Carbapenems are potent β-lactam antibiotics used to treat serious infections in hospital settings. In comparison to penicillins, cephalosporins or β-lactam/β-lactamase inhibitor they have broad antimicrobial spectrum that includes Gram-positive (e.g. imipenem, doripenem) and Gram-negative bacteria (e.g. meropenem, ertapenem). Imipenem and meropenem have better activity against P. aeruginosa while imipenem and doripenem have better activity than meropenem against Acinetobacter baumannii. Doripenem has the lowest MIC against P. aeruginosa and A. baumannii in comparison to imipenem and meropenem, and it is least susceptible to hydrolysis by carbapenemases. To act on PBPs, carbapenems have to enter the wall of Gram-negative bacteria through outer membrane proteins (porins). Binding to different PBPs they inhibit the synthesis of cell wall finally leading to the death of bacterium [1]. Carbapenem resistance in Gram-negative bacteria can be the consequence of the production of a β-lactamase, expression of efflux pumps, porin loss and alterations in PBPs. Since β-lactams, including carbapenem-like compounds, are natural products of several environmental bacteria and fungi, it is supposed that other bacteria started to produce their intrinsic β-lactamase to give them selective advantage for survival. Thus, several genes encoding different carbapenemases can be found in environmental bacteria like Bacillus anthracis, Serratia fonticola, Pseudomonas cepacia or Acinetobacter spp. as part of their chromosome [1, 2]. Further step in this evolution of resistance was the escape of carbapenemase encoding genes to mobile genetic elements (plasmids, transposons) providing possibility of successful horizontal spread of resistance genes even between different genera [3]. Since this discovery, carbapenemases became global problem. According to the Ambler classification (based on structural similarities) they belong to the class A, B and D [1]. Class A carbapenemases contain serine at their active site and are capable of hydrolyzing all β-lactams, including aztreonam. In this group of carbapenemases, Sme (Sme-1 to Sme-3), IMI (IMI-1-3), NmcA and SFC-1 enzymes are mostly chromosomally encoded, while KPC (KPC- 2 to KPC-13) and GES (GES 1-GES-20) are plasmid encoded. Dominant carbapenemase from this group is KPC, identified in 1996 in North Caroline, USA, now causing many regional outbreaks, with endemicity in northeastern part of the USA, Israel, China, Porto Rico, Colombia, Israel, Greece, and becoming more and more prevalent throughout the Europe [4]. Beside K. pneumoniae, represented by a predominant clone (ST258), it has been found in other Enterobacteriaceae, as well as in P. aeruginosa and A. baumannii–calcoaceticus complex. It is sometimes difficult to be recognized since MICs to carbapenems are in many cases lower than the breakpoints [2, 5]. Class B carbapenemases are also known as metallo-β-lactamase (MBL) since they contain metal ion(s) in their active site. Beside those chromosomally located in environmental bacteria (Bacillus cereus-BCI, BCII, Aeromonas spp-CphA, S. maltophilia-L1), acquired MBL encoding genes are often located in gene cassettes within integron, being part of a plasmid or chromosome. Firstly described acquired MBLs were in Japan in 1991, so called IMP-enzymes (there are now more than 30 derivatives) and are still dominant MBLs in Asian continent causing mainly sporadic outbreaks [6]. VIM-enzymes (there are now more than 30 derivatives) were firstly described in P. aeruginosa but later arisen to Enterobacteriaceae as well, and fastly spread over whole Europe, causing outbreaks in many Mediterranean countries (like Greece, Italy, Turkey). VIM metallo-β-lactamase are now the most prevalent carbapenemase spreading globally, and although largely connected to P. aeruginosa, now reported more often from Enterobacteriacea from Mediterranean countries, particulary Greece and Turkey, with the description of many panresistant strains [6, 7]. Another worrisome metallo-enzyme, arose from India in 2008, namely New-Delhi MBL (NDM-1 ; until now more than ten variants are described), and spread fastly over Indian subcontinet in next few years. NDM-enzymes are mostly associated with nonclonally related isolates of K. pneumoniae and E. coli, but also described in P. aeruginosa and A. baumannii [8]. Beside proven facts that those enzymes exist in isolates spreading in environment, and are carried in general population by enteric flora, the magnitude of the problem potentiates the huge population reservoir from Indian subcontinet and Middle Asia that moves across the world spreading further the resistance genes [9, 10, 11]. Another new source of those enzymes could be the Balkan region [12, 13]. Oxacillinases from molecular class D demonstrating carbapenemase activity are often found in Acinetobacter spp. They are divided into the most globally spread OXA-23 group, found also in environmental isolate of Acinetobacter spp. suggesting the possible natural and not nosocomial source of these genes, OXA-24 group, not so widespread as OXA-23, mostly described in Europe and USA, and OXA-58 group, described in several outbreaks all over the world [14]. The problem became more global with the discovery of OXA-48 in Enterobacteriaceae, particulary in K. pneumoniae and to lesser extent in E. coli, spreading all around the world but specifically in countries close to the Mediterranean Sea [14-16]. Carbapenemase producing Gram-negative bacteria can cause a wide spectrum of infections including bacteraemia, nosocomial pneumonia, wound infections, endocarditis, urinary tract infections. Those infections are often associated with treatment failures, long hospital stay and high mortality rates ; for example attributable mortality for carbapenem resistant P. aeruginosa infections ranged between 51.2 and 95% [17, 18].

Tourist destinations around the world are trying to cope with the needs of visitors which are very susceptible to change. Nowadays, tourists are becoming more sophisticated and knowledgeable, and their needs for extensive  and diverse experiences are increasing. As opposed to the destinations whose tourism development depends on the natural resources that are difficult to influence, and whose business is susceptible to the negative impacts of seasonality, destinations of city and cultural tourism have more space to design their offers and contents that can satisfy the needs of travelers of the modern age. Content that can make a destination unique and well-known, is the cultural heritage created in the Art Nouveau style. The secessionist architectural masterpieces can represent a major tourist attractions in some destinations. For example, many attractive tourist cities such as Aveiro, Barcelona, Prague and Hamburg tourists visit just in order to feel and experience these works of art. For this reason it is very important to point out Art Nouveau as an essential part of the cultural heritage of the destination and enable informing and introducing tourists with this valuable tourism potential. The initial hypothesis of this paper is that Aveiro has authentic cultural heritage in the Art Nouveau style that enriches the tourist offer of the city and that attracts a certain segment of the tourism market. Aim of the paper is to percieve the participation and influence of Art Nouveau heritage in the tourism industry of Aveiro. Keywords: Secession, Art direction, Tourism, Aveiro

Relevant for various areas of human genetics, Y‐chromosomal short tandem repeats (Y‐STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17‐loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality‐controlled data of 13 rapidly mutating (RM) Y‐STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, >99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836–0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father–son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y‐STRs in identifying and separating unrelated and related males and provides a reference database.

The authors assessed the overall response rate, including confirmed complete response (CR) and partial response, in patients with relapsed/refractory multiple myeloma treated with sorafenib. Qualitative and quantitative toxicities associated with this regimen were evaluated. Patients were eligible if they had a confirmed diagnosis of refractory or relapsed (RR) multiple myeloma (MM) with measurable monoclonal protein. Patients had to have adequate renal, hepatic, hematologic, and cardiac function with a Zubrod performance status of 0–2. Patients were given 400 mg sorafenib by mouth twice daily for 28‐day treatment cycles. These patients were followed up for a maximum of 3 years to assess responses and adverse events. Twenty‐three patients were enrolled. Of these, five were found to be ineligible for the following reasons: four had insufficient documentation of the baseline disease and one patient did not have measurable disease. All eighteen eligible patients were evaluable for toxicities. Three patients experienced grade 4 toxicities: one with thrombocytopenia, one with anemia, and one with renal failure. Four of the eighteen eligible patients were not assessable for response due to removal from protocol treatment prior to adequate disease assessment. Specifically, three were removed for either grade 4 toxicity or progression of disease and one was removed per patient choice (due to reasons unrelated to treatment). Of the 18 patients who were assessed for toxicities, 5 (27.8%) received at least one fully dosed cycle, 2 (11.1%) of whom had all cycles fully dosed. No responses were observed on this study of the 14 patients who were assessable for response. All patients have discontinued protocol treatment as of August 2008. Overall survival at 12 months was 50% (95% CI 27–73%) and median progression‐free survival was 1.2 months (95% CI 1.0–5.4). The trial did not exhibit activity by the International Uniform Response Criteria for MM. Further research should focus on combination therapy of sorafenib with standard treatments in selected patients with RR MM.