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Supplemental Digital Content is available in the text, There is limited comparative effectiveness evidence to guide approaches to managing diabetes in individuals failing metformin monotherapy. Our aim was to compare the incidence of all-cause mortality and major adverse cardiovascular events (MACEs) among new metformin monotherapy users initiating a dipeptidyl-peptidase-4 inhibitor (DPP4i), glucagon-like peptide-1 receptor agonist (GLP-1RA), sulfonylurea (SU), thiazolidinedione, or insulin. We conducted a cohort study using the UK-based Clinical Practice Research Datalink. Participants included a cohort of 38,233 new users of metformin monotherapy who initiated a 2nd antidiabetic agent between January 1, 2007 and December 31, 2012 with follow-up until death, disenrollment, therapy discontinuation, or study end-date. A subcohort of 21,848 patients with linked hospital episode statistics (HES) and Office of National Statistics (ONS) data were studied to include MACE and cardiovascular-related death. The primary exposure contrasts, defined a priori, were initiation of a DPP4i versus an SU and initiation of a GLP-1RA versus an SU following metformin monotherapy. Cox proportional hazards models were used to assess the relative differences in time to mortality and MACE between exposure contrasts, adjusting for important baseline patient factors and comedications used during follow-up. The main study cohort consisted of 6213 (16%) patients who initiated a DPP4i, 25,916 initiated an SU (68%), 4437 (12%) initiated a TZD, 487 (1%) initiated a GLP-1RA, 804 (2%) initiated insulin, and 376 (1%) initiated a miscellaneous agent as their 2nd antidiabetic agent. Mean age was 62 years, 59% were male, and mean glycated hemoglobin was 8.8% (92.6 mmol/mol). Median follow-up was 2.7 years (interquartile range 1.3–4.2). Mortality rates were 8.2 deaths/1000 person-years for DPP4i and 19.1 deaths/1000 person-years for SU initiators. Adjusted hazards ratio (aHR) for mortality in DPP4i versus SU initiators = 0.58, 95% CI 0.46 to 0.73, P

© 2016 The Author(s). In this study a skilled soccer player performed throws for maximum distance while manipulating the backspin on the ball. A video analysis was used to obtain measures of the ball projection variables. We found that putting greater backspin on the ball did not reduce the player’s ability to produce a high projection velocity. Throw distance increased at a rate of about 0.6 m per 1 rev/s increase in backspin, and the experimental data was consistent with the predictions of a mathematical model. We recommend players apply the highest possible backspin when performing a long throw-in.

Proteins containing a glutamic acid-proline (EP) repeat epitope were immunologically detected in midguts from eight species of Glossina (tsetse flies). The molecular masses of the tsetse EP proteins differed among species groups. The amino acid sequence of one of these proteins, from Glossina palpalis palpalis, was determined and compared to the sequence of a homologue, the tsetse midgut EP protein of Glossina in. morsitans. The extended EP repeat domains comprised between 36% (G. in. morsitans) and 46% (G. p. palpalis) of the amino acid residues, but otherwise the two polypeptide chains shared most of their sequences and predicted functional domains. The levels of expression of tsetse EP protein in adult teneral midguts were markedly higher than in midguts from larvae. The EP protein was detected by immunoblotting in the fat body, proventriculus and midgut, the known major immune tissues of tsetse and is likely secreted as it was also detected in hemolymph. The EP protein was not produced by the bacterial symbionts of tsetse midguts as determined by genome analysis of Wigglesmorthia glossinidia and immunoblot analysis of Sodalis glossinidius. Bacterial challenge of G. m. morsitans, by injection of live E. coli, induced augmented expression of the tsetse EP protein. The presence of EP proteins in a wide variety of tsetse, their constitutive expression in adult fat body and midguts and their upregulation after immunogen challenge suggest they play an important role as a component of the immune system in tsetse. (c) 2005 Elsevier Ltd. All rights reserved.

Background Tropical diseases caused by parasites continue to cause socioeconomic devastation that reverberates worldwide. There is a growing need for new control measures for many of these diseases due to increasing drug resistance exhibited by the parasites and problems with drug toxicity. One new approach is to apply host defense peptides (HDP; formerly called antimicrobial peptides) to disease control, either to treat infected hosts, or to prevent disease transmission by interfering with parasites in their insect vectors. A potent anti-parasite effector is bovine myeloid antimicrobial peptide-27 (BMAP-27), a member of the cathelicidin family. Although BMAP-27 is a potent inhibitor of microbial growth, at higher concentrations it also exhibits cytotoxicity to mammalian cells. We tested the anti-parasite activity of BMAP-18, a truncated peptide that lacks the hydrophobic C-terminal sequence of the BMAP-27 parent molecule, an alteration that confers reduced toxicity to mammalian cells. Methodology/Principal Findings BMAP-18 showed strong growth inhibitory activity against several species and life cycle stages of African trypanosomes, fish trypanosomes and Leishmania parasites in vitro. When compared to native BMAP-27, the truncated BMAP-18 peptide showed reduced cytotoxicity on a wide variety of mammalian and insect cells and on Sodalis glossindius, a bacterial symbiont of the tsetse vector. The fluorescent stain rhodamine 123 was used in immunofluorescence microscopy and flow cytometry experiments to show that BMAP-18 at low concentrations rapidly disrupted mitochondrial potential without obvious alteration of parasite plasma membranes, thus inducing death by apoptosis. Scanning electron microscopy revealed that higher concentrations of BMAP-18 induced membrane lesions in the parasites as early as 15 minutes after exposure, thus killing them by necrosis. In addition to direct killing of parasites, BMAP-18 was shown to inhibit LPS-induced secretion of tumour necrosis factor alpha (TNF-α), a cytokine that is associated with inflammation and cachexia (wasting) in sleeping sickness patients. As a prelude to in vivo applications, high affinity antibodies to BMAP-18 were produced in rabbits and used in immuno-mass spectrometry assays to detect the intact peptide in human blood and plasma. Conclusions/Significance BMAP-18, a truncated form of the potent antimicrobial BMAP-27, showed low toxicity to mammalian cells, insect cells and the tsetse bacterial symbiont Sodalis glossinidius while retaining an ability to kill a variety of species and life cycle stages of pathogenic kinetoplastid parasites in vitro. BMAP-18 also inhibited secretion of TNF-α, an inflammatory cytokine that plays a role in the cachexia associated with African sleeping sickness. These findings support the idea that BMAP-18 should be explored as a candidate for therapy of economically important trypanosome-infected hosts, such as cattle, fish and humans, and for paratransgenic expression in Sodalis glossinidius, a bacterial symbiont in the tsetse vector, as a strategy for interference with trypanosome transmission., Author Summary Protozoan parasites cause serious diseases in large areas of the tropics. Control of these diseases depends to a great extent on the use of therapeutic drugs, many of which are highly toxic. In addition, parasite resistance to several of the front-line drugs is increasing. Host defense peptides (HDP; formerly called antimicrobial peptides) have recently received attention as potential anti-parasite effector molecules. We earlier reported that one such peptide, bovine myeloid antimicrobial peptide (BMAP-27), is a potent inhibitor of the growth of trypanosomes and Leishmania in vitro. Here we report our studies on BMAP-18, a truncated form of BMAP-27, which showed reduced toxicity to mammalian and insect cells and yet retained its direct toxicity to parasites in vitro. BMAP-18 also strongly inhibited LPS-induced release of tumour-necrosis factor alpha (TNF-α) from human leukocytes, and thus has immunomodulatory activity. These findings suggest that BMAP-18 has potential as a therapeutic agent for treatment of infected animals or as an inhibitor of parasite transmission by their insect vectors. In anticipation of using BMAP-18 in vivo, we have also developed high affinity antibodies to BMAP-18 and have shown that these can be used, in conjunction with mass spectrometry, to detect the peptide in whole blood or plasma.

Background Under conditions of no strand bias the number of Gs is equal to that of Cs for each DNA strand; similarly, the total number of Ts is equal to that of As. However, within each strand there are considerable local deviations from the A = T and G = C equality. These asymmetries in nucleotide composition have been extensively analyzed in prokaryotic and eukaryotic genomes and related to chromosome organization, transcription orientation and other processes in certain organisms. To carry out analysis of intra-strand nucleotide distribution several graphical methods have been developed. Results GraphDNA is a new Java application that provides a simple, user-friendly interface for the visualization of DNA nucleotide composition. The program accepts GenBank, EMBL and FASTA files as an input, and it displays multiple DNA nucleotide composition graphs (skews and walks) in a single window to allow direct comparisons between the sequences. We illustrate the use of DNA skews for characterization of poxvirus and coronavirus genomes. Conclusion GraphDNA is a platform-independent, Open Source, tool for the analysis of nucleotide trends in DNA sequences. Multiple sequence formats can be read and multiple sequences may be plotted in a single results window.