Defibrotide is approved for the treatment of sinusoidal obstruction syndrome after allogeneic stem cell transplantation. The exact mode of action of defibrotide is unclear and human in vivo data are scarce. In this randomized, double blind, crossover trial we included 20 healthy volunteers. Four were randomized to receive placebo, while 16 received a 2 ng/kg bodyweight bolus of lipopolysaccharide (LPS). Infusion of 6.25 mg/kg defibrotide or placebo was started one hour before the injection of the LPS bolus. Plasma levels of prothrombin fragments F1 + 2, thrombin-antithrombin complexes, von Willebrand factor, E-selectin, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes (PAP), tumor necrosis factor-α, interleukin 6, and C-reactive protein were measured. Thromboelastometry was performed. Infusion of defibrotide did not reduce the LPS-induced activation of coagulation, the endothelium or the release of pro-inflammatory cytokines. However, defibrotide increased t-PA antigen levels by 31% (Quartiles: 2–49%, p = 0.026) and PAP concentrations by 13% (−4–41%, p = 0.039), while PAI-1 levels remained unaffected. Moreover, defibrotide reduced C-reactive protein levels by 13% (0–17%, p = 0.002). A transient increase in the clotting time in thromboelastometry and a decrease in F1 + 2 prothrombin fragments suggests modest anticoagulant properties. In conclusion, defibrotide infusion enhanced fibrinolysis and reduced C-reactive protein levels during experimental endotoxemia.

We present the case of a 36-year-old woman who works as a kindergarten teacher, often she is kneeling on her knees due to the nature of the job. Since a year ago, she noticed that her right knee was swelling. She had an orthopaedic examination when she could no longer bend her knee. Inspection and palpation revealed the swelling of the anterior and anterior-lateral aspect of the knee. MRI imaging revealed a large, sharply defined, lobulated lesion of the infrapatellar fat pad. After the surgical incision, a lobular lesion was found and surgically removed. Histological analysis confirmed a ganglion cyst.

Three commercial apple cultivars ('Jonagold', 'Granny Smith' and 'Idared') and the local apple cultivar ('Prijedorska Zelenika') from Bosnia and Herzegovina were analysed by HPLC-MS for the content of phenolic compounds in peel and pulp as well content of individual sugars and organic acids. Catechin, (-)-epicatechin, chlorogenic acid, caffeic acid, quercetin 3-O-xyloside, quercetin 3-O-arabinoside, quercetin 3-O-rhamnoside, quercetin 3-O-rutinoside, quercetin 3-O-galactoside and quercetin 3-O-glucoside were identified in apple peel and (-)-epicatechin, chlorogenic acid and caffeic acid in apple pulp at all observed cultivars. The total sugars content of analysed apple cultivars ranged between 91.61 and 105.45 g kg-1 FM, while the total organic acids content was from 5.70 to 15.05 g kg-1 FM. The levels of total organic acids and sugars, glucoce/fructose ratio and sugar/acid ratio were affected by cultivars. The mean content of total phenolic compounds was between 427.92 and 1457.95 mg kg-1 FM in peel and from 113.58 to 439.83 mg kg-1 FM in pulp and depending upon the cultivars. The presented data clearly demonstrated that traditional apple cultivar ('Prijedorska Zelenika') had significantly higher individual phenolic compounds in pulp in comparison to the commercial cultivars, i.e., 'Idared', 'Jonagold' and 'Granny Smith' and with respect of that 'Prijedorska Zelenika' is recommended as raw material for cloudy juice processing.

High blood pressure or hypertension is an outstanding public health problem affecting nearly 40% of the World’s adult population. Prevalence of hypertension has a strong socioeconomic impact and health burden. Recently, hypertension has reached epidemic proportions, and it is estimated that ≈25% of adult individuals will be hypertensive in the World by 2025. Untreated hypertension can result in various health complications, such as stroke, myocardial infarction, vascular disease, and chronic kidney diseases. Generally, hypertension is categorized as either primary or secondary according to its cause. However, there are several types of hypertension that are more or less common such as essential hypertension (EHT), pulmonary hypertension (PHT), pulmonary arterial hypertension (PAHT), white coat hypertension, and nocturnal hypertension. This article focuses on the 3 first types for which a significant amount of information on the role of noncoding RNAs (ncRNAs) is available. Essential, primary, or idiopathic hypertension refers to elevated blood pressure in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension, or Mendelian forms are not present. EHT is the most frequent type of hypertension, which accounts for 95% of all cases. PHT refers to an elevation of the pulmonary arterial pressure above 25 mm Hg at rest as assessed by right heart catheterization. This elevation can be caused by different underlying diseases, such as liver disease, thromboembolic disease, rheumatic disorders, lung conditions, including tumors, chronic obstructive pulmonary disease, pulmonary fibrosis, or cardiovascular diseases, including aortic valve disease, heart failure, and congenital heart disease. According to the latest World Health Organization classification, PHT is classified depending on its cause into 5 groups: PAHT, PHT caused by left heart disease, PHT caused by lung disease, PHT caused by chronic blood clots, and PHT associated with other unclear conditions. PAHT is defined as pulmonary vasculopathy and progressive pulmonary vasculature remodeling that cause the rise of pulmonary arterial pressure. Although PAHT is classified as a specific subgroup of PHT, in the literature, PHT is often used instead of PAHT. Thus, while PHT refers to an elevation of pressure in the lung arteries caused by a side disease, PAHT is caused by remodeling of pulmonary blood vessels. Owing to the fact that blood pressure is regulated by multiple physiological pathways, it is difficult to decipher a single causative agent of hypertension. Recent studies have shown that complex multifactorial cause of hypertension results from a dynamic interplay of genetic and environmental factors. Polygenic nature of hypertension involves many genes each with mild cumulative effects reacting to environmental factors that contribute to hypertension. Population-based studies have demonstrated that Mendelian forms of hypertension can be found in about 20% of families and reach 60% in twins. Integration of data from genome-wide linkage and association studies and system genetics approaches allowed the identification of >100 single nucleotide polymorphisms implicated in high blood pressure. Studies aiming to decipher the molecular pathways of high blood pressure have identified genes involved in the renin-angiotensin-aldosterone system (RAAS), signaling through G protein-coupled receptors, vascular inflammation, remodeling, and in the structure and regulation of vascular senescence and developmental programming. Although significant progress has been achieved in elucidating the molecular pathways involved in the pathophysiology of hypertension, the regulatory function of these pathways remains to be fully elucidated. Recent advances in epigenetics may provide at least some of the missing pieces of the hereditary puzzle that can explain the fact that a same genome can provide distinct phenotypes, without alterations in primary DNA structure. The key factor in figuring out the complex multifactorial nature of hypertension might well hence be the dark matter of the human genome. Indeed, while it used to be commonly accepted that each of human genes would encode proteins, it has more recently been discovered that the majority (>95%) of these genes are unable to produce proteins. These genes are transcribed into ncRNA molecules and they play multiple important roles in regulating protein-coding genes. The ubiquitous expression of ncRNAs allows them to regulate many physiological and pathological processes, in virtually all cell types. Because their discovery, ncRNAs have attracted an exponential interest by the biomedical research community, notably in the area of cardiovascular diseases and their major risk factor, hypertension. NcRNAs have been arbitrarily classified into short and long ncRNAs with a threshold of 200 nucleotides. In addition, ncRNAs have been classified according to their cellular localization (nuclear versus cytoplasmic), mechanism of action and

The aim of this study was to evaluate the dynamics of Mn in ‘soil - raspberry’ system on the area around the manganese ore deposits Radostovo in Bužim municipality. Atomic absorption spectroscopy was used to determine the concentration of Mn in soil and plant samples. Fe, Zn and Cu concentration in soil and raspberry plants was also subject of analysis, since these elements have antagonistic relationship with Mn in soils. The concentration of available Mn in soils was low, although the total Mn in the same soils exceeded the Mn toxic values noted in the scientific literature. The chemical and physical properties of the examined soils characterized by a relatively high pH value and good ability to store root-zone air certainly contributed to the decreasing release of available Mn2+ from manganese oxides in soils as well as Mn2+ oxidation to insoluble Mn3+ or Mn4+ ions, resulting in low uptake of Mn by plant roots. The results of study also showed that the absorbed Mn mostly accumulates in leaves and roots of raspberry, and much less in the stem and fruits. That rule in Mn distribution within raspberry plant is in fact identical to all food crops.

Druga polovina prošlog vijeka okarakterisana je vrtoglavim razvojem računarskeindustrije koja je ubrzo postala osnovni preduslov razvoja svih sektora privrede.Uzimajući u obzir pomenuto, porasla je i potreba za stručnjacima koji će u segmentuposlovanja biti u stanju povezati tehničke i upravljačke zajednice. Rezultat je biopokretanje studija poslovne informatike, pod tim istim, sličnim ili različitim imenima,najčešće u okviru poslovnih škola kao studij prvog ciklusa. Međutim, razvojem upodručju poslovanja, a pogotovo kompjutinga, u novom mileniju se ovaj studij sve višepojavljuje kao samostalan sa tendencijom da postane ravnopravna organizacijskajedinica unutar hijerarhije univerziteta. Ovaj rad ima za cilj da predstavi teoretskuosnovu kurikuluma i praktičan primjer studija Poslovna informatika koji je rezultatzajedničkog rada Ekonomskog fakulteta i Fakulteta informacijskih tehnologijaUniverziteta „Džemal Bijedić“ u Mostaru.

Ovaj rad istražuje problem malih i srednjih preduzeća (MSP) vezane za pristup izvorima finansiranja uFederaciji Bosne i Hercegovine (FBiH). Fokus istraživanja je na analiziranju potreba MSP za eksternimfinansiranjem, karakteristikama nedavno dobijenih eksternih izvora finansiranja te preprekama zadobijanje finansijskih izvora, kao i da se pomogne u razumijevanju budućih potreba MSP i finansijskeklime. Kako bi se procijenila adekvatnost pristupa finansiranju MSP u FBiH, istraživanje je provedenokorištenjem SAFE metodologije Evropske centralne banke, i to na uzorku MSP u FBiH. Podaci suprikupljeni u 2016. godini, a uzorak je činilo 80 MSP. Adaptirani upitnik za ovo istraživanje kreiran jena način da analizira percepcije MSP u FBiH u pogledu dostupnosti i adekvatnosti finansijskihproizvoda/usluga, koje nude banke i druge finansijske institucije. Očekuje se da će istraživanje pružitiinformacije o identifikaciji problema iz perspektive MSP prilikom traženja eksternih finansijskih izvorai može se koristiti kao smjernica za poboljšanje postojećeg institucionalnog okvira u FBiH radi boljegpristupa finansijama za MSP.

Abstract Background and aims Wastewater‐based epidemiology is an additional indicator of drug use that is gaining reliability to complement the current established panel of indicators. The aims of this study were to: (i) assess spatial and temporal trends of population‐normalized mass loads of benzoylecgonine, amphetamine, methamphetamine and 3,4‐methylenedioxymethamphetamine (MDMA) in raw wastewater over 7 years (2011–17); (ii) address overall drug use by estimating the average number of combined doses consumed per day in each city; and (iii) compare these with existing prevalence and seizure data. Design Analysis of daily raw wastewater composite samples collected over 1 week per year from 2011 to 2017. Setting and Participants Catchment areas of 143 wastewater treatment plants in 120 cities in 37 countries. Measurements Parent substances (amphetamine, methamphetamine and MDMA) and the metabolites of cocaine (benzoylecgonine) and of Δ9‐tetrahydrocannabinol (11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol) were measured in wastewater using liquid chromatography–tandem mass spectrometry. Daily mass loads (mg/day) were normalized to catchment population (mg/1000 people/day) and converted to the number of combined doses consumed per day. Spatial differences were assessed world‐wide, and temporal trends were discerned at European level by comparing 2011–13 drug loads versus 2014–17 loads. Findings Benzoylecgonine was the stimulant metabolite detected at higher loads in southern and western Europe, and amphetamine, MDMA and methamphetamine in East and North–Central Europe. In other continents, methamphetamine showed the highest levels in the United States and Australia and benzoylecgonine in South America. During the reporting period, benzoylecgonine loads increased in general across Europe, amphetamine and methamphetamine levels fluctuated and MDMA underwent an intermittent upsurge. Conclusions The analysis of wastewater to quantify drug loads provides near real‐time drug use estimates that globally correspond to prevalence and seizure data.

I read with a great interest a recently published clinical study of Takala et al 1 on metaplastic carcinoma of the breast. The authors explored 78 patients with the diagnosis of metaplastic carcinoma in the period 2002‐2016. In line with previous studies, the authors confirmed predominantly triple‐negative phenotype of metaplastic carcinomas (85%) exhibiting a poor therapeutic response with an ag‐ gressive clinical course and poor outcome. Two things are worthy of further discussion: First, 12% of the pa‐ tients were estrogen receptor (ER)‐positive, eight of which received adjuvant endocrine therapy. I would appreciate more information from the authors regarding the percentage of ER positivity in these metaplastic carcinomas and a potential response to endocrine treat‐ ment. It is well known that most metaplastic carcinomas are ER‐neg‐ ative and if ER‐positive, the percentage of positive cancer cells is usually low (range, 1%‐10%). This fact may substantially affect the response to endocrine therapy, as the patients with lower ER posi‐ tivity in their breast cancers are less responsive to anti‐ER treatment modalities. Another important issue is a targeted therapy of metaplastic carcinomas that has recently come into focus. Multiple molecular studies have revealed potentially targetable biomarkers in met‐ aplastic carcinomas of the breast. These include PI3K (PIK3CA, PTEN, PIK3R1), MAPK (NF1, KRAS, NRAS), RB1, and Wnt path‐ ways.2‐9 Of these, PI3K pathway alterations are of particular im‐ portance in metaplastic carcinoma given that several studies have shown their relevance in predicting the response to mTOR/PIK3CA inhibitors.6,10‐13 In addition, programmed death‐ligand 1 (PD‐L1) expression in cancer and/or inflammatory cells, as a predictor of response to immune checkpoint inhibitors, has also been described in a substantial proportion of metaplastic carcinomas.3,14‐16 A pecu‐ liar case report of Adams et al revealed an impressive therapeutic response of the PD‐L1‐positive metaplastic carcinoma to the com‐ bined treatment with pembrolizumab (anti‐PD‐1 drug) and nab‐ paclitaxel therapy.16 Of note, the Food and Drug Administration (FDA) has recently approved atezolizumab, an anti‐PD‐L1 drug, for the treatment of PD‐L1‐positive triple‐negative breast cancers.17,18 Given the period of your cohort, I was wondering if any of the pa‐ tients were profiled for the aforementioned targetable biomarkers and treated accordingly? Semir Vranic MD, PhD

The goal of this research is to determine the differences between spinal deformities of students in urban and rural areas with regard to the initial and final measurements. This research was conducted on a sample of 1105 students. This research program includes students from the first to the fifth grade in the following 11 elementary schools in Sarajevo. Method of measuring the curvature of the spine based on Napoleon Wolanski ’ s criteria from 1975 entitled D-5 spine posture (ESP). The analysis of spinal deformity of students in urban and rural classrooms was done by using the descriptive chi-square statistics. It has been determined that in the initial measurement, a greater number of examinees with no spinal deformity came from the rural schools. The examinees from the urban schools displayed first- and second-degree spinal deformity. In the final measurement, a greater number of examinees without spinal deformity came from rural schools, 28 (2%) to be precise. There was also a greater representation of first-degree spinal deformity in the examinees from urban schools, 49 (8%) to be precise. However, the representation of second-degree spinal deformity was not present in either of the examinees from rural or urban schools.

This study aims to characterize traumatic spinal cord injury (TSCI) neurophysiologically using an intramuscular fine-wire electromyography (EMG) electrode pair. EMG data were collected from an agonist-antagonist pair of tail muscles of Macaca fasicularis, pre- and post-lesion, and for a treatment and control group. The EMG signals were decomposed into multi-resolution subsets using wavelet transforms (WT), then the relative power (RP) was calculated for each individual reconstructed EMG sub-band. Linear mixed models were developed to test three hypotheses: (i) asymmetrical volitional activity of left and right side tail muscles (ii) the effect of the experimental TSCI on the frequency content of the EMG signal, (iii) and the effect of an experimental treatment. The results from the electrode pair data suggested that there is asymmetry in the EMG response of the left and right side muscles (p-value < 0.001). This is consistent with the construct of limb dominance. The results also suggest that the lesion resulted in clear changes in the EMG frequency distribution in the post-lesion period with a significant increment in the low-frequency sub-bands (D4, D6, and A6) of the left and right side, also a significant reduction in the high-frequency sub-bands (D1 and D2) of the right side (p-value < 0.001). The preliminary results suggest that using the RP of the EMG data, the fine-wire intramuscular EMG electrode pair are a suitable method of monitoring and measuring treatment effects of experimental treatments for spinal cord injury (SCI).