuous variables, statistically significant is the difference in the A-FABP level in relation to age (p = 0.002), creatinine (p = 0.026), insulin (p = 0.005), and BMI (p = 0.031)., Conclusion: Our study confirmed the correlation of the A-FABP level with insulin resistance indices, BMI, age, gender, and insulin and creatinine levels in a group of asymptomatic first degree relatives of patients with cardiovascular diseases. A-FABP could potentially be a marker when determining the risk of CVD; however, this conclusion requires additional clinical trials.

Toll-like receptor 4 (TLR4) in complex with its accessory protein MD-2 represents an emerging target for the treatment of severe sepsis and neuropathic pain. We performed structure-based and ligand-based virtual screening targeting the TLR4-MD-2 interface. Three in silico hit compounds showed promising TLR4 antagonistic activities with micromolar IC50 values. These compounds also suppressed cytokine secretion by human peripheral blood mononuclear cells. The specific affinity of the most potent hit was confirmed by surface plasmon resonance direct-binding experiments. The results of our study represent a very promising starting point for the development of potent small-molecule antagonists of TLR4., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Cinnamic acid is an organic acid occurring naturally in plants that has low toxicity and a broad spectrum of biological activities. In the search for novel pharmacologically active compounds, cinnamic acid derivatives are important and promising compounds with high potential for development into drugs. Many cinnamic acid derivatives, especially those with the phenolic hydroxyl group, are well-known antioxidants and are supposed to have several health benefits due to their strong free radical scavenging properties. It is also well known that cinnamic acid has antimicrobial activity. Cinnamic acid derivatives, both isolated from plant material and synthesized, have been reported to have antibacterial, antiviral and antifungal properties. Acids, esters, amides, hydrazides and related derivatives of cinnamic acid with such activities are here reviewed.

Aim: Obstructive sleep apnea (OSA) can be associated with the metabolic syndrome. Adipocyte fatty acid-binding protein (A-FABP) may play a role in OSA. The aim of this study was to determine whether continuous positive airway pressure (CPAP) treatment results in decreased serum A-FABP levels., Subjects and Methods: 81 patients (70 males, a mean age of 53.9±10.3 years) were evaluated by polysomnography, diagnosed with OSA and indicated for CPAP treatment. Anthropometric, clinical and laboratory investigations were carried out and repeated after 1 month/ 1 year of CPAP treatment. The data were analyzed using the SPSS Statistics 15 software (SPSS Inc., Chicago, USA)., Results: Patients had significantly decreased A-FABP levels (34.4 ng/ml, 31.2 ng/ml, 24.8 ng/ml, P=0.048, P=0.001) and improved OSA parameters: AHI (53.9, 5.0, 5.6, P<0.0001), mean nocturnal oxygen saturation (91%, 93%, 94%, P<0.0001), ODI (55, 9, 8, P<0.0001), and percentage of sleep time with oxygen saturation below 90% (28.2, 0.2, 0, P<0.0001). BMI, waist, neck circumference, and blood pressure did not statistically significantly change., Conclusion: CPAP therapy in OSA patients has a positive effect on A-FABP levels. Decreased A-FABP levels play an important role in regulating glucose metabolism and affect the regulation of lipid metabolism and thus may contribute to decrease in the cardiovascular complications of OSA.

Searching for the answer whether the bullet cal. 6.35 mm Browning (25 Auto) could entrance the human skull and stay inside without resting the head against the solid barrier inside the vehicle, forensic experts in the field of ammunition and wound ballistics used mathematical model of the monoogival pistol bullet's velocity decrease through the penetration of the several type of human tissue due to physical and mechanical properties. The result of the expert's terminal ballistics task was the mathematical prediction of wound track length at the moment of bullet's stop in the tissue. The results has been compared with the cases where the similar weapon system with the resembling energetic output has been used.

The role of nonclassical human leukocyte antigens G and E (HLA-G and HLA-E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA-G and HLA-E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA-G and HLA-E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA-G and HLA-E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA-G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA-E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro-host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study., (© 2010 Japanese Society of Neuropathology.)

Background: Obstructive sleep apnea (OSA) can activate pathological routes which can lead to insulin resistance, development of atherosclerosis and hypertension. The combination of hypertension and OSA has an additive effect on the development of atherosclerosis. As a number of studies have revealed, that the incidence of OSA in patients with myocardial infarction is likely to be high., Methods and Results: We present a patient with acute myocardial infarction and no classical coronary artery disease risk factors: non-smoker, normal blood pressure, normal total and low-density lipoprotein cholesterol levels, borderline high-density lipoprotein cholesterol level, with good physical activity, no diabetes mellitus, no abdominal obesity, a negative family history. The only risk factor was untreated obstructive sleep apnea. The course of disease was complicated by subsequent in-stent restenosis and progression of atherosclerotic plaques, which led to the need for acute coronary artery bypass graft surgery complicated by consecutive in-anastomosis stenosis despite maximum cardiovascular therapy. One year of continuous positive airway pressure treatment was needed to stabilize his health condition, which is now stable for up to two years., Conclusions: Given the complicated course of ischemic heart disease in patients with OSA, we believe that OSA diagnosis would be advisable each time these patients with symptoms of myocardial infarction, ischemic heart disease and OSA are examined. Even more important, however, is proper treatment of the OSA when it is present.

Background: Based on a 11-year implementation of the Amiantus Project, this paper reports the results of prophylactic medical examinations of the former workers of asbestos processing plants. The Project involving employees of 28 former asbestos plants was started by the Ministry of Health in 2000 under the Act on the ban of all products containing asbestos., Material and Methods: Preventive examinations, continued in 13 centers of occupational medicine throughout the whole territory of Poland, have been coordinated by the Nofer Institute of Occupational Medicine in Lodz (NIOM). During the examinations, a specific Examination Form is filled-in by a physician. The Form is then sent to NIOM for monitoring health effects in the population covered by the Project. The results obtained by analyzing the lung radiological images are recorded in the Examination Form according to the ILO 1980 classification of pneumoconiosis. The diagnosis of the asbestos-related pathologies is based on the Helsinki criteria., Results: During the years 2000-2010, altogether 6,853 people were involved in the Project, and they were subjected to a total of 18,955 preventive examinations. Asbestosis was diagnosed in 1475 people, representing 21% of all respondents, lung cancer in 68 and mesothelioma in 40 people. Pleural radiographic changes were observed in 3027 (44%) patients, pulmonary parenchymal opacities in 4086 (60%) patients. The analysis showed that the asbestos-related pathologies were most frequent in the group of former employees of asbestos-cement plants. This group was also characterized by an age-, tenure-, and latency-related increasing trend in the prevalence of silicosis and the frequency of radiographic lesions in the lungs of those subjects., Conclusions: The continuation of the examinations of former workers of asbestos processing industry has improved the detection of pathologies associated with exposure to asbestos and enabled undertaking an appropriate preventive action. The growing percentage of poorer radiography results reflects the progressive development of pathological processes in the respiratory system of people occupationally exposed to asbestos dust in the past.

The possible role of immune-modulatory nonclassical molecules HLA-G and HLA-E in an anti-tumoral response and development of glioblastoma is not well characterized. In this study, we evaluated an expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages. We found production of HLA-G and HLA-E by tumor infiltrating activated microglia/macrophages in a majority of glioblastomas. We speculate that the expression of these molecules by activated microglia/CNS macrophages plays a role in the anti-tumoral immunity in the development of glioblastoma. Mechanisms of microglia-glioblastoma cell interactions with respect to the expression of these molecules deserves further study., (Copyright 2010 Elsevier B.V. All rights reserved.)

Enzymes involved in the biosynthesis of bacterial peptidoglycan represent important targets for development of new antibacterial drugs. Among them, Mur ligases (MurC to MurF) catalyze the formation of the final cytoplasmic precursor UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid. We present the design, synthesis and biological evaluation of a series of phosphorylated hydroxyethylamines as new type of small-molecule inhibitors of Mur ligases. We show that the phosphate group attached to the hydroxyl moiety of the hydroxyethylamine core is essential for good inhibitory activity. The IC(50) values of these inhibitors were in the micromolar range, which makes them a promising starting point for the development of multiple inhibitors of Mur ligases as potential antibacterial agents. In addition, 1-(4-methoxyphenylsulfonamido)-3-morpholinopropan-2-yl dihydrogen phosphate 7a was discovered as one of the best inhibitors of MurE described so far.

17beta-Hydroxysteroid dehydrogenase (17beta-HSD) type 1 converts estrone to estradiol, a potent ligand for estrogen receptors. It represents an important target for the development of drugs for treatment of estrogen-dependent diseases. In the present study, we have examined the inhibitory activities of some flavonoids, their biosynthetic precursors (cinnamic acids and coumaric acid), and their derivatives. The proliferative activity of flavonoids on the T-47D estrogen-receptor-positive breast cancer cell line was also evaluated. Among 10 flavonoids, 7,4'-dihydroxyflavone, diosmetin, chrysoeriol, scutellarein, genkwanin and fisetin showed more than 70% inhibition of 17beta-HSD type 1 at 6microM. In a series of 18 derivatives of cinnamic acid, the best inhibitor was 4'-cyanophenyl 3,4-methylenedioxycinnamate, with more than 70% inhibition of 17beta-HSD type 1. None of flavonoids affected the proliferation of T-47D breast cancer cells.

Bacterial beta-ketoacyl-[acyl carrier protein] (beta-ketoacyl-ACP) reductase (FabG) is a highly conserved and ubiquitously expressed enzyme of the fatty-acid biosynthetic pathway of prokaryotic organisms that catalyzes NADPH-dependent reduction of beta-ketoacyl-ACP intermediates. Therefore, FabG represents an appealing target for the development of new antimicrobial agents. A number of trans-cinnamic acid derivatives were designed and screened for inhibitory activities against FabG from Escherichia coli. These inhibited FabG enzymatic activity with IC(50) values in the microM range, and were used as templates for the subsequent diversification of the chemotype. Introduction of an electron-withdrawing 4-cyano group to the phenol substituent showed improved inhibition over the non-substituted compound. The benzo-[1,3]-dioxol moiety also appeared to be essential for inhibitory activity of trans-cinnamic acid derivatives against FabG from E. coli. To explain the possible binding position, the best inhibitor from the present study was docked in the active site of FabG. The results for the best scoring conformers chosen by the docking programme revealed that cinnamic acid derivatives can be accommodated in the substrate-binding region of the active site, above the nicotinamide moiety of the NADPH cofactor. Additionally, a phage-displayed library of random linear 15-mer peptides was screened against FabG, to identify ligands with the common PPLTXY motif.

The Van enzymes are ATP-dependant ligases responsible for resistance to vancomycin in Staphylococcus aureus and Enteroccoccus species. The de novo molecular design programme SPROUT was used in conjunction with the X-ray crystal structure of Enterococcus faeciumd-alanyl-d-lactate ligase (VanA) to design new putative inhibitors based on a hydroxyethylamine template. The two best ranked structures were selected and efficient syntheses developed. The inhibitory activities of these molecules were determined on E. faecium VanA, and due to structural similarity and a common reaction mechanism, also on d-Ala-d-Ala ligase (DdlB) from Escherichia coli. The phosphate group attached to the hydroxyl moiety of the hydroxyethylamine isostere within these systems is essential for their inhibitory activity against both VanA and DdlB.

The biosynthesis of bacterial cell wall peptidoglycan is a complex process that involves enzyme reactions that take place in the cytoplasm (synthesis of the nucleotide precursors) and on the inner side (synthesis of lipid-linked intermediates) and outer side (polymerization reactions) of the cytoplasmic membrane. This review deals with the cytoplasmic steps of peptidoglycan biosynthesis, which can be divided into four sets of reactions that lead to the syntheses of (1) UDP-N-acetylglucosamine from fructose 6-phosphate, (2) UDP-N-acetylmuramic acid from UDP-N-acetylglucosamine, (3) UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid and (4) D-glutamic acid and dipeptide D-alanyl-D-alanine. Recent data concerning the different enzymes involved are presented. Moreover, special attention is given to (1) the chemical and enzymatic synthesis of the nucleotide precursor substrates that are not commercially available and (2) the search for specific inhibitors that could act as antibacterial compounds.

The synthesis and activity of a new series of non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase that are based on a 1,5-benzodiazepine scaffold are presented. Their inhibitory potential was screened against 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl), a model enzyme of the short-chain dehydrogenase/reductase superfamily. Some of these compounds are potent inhibitors of 17beta-HSDcl activity, with IC50 values in the low micromolar range and represent promising lead compounds that should be further developed and investigated as inhibitors of human 17beta-HSD isoforms, which are the enzymes associated with the development of many hormone-dependent and neuronal diseases.

The reasons for transcranial operative revision of anterior cranial fossa are cerebrospinal fluid (CSF) leakage, pneumocephalus, recurrent meningitis and eventually other causes. The trauma is the most common etiology of previously mentioned pathologic statuses, rarely it can also be long-lasting intracranial hypertension. We retrospectively analyzed our 61 patients, operatively treated at Department of Neurosurgery in Brno-Bohunice between 1997 and 2005, at whom the cranionasal communication must have been treated by means of transcranial neurosurgical repair of anterior fossa skull base. Each year approximately 10-15 operations of this kind were performed. The main goal of operative solution was the water-tight closure of dural defect and cranial base by means of direct dural suture duroplasty with periostal flap, fascial flap or other graft. Each case solution was dependent on actual operative appearance of the operative field. The majority of transcranial repairs of frontal cerebral fossas were performed acutely as a part of frontobasal injury operation with haematoma, calvar impressive fractures and open cerebral injury. The minority of repairs is formed by elective operations for posttraumatic rhinnorhea and meningitis. In our announcement we also mention possible conservative treatment.

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) modulate the biological potency of estrogens and androgens by interconversion of inactive 17-keto-steroids and their active 17beta-hydroxy- counterparts. We have shown previously that flavonoids are potentially useful lead compounds for developing inhibitors of 17beta-HSDs. In this paper, we describe the synthesis and biochemical evaluation of structurally analogous inhibitors, the trans-cinnamic acid esters and related compounds. Additionally, quantitative structure-activity relationship (QSAR) and modelling studies were performed to rationalize the results and to suggest further optimization. The results stress the importance of a hydrogen bond with Asn154 and hydrophobic interactions with the aromatic side chain of Tyr212 for optimal molecular recognition.

Background: Prophylactic examinations of workers formerly employed in asbestos processing plants were performed by virtue of the Act, dated 19 June 1997, putting a ban on the production of asbestos-containing products. To enforce the provisions of the Act, the Ministry of Health has initiated the Amiantus project implemented by 13 Occupational Medicine Centers throughout the country and coordinated by the Nofer Institute of Occupational Medicine (IMP) in Lódź., Material and Methods: All the Centers perform diagnostic procedures according to the same criteria (clinical, radiological, spirometric and histological), based on the 1997 Helsinki criteria, to diagnose asbestos-related diseases. A specific "Examination Form", developed for the needs of the Amiantus project, is completed by an occupational physician during examinations and sent to the IMP, where health effects in the whole population covered by the project are monitored. Periodical medical examinations are performed at least every three years and they include: general examination, chest x-ray, resting spirometric examination and supplementary examinations (e.g., resting gasometric examination) or other diagnostic examinations if necessary (e.g., computed tomography)., Results: Owing to the project implementation, it was possible to collect in the database information on 5466 persons who underwent 8763 prophylactic examinations in 2000-2004. Of the total population examined during a five-year period, occupational disease was certified in 728 (13%) persons. Asbestosis was diagnosed in 790 persons, lung cancer in 19 persons and pleural mesothelioma in 12 persons. Pleural changes in x-ray imaging were found in 1662 (30%) persons and opacities in pulmonary parenchyma in 2088 (38%) persons. Having compared these results with those from previous examinations, the total health condition deterioration was observed in 882 (16%) persons, including worsening of the lung x-ray imaging in 512 (9%) persons. An analysis showed the highest incidence of asbestos-related pathologies in workers of asbestos-cement plants. The collected data also confirmed an upward trend in the incidence of asbestosis and changes in the lung x-ray imaging related to age, duration of employment and latency., Conclusion: The implementation of the Amiantus project has contributed to an increased detection of pathologies related with exposure to asbestos fibers. A growing proportion of radiograms, which indicate worsening of health condition provides evidence that morbid processes in the respiratory system are progressing in persons who in the past were occupationally exposed to asbestos dust.

We present the synthesis of a new family of nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase, designed from flavones and chalcones. Their inhibitory potential was screened on 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl), a model enzyme of the short-chain dehydrogenase/reductase superfamily. In a series of cinnamates and related coumarin-3-carboxylates, a number of compounds proved to be potent inhibitors of both the oxidative and reductive reactions catalyzed by 17beta-HSDcl, with IC(50) values in the low micromolar range.

In some cases of shunt malfunction in pregnant women the symptoms can be so severe and occur so early that not only the mother but also the baby is threatened. In such a situation the close co-operation of a neurosurgeon and a gynaecologist is mandatory. Both conservative and surgical treatment have to be applied to overcome the time until the delivery carries an acceptable risk for the child. In such a case a pre-term delivery by Cesarean section should be recommended. (Fig. 1, Ref. 2.)

A reaction of potassium thiocyanate with methyl and ethyl ester of chloroformic acid (I-II) resulted in methoxy- and ethoxycarbonyl isothiocyanates which through an addition reaction with various primary and secondary amines, diamines and hydrazines yielded the perinently substituted esters of thioallophanic acid (III-XXI). The obtained agents were tested for anthelmintic and anticoccidial effects.