5 (1.0–6.0) 1.5

(0.7–8.0) t 1/2 (h) 1.5 (0.7) 1.4 (0.7) K el (L/h) 0.56 (0.22) 0.62 (0.26) AUC 0–24 area under the JQEZ5 order plasma concentration-time curve from time 0 to 24 h, C max maximum observed concentration, K el apparent terminal elimination rate constant, PK pharmacokinetic, t 1/2 apparent terminal elimination half-life, T max time of maximum observed concentration aMean (standard deviation) displayed for all PK parameters except T max, which is displayed as median (minimum–maximum) Table 2 Statistical analysis of drug–drug interaction following omeprazole 40 mg/day without or with oral icosapent ethyl 4 g/day (pharmacokinetic analysis population, n = 28) PK Parameter (unit) Statistica Treatment Omeprazole 40 mg Icosapent Ethyl 4 g + Omeprazole 40 mg AUC0–24 (ng·h/mL) LSGM 2,973 2,484 Ratio 0.84 90 % CI 75.99–91.87 C max (ng/mL) LSGM 1,051 1,059 Ratio 1.01 90 % CI 87.36–116.3 AUC 0–24 area under the plasma concentration-time curve from time 0 to 24 h, CI confidence MAPK inhibitor interval, C max maximum observed concentration, LSGM least squares geometric means, PK pharmacokinetic aLSGM derived from mixed models; LSGM ratios are provided for icosapent ethyl plus omeprazole/omeprazole alone 3.3 Safety There were no clinically significant findings from laboratory test results or following physical examination and vital sign assessments.

All reported AEs were mild or moderate in severity and there were no discontinuations because of

an AE. 4 Discussion This drug–drug interaction study examined the effects of IPE on the EVP4593 PK of omeprazole. The ratio of least squares means for AUC0–24 and C max (without or with IPE) and the resulting 90 % almost CIs indicated that a regimen of IPE 4 g/day did not inhibit omeprazole PK. Administration of omeprazole alone or co-administered with IPE was well tolerated in healthy subjects. IPE is a prescription form of EPA ethyl ester and has been studied for potential CYP-mediated drug–drug interactions in healthy adults. In addition to the effects described herein for omeprazole (CYP2C19 substrate), the administration of IPE 4 g/day did not display a significant effect on the AUC or C max of atorvastatin (CYP3A4 substrate), rosiglitazone (CYP2C8 substrate), or warfarin (CYP2C9 substrate) [4]. Patients with hypertriglyceridemia often have comorbidities including obesity, metabolic syndrome, and diabetes mellitus [1, 2]. Obesity and metabolic syndrome are associated with erosive esophagitis [14–17], with obesity being a very strong independent risk factor for GERD symptoms [14]. Consequently, many candidates for IPE TG-lowering therapy may be taking a concomitant medication for GERD or erosive esophagitis, such as omeprazole. Other proton pump inhibitors, including lansoprazole and esomeprazole, may also be involved in CYP2C19-mediated metabolism [18].

It seems to be a freak of nature that in M. hominis, OppA has gained an additional ATPase Selleckchem Saracatinib activity which raises the question as to its function. To date ecto-ATPase activity of OppA is unique to M. hominis among substrate-binding proteins of ABC-transporters of all three kingdoms. Thus it seems illogical that the ecto-ATPase is required for optimized peptide import. The findings of this study clearly demonstrate

that the OppA ecto-ATPase is essential for maximal cytoadhesion of M. hominis. In studying bacterial adhesion to polymer surfaces Stollenwerk and coworkers found that under conditions of starvation – by incubation in nutrient-poor buffer – the ATP content of adherent bacteria decreased after 24 h to 96 h whereas that of planktonic bacteria remained stable for up to 20 days [28]. This suggests that cytoadhesion is an energy-consuming process. Similar to our results presented here an ecto-ATPase-dependent cytoadherence has already been suggested

for Trypanosoma cruzi whose ATPase activity was strongly inhibited by using DIDS or suramin attended by a reduced adhesion to mouse resident macrophages [25]. Early work of Bredt and coworkers in the 1980′s demonstrated that cytoadhesion of the cell wall-less mollicutes is modulated by ATP. By monitoring the ATP content in the supernatant attachment of M. pneumoniae to glass surfaces was shown to depend on an intact energy metabolism [29]. In using a glucose-inhibitor, the ATP content declined and attachment was abrogated. In using Tideglusib an ATPase inhibitor, ATP content accumulates leading

this website to a decreased cytoadherence. Bredt and coworkers hypothesized that the first step of colonization is energy dependent either to energize the AZD1390 clinical trial membrane thus increasing some binding sites on the surface, or to modulate the contractile cytoskeleton [29]. The free energy of ATP hydrolysis by P-loop NTPases is typically utilized to introduce conformational changes in other molecules [30]. As adhesion of mycoplasmal cytoadhesins does not depend on ATP-hydrolysis at all, as demonstrated in this study for the P60/P80 membrane complex of M. hominis, ATPase dependent adhesion of OppA is predicted to play a special role in M. hominis. In 2008 OppA was shown to mediate apoptosis, to induce ATP-efflux and a concomitant ATP-depletion of the M. hominis-colonized host cell [15]. This is in accordance to the recent findings that the cytoadherence of M. pneumoniae induces an ATP-efflux from the colonized host [31]. ATP- efflux was considered as a stress-associated danger signal as it stimulates P2X7-receptors of the host leading to the expression of pro-inflammatory cytokines. It is well known that extracellular ATP signals through P2 receptors to modulate the immune and inflammatory response in a variety of host cells, including immune and non-immune cells, sometimes leading to apoptosis or necrosis of the cells [32].

Similarly, in case of cucumber plant’s endogenous GAs, endophytic fungal application NU7026 nmr have rescued GAs biosynthesis as the level of bioactive GAs were much

pronounced compared to sole NaCl treated plants. Phytohormones, like GAs have been widely known for their role in plant growth and various developmental processes during plant’s life cycle [1, 3, 57]. Normal response of a plant to stress is to reduce growth by inter alia increasing ABA content and reducing GAs [56, 57]. GA-deficient plants are more susceptible to stress than those with higher levels of this hormone [56]. The higher amount of GA12 in endophyte-treated plant under salinity stress elucidates the activation of GAs biosynthesis pathway, while higher production of GA3 and GA4 confirm plant growth maintenance during stress condition. Thus, by maintaining GAs and, therefore, growth under PF-4708671 nmr stressful conditions, the endophyte is having a detrimental effect on the plant long-term survival. There Caspase inhibitor are many previous reports

showing the ameliorative effects of exogenous application of GAs (GA3/GA4) and IAA on cucumber growth under abiotic stress [58–60], while very little or no information’s are available on the regulation of plant endogenous hormones in association with phytohormones producing endophytic fungi under abiotic stress conditions. Some physiological evidence suggests that plants infected with endophytic fungi often have a distinct advantage against biotic and abiotic stress over their endophyte-free counterparts [61]. Beneficial features have been offered in infected plants; including drought acclimisation [62, 63] enhanced tolerance to stressful factors such high salinity [12]. Foliar application of GAs has been known for its role in plant stem elongation and mitigation of abiotic stress [54–60] while the same was observed in current study that endophytes producing GAs triggered the adverse effect of salinity stress. Conclusion P. formosus LHL10 produced many physiologically active and inactive GAs and IAA, which helped the Waito-C and Dongjin-byeo rice plants to

grow well and significantly mitigated the negative impacts of salinity stress on cucumber plants. The P. formosus LHL10 also minimized the lethal effects of salt stress on cucumber leaf tissues as evidenced from EL, RWC, photosynthesis rate, Verteporfin price nitrogen assimilation, antioxidant activity and lipid peroxidation. The cucumber plants inoculated with P. formosus LHL10 have ameliorated their growth by possessing lower levels of stress responsive endogenous ABA and elevated GAs contents. Current study reveals that such endophytic fungal interactions can improve the quality and productivity of economically important crop species. However, the favourable role of this fungus still needs to be investigated under field conditions. Acknowledgements The present research work was funded by the Eco-Innovation Project, Korean Government’s R & D program on Environmental Technology and Development.

BioMetals 2010, 23:431–439.PubMedCrossRef 43. Schägger H: Tricine–SDS-PAGE. Nat Protoc 2006, 1:16–22.PubMedCrossRef 44. Iwatani S, Zendo T, Yoneyama F, Nakayama J, Sonomoto K: Characterization and structure analysis of a novel bacteriocin, lacticin Z, produced by Lactococcus lactis QU 14. Biosci Biotechnol Biochem 2007, 71:1984–1992.PubMedCrossRef Competing interests The authors declare that

they have no competing interests. Authors’ contributions XH carried out the reference collection and analysis, most experimental running of whole expermental work; RM participated partial experimental design, method improvement and partial paper writing; YZ was charge of expression and mainly fermentor Tozasertib cell line running; DT was charge of codon optimization and all materials preparation; XW was charge of partial DNA cloning and PCR techinque, and partial result analysis; DX participated partial peptide purification; JH corrected partial techincal design on microbiological methods; JW participated Milciclib mouse and coordinated all sections of this work, design and running, results analysis and disscussion, paper writing and correction. All authors read and approved the final manuscript.”
“Background The Gram positive bacterium Streptococcus

pneumoniae frequently colonizes the nasopharynx but can also invade the host causing serious illnesses such as pneumonia, meningitis or bacteraemia [1]. A principal virulence factor of S. pneumoniae is the polysaccharide AZD1480 capsule protecting it from host immune defences by interfering with the deposition of complement and therefore opsonophagocytosis [2-4]. The capsule is the target of all currently available pneumococcal vaccines including the 13-valent pneumococcal

conjugate vaccine (PCV13) for children. The biochemical structure and linkage of repeating polysaccharide subunits determines the serotype of encapsulated strains. So far, more than 90 different serotypes have been identified [5-11] which differ in the type and number of genes encoding the proteins responsible for transcription, oxyclozanide polymerization, elongation and export of the capsule. For almost all serotypes the capsule-encoding operon is located between non-capsule genes dexB and aliA [6,12,13]. The first four genes cpsA, cpsB, cpsC and cpsD are thought to play a role in regulation of capsular production and are largely conserved between serotypes [14,15]. Despite the importance of the capsule as a virulence factor, nonencapsulated pneumococci occur and in the nasopharynx may represent around 15% of pneumococcal isolates [16]. Nonencapsulated pneumococci are generally considered not to be virulent but are associated with outbreaks of conjunctivitis [17-19]. Although lacking the protection from opsonophagocytosis which a capsule affords, the absence of capsule may confer advantages.

0 software [28], which is available online (http://​tools.​neb.​com/​NEBcutter2/​index.​php). Experimental validation of the selected enzymes was carried out following the manufacturers’ instructions, under the conditions described above. Acknowledgments The authors thank Dr. Maqsudul Alam (University of Hawaii, Manoa, HI),

selleck Dr. Kurt Houf (Ghent University, Belgium), Dr. Nalini Chinivasagam (Animal Research Institute, Queensland, Australia) and Dr. Robert Madden (Queen’s University Belfast, Ireland) for kindly providing Arcobacter strains. AL is thankful to Universitat Rovira i Virgili for a doctoral grant and to CONICYT, Chile, for financial support through Becas Chile. This work was supported in part by the project with reference AGL2011-30461-C02-02 from the Ministerio de Ciencia e Innovación (Spain). Electronic supplementary material Additional file 1: Table S1. Computer simulated profiles of Arcobacter spp. 16S rRNA gene (1026 bp) digestion with MseI endonuclease. Species with specific RFLP patterns are in bold. (DOC

80 KB) Additional file 4: Figure S1. Microheterogeneities (or mutations) in the 16S rRNA gene of seven atypical A. cryaerophilus A-1210477 chemical structure strains in relation to the type strain (LMG 9904T), strain LMG 10829 (A. cryaerophilus subgroup 1B) and the type strain ofA. butzleri (LMG 10828T). Sequence alignment of the 16S rRNA gene (positions 190–207 in relation to Escherichia coli) of seven atypical A. cryaerophilus MCC950 in vitro strains showing mutations at positions 192 (T→C) and 205 (A→G), which alter the MseI restriction enzyme recognition site (TTAA). IUPAC code, Y = Pyrimidine (C or T); R = Purine (A or G). (DOC 34 KB) Additional file 5: Figure S2. Agarose gel (3.5%) comparing the 16S rRNA-RFLP patterns obtained using endonucleases a\) TasI and b) MnlI for species A. butzleri , A. thereius and A. trophiarum. Lanes 1 and 14, 50 bp ladder (Fermentas); 2, A. butzleri LMG 10828T; 3, A. butzleri F42;

4, A. butzleri F43; 5, A. butzleri F44; 6, A. butzleri F50; 7, A. butzleri LMG 11118; 8, A. Inositol monophosphatase 1 thereius LMG 24486T; 9, A. thereius SW24; 10, A. thereius F89-4; 11, A.thereius F93-4 y 12, A.thereius LMG 24487; 13, A. trophiarum CECT 7650 (identical pattern to that of the 11 atypical strains of A. cryaerophilus, Additional file 2: Table S2). MnlI was selected because it produced more distinctive patterns among the species than TasI. (DOC 310 KB) Additional file 2: Table S2. Computer simulated profiles of Arcobacter spp.16S rRNA gene (1026 bp) digestion with MnlI endonuclease. Species in bold are those that show a specific RFLP pattern that was not distinguished with MseI. (DOC 72 KB) Additional file 3: Table S3. Computer simulated profiles of Arcobacter spp. 16S rRNA gene (1026 bp) digestion with BfaI endonuclease. Species in bold are those that now show a specific RFLP pattern that was not distinguished previously with MseI or MnlI. (DOC 61 KB) References 1.

(XLS 43 KB) Additional file 4: Figure S2: Predicted T7G translational

frameshift sites in Smp131 and closely related prophages from Xanthomoas and Stenotrophomonas. (A) T7G (enclosed by a rectangle) and the surrounding regions including genes p27, p27.1 and p28 of Smp131. Stop codons are denoted by three dots after the amino acids. Predicted start codon ATG of p27.1 is underlined, whereas ribosomal binding site AGAGG for gene p28 is in gray background. (B) DNA sequence alignment of the regions surrounding T7G translational frameshift sites (enclosed in rectangles) from Smp131 and the related prophages from X. campestris pv. campestris 33913, X. oryzae pv. oryzae strains KACC10331, EX 527 concentration MAFF311018 and PXO99A. An asterisk indicates identical nucleotides in all phages. (PPT 1 MB) Additional file 5: Figure S3: Comparison of tyrosine integrase of Smp131 and its homologues. Identical residues found in JNK-IN-8 datasheet more than 3 residues are highlighted. Active sites determined for XerD are indicated by downward arrowhead and the RKHRH pentad conserved

residues are indicated above. The α-helix (empty rectangle) and β-sheet (empty arrow) structural motifs under the alignments are based on the crystal structure of E. coli XerD. Abbreviations: Smp131, integrase deduced from Smp131 orf43; P2, integrase of Enterobacteria phage P2 (GenBank:P36932); 186, integrase of Enterobacteria phage 186 (GenBank:P06723); XerD, site-specific recombinase AC220 in vivo of E. coli (GenBank:1A0P_A). (PPT 2 MB) Additional file 6: Table S3: Identities of amino acid sequence shared between the proteins deduced from Smp131 and those from bacteriophages. (XLS 44 KB) Additional file 7: Table S4: Positions and sequences of att sites and tRNA of Smp131 and prophages in Xanthomonas and Stenotrophomonas. (XLS 26 KB) Additional file 8: Figure S4: Strategy for cloning the host-prophage junctions from Smp131-lysogenized S. maltophilia T13. (A) Sketch depicting the circular Smp131 filipin genome and genes near the predicted attP site. Arrows represent the genes and predicted attP site. (B) Sketch showing the host S. maltophilia

T13 chromosome and its attB site. (C) Map showing relative positions of genes after Smp131 integration into host S. maltophilia T13. Primers used in PCR were: L1; 5′-TGAAAGGTGCCATGACCACACG-3′; L2, 5′-GCGTTGCCAAGGTCAGATCGG-3′; L3; 5′-CGCATCGCACTCTAGGAAGTGAAG-3′; L4, 5′-AACTGCCAGAACCTCTGCAGTG-3′; R1, 5′-CTCTTGTCCTCGCTGTCGGT-3′; R2, 5′-TGATAGCCCTATTTTCAAGGGC-3′; R3, 5′-AGGCCCAGCAGCGCA-3′; R4, 5′-TGCCTGCCGCCAGCT-3′. S. maltophilia T13 chromosome containing prophage Smp131 was digested with HincII and NaeI. The fragments were self-ligated and the circularized DNA was then used as the templates for inverse PCR. Amplicons obtained were sequenced for comparison. (PPT 183 KB) References 1. Palleroni NJ, Bradbury JF: Stenotrophomonas, a new bacterial genus for Xanthomonas maltophilia (Hugh 1980) Swings et al. 1983.

mycoides SC. Vet Microbiol 2004, 98:229–234.CrossRefPubMed 3. Gonçalves R, Regalla J, Nicolet J, Frey J, Nicholas R, Bashiruddin J, De Santis P, Gonçalves AP: Antigen heterogeneity among Mycoplasma mycoides subsp. mycoides SC isolates: discrimination of major surface proteins. Vet Microbiol 1998, 63:13–28.CrossRefPubMed Fedratinib mouse 4. Niang M, Diallo M, Cisse O, Kone M, Doucoure M, Roth JA, Balcer-Rodrigues V, Dedieu L: Pulmonary and serum antibody responses elicited in zebu cattle experimentally infected with Mycoplasma mycoides subsp. mycoides SC by contact exposure.

Vet Res 2006, 37:733–744.CrossRefPubMed 5. Westberg J, Persson A, Holmberg A, Goesmann A, Lundeberg J, Johansson KE, Pettersson B, Uhlen M: The genome MAPK Inhibitor Library cost sequence of

Mycoplasma mycoides subsp. mycoides SC type strain PG1 T , the causative agent of contagious bovine pleuropneumonia (CBPP). Genome Res 2004, 14:221–227.CrossRefPubMed 6. Masiga WN, Roberts DH, Kakoma I, Rurangirwa FR: Passive immunity to contagious bovine pleuropneumonia. Res Vet Sci 1975, 19:330–332.PubMed 7. Masiga WN, Windsor RS: Immunity to contagious bovine pleuropneumonia. Vet Rec 1975, 97:350–351.CrossRefPubMed 8. Dedieu L, Balcer-Rodrigues Selleckchem HDAC inhibitor V, Cisse O, Diallo M, Niang M: Characterisation of the lymph node immune response following Mycoplasma mycoides subsp. mycoides SC infection in cattle. Vet Res 2006, 37:579–591.CrossRefPubMed 9. Dedieu L, Balcer-Rodrigues V, Yaya A, Hamadou B, Cisse

O, Diallo M, Niang M: Gamma interferon-producing CD4 T-cells correlate with resistance to Mycoplasma mycoides subsp. mycoides S.C. infection in cattle. Vet Immunol Immunopathol 2005, 107:217–233.CrossRefPubMed 10. Totté P, Rodrigues V, Yaya A, Hamadou B, Cisse O, Diallo M, Niang M, Thiaucourt F, Dedieu L: Analysis of cellular responses to Mycoplasma mycoides subsp. mycoides small colony biotype associated with control of contagious bovine pleuropneumonia. Vet Res 2008, 39:8.CrossRefPubMed Progesterone 11. Dedieu-Engelmann L: Contagious bovine pleuropneumonia: a rationale for the development of a mucosal sub-unit vaccine. Comp Immunol Microbiol Infect Dis 2008, 31:227–238.CrossRefPubMed 12. Smith GP: Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 1985, 228:1315–1317.CrossRefPubMed 13. Wang LF, Yu M: Epitope identification and discovery using phage display libraries: applications in vaccine development and diagnostics. Curr Drug Targets 2004, 5:1–15.CrossRefPubMed 14. Wang LF, du Plessis DH, White JR, Hyatt AD, Eaton BT: Use of a gene-targeted phage display random epitope library to map an antigenic determinant on the bluetongue virus outer capsid protein VP5. J Immunol Methods 1995, 178:1–12.CrossRefPubMed 15. Fehrsen J, du Plessis DH: Cross-reactive epitope mimics in a fragmented-genome phage display library derived from the rickettsia, Cowdria ruminantium.

Within the group of closely related strains RtTA1, R. leguminosarum bv. viciae 3841 (Rlv), R. etli CFN42 (Rhe),

RltWSM2304 and RltWSM1325 clusters of replicons carrying the most similar replication systems can be distinguished. They comprise pRleTA1d-pRL12-p42f-pRLG201-pR132501 and pRleTA1b-pRL11-p42e-pRLG202-pR132502, respectively. Therefore, detection of positive hybridization signals with probes derived from rep genes of RtTA1 chromid-like replicons (i.e. pRleTA1b or pRleTA1d) to any of the replicons of the sampled strains allowed regarding those as a chromid-like. Based on the similarity of replication-partition genes detected in our assays, we divided the replicons of the studied strains into three genome compartments: chromosome, #TH-302 manufacturer randurls[1|1|,|CHEM1|]# chromid-like and ‘other plasmids’ (i.e. those replicons which gave a hybridization signal with molecular probes originating from repA and repC genes of pRleTA1a or pRleTA1c, as well as those that gave no signal with any rep probes of RtTA1 replication genes). The compartment designated ‘other plasmids’ also comprised pSym. Such replicon division was taken into consideration in the subsequent analyses of distribution of other markers in the studied strains. Ilomastat ic50 Variability of chromosomal and plasmid marker location In further studies, the extent of gene content diversity in the sampled nodule isolates was examined. We aimed to estimate whether, besides repA and repC displacement

events, we could demonstrate changes in the location

of the chromosomal and plasmid genes. The same experimental approach was used, i.e. a series of Southern hybridizations with different genes with a well-defined chromosomal or plasmid location in RtTA1 (Table 1) [36]. For assays of chromosomal marker variability, essential bacterial genes were chosen: rpoH2, dnaK, dnaC, rrn, lpxQ as well as genes that are not essential or with unspecified essentiality but chromosomal in RtTA1, i.e. bioA, stbB, exoR, pssL (Pss-I) and rfbADBC (Pss-V) (Table 1). In addition, location of fixGH genes was assayed, even though they 17-DMAG (Alvespimycin) HCl are known to be plasmid located on the sequenced RltWSM2304, RltWSM1325 [33, 34], Rlv [6] and Rhe [5] genomes, but chromosomal in RtTA1 [36]. A majority of the studied genes (rpoH2, dnaK, dnaC, rrn, lpxQ, bioA, stbB, exoR and pssL) were located on the chromosome in all the sampled strains, showing considerable conservation of chromosomal markers (Figure 3). Exceptionally, the Pss-V region was identified on the chromosome of the K3.6, K5.4 and RtTA1 but it was missing in the other strains (Figure 3) Moreover, fixGH symbiosis-related genes, which were chromosomal in the RtTA1, K3.6, K4.15 and K5.4 strains, were located mainly in the genome compartment designated as ‘other plasmids’ (pSym to be exact) in the remaining strains. The variable location of fixGH genes which were found on the chromosome, pSyms and chromid-like replicons (K12.

Assessment of the physical work LGX818 in vivo ability is a common practice in disability claim procedures. It is, however, a complex task, and IPs cannot rely on many instruments to support them in that task. Several studies indicate the weak relation between pathoanatomic findings and functional capacity (Tait et al. 2006; Vasudevan 1996). One instrument that might help IPs to assess the physical work ability of claimants with MSD is functional capacity evaluation (FCE). This approach makes use of highly structured,

scientifically developed, individualized work simulators, designed to provide a profile of an individual’s work-related HSP inhibition physical and functional capabilities (Lyth 2001). According to Harten (1998), FCE offers a comprehensive, objective test that measures the individual’s current functional status and ability to meet the see more physical demands of a current or prospective job. In particular, FCE provides information on physical work ability, being especially important in the assessment of disability in claimants

with MSD and pain syndromes (Vasudevan 1996). The information of an FCE assessment can be used for several purposes, among which making disability determinations (King et al. 1998). Innes and Straker (1999a, b) reported the level of reliability and validity of several FCE methods and concluded that both for reliability as for validity adequate levels were lacking. However, in an update Innes (2006) concluded that since 1997 there had been a dramatic increase in the research in

this field, with several FCEs showing moderate Flavopiridol (Alvocidib) to excellent levels of reliability. FCE information offers a view on the ability to perform physical activities, which is an important part of the full work ability, especially in patients with MSDs. In a previous study, we found that IPs who assess claimants with long-term disability have mixed opinions on the utility of FCE (Wind et al. 2006). In fact, it appeared that only few physicians were familiar with FCE. Therefore, the topic of this study is whether FCE information can be of assistance to IPs in the assessment of the physical work ability of claimants, irrespective of their previous familiarity with the instrument. This is a first step in the process of possibly introducing FCE in the process of assessing disability claims of claimants with MSDs.

Table 3 The mean (range) and p-values for Dmean, Dmax of both heart and LAD     Conventional fractionation Hypofractionation Organ Parameter DIBH FB p-value DIBH FB p-value Heart Dmax (Gy)(*) 5.00 29.19 0.0015 3.85 24.75 0.0025 (2.00 – 10.00) (5.00 – 52.00) (1.00 – 8.00) (3.00 – 46.00) Dmean (Gy) 1.24 1.68 0.0106 0.84 1.14 0.0106 (1.03 – 1.43) (1.29 – 2.48) (0.70 – 0.97) (0.87 – 1.68) V20 (**) (%) 0.00 0.39 0.1574 0.00 0.33 0.1644 (0.00 -0.00) (0.00 -1.61) (0.00-0.00) (0.00 – 1.40) V40 (**) (%) 0.00 0.16 0.1719 0.00 0.07 0.1708 (0.00 -0.00)

(0.00 – 0.70) (0.00-0.00) (0.00 -3.00) LAD Dmax (Gy)(*) 4.25 19.62 0.0488 ITF2357 cost 3.10 16.75 0.0479 (2.00 – 11.00) (3.00 – 52.00) (1.00 – 8.00) (2.00

– 46.00) Dmean (Gy) 2.74 9.01 0.0914 1.86 6.12 0.9140 (0.80 – 7.55) (1.45 – 28.05) (0.54 – 5.13) (0.99 – 19.07) (*)EQD2 values using α/β =2.5 Gy for Pericardites in heart an for LAD. As shown in the Table 3 the maximum doses to the heart and LAD and the mean dose to the heart were significantly lower in DIBH, (Caspase-dependent apoptosis minimum 78.3% and 2.6% decrease with respect to FB, respectively) regardless of the schedule type. In our series the maximum HDAC inhibitor review dose to LAD exceeded 20 Gy in 3/8 patients in FB, while it was lower than 20 Gy in all patients in DIBH. TCP and NTCP analysis The TCP and NTCPs for lung and heart are reported in Table 4 as mean values with ranges. TCP values were increased in the hypo-fractionated schedule, as expected from the literature [17]. The NTCPs for Lung toxicity and long term cardiac mortality were at least 11.2% lower diglyceride for DIBH with respect to FB, but the difference was statistically significant

only for the long term cardiac mortality in the conventional fractionation. The NTCP for pericarditis and for LAD toxicity were 0% in all cases. Table 4 TCP and NTCP for FB and DIBH   Conventional fractionation Hypofractionation Parameter DIBH FB p-value DIBH FB p-value TCP (%) 96.40 96.30 0.3604 99.99 100.00 0.3506 (92.5 – 98.23) (94.33 – 97.36) (99.97 – 100) (100.00- 100.00) Heart NTCP (%) [pericarditis] 0.00 0.00 —— 0.00 0.00 ——   (0.00 – 0.00) (0.00 – 0.00) (0.00 – 0.00) (0.00 – 0.00) Heart NTCP (%) [long term mortality] 0.71 0.80 0.0385 0.72 0.87 0.0667   (0.69 – 0.74) (0.72 – 0.99) (0.69 – 0.75) (0.73 – 1.22) Lung NTCP (%) [pneumonitis] 6.58 11.48 0.2212 16.71 29.26 0.1618   (0.23 – 13.18) (0.77 – 33.54) (8.19 – 29.43) (9.57 – 97.70) Discussions The aim of this paper was to investigate clinical and dosimetric benefits of DIBH gating technique.