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  • Tanhuanpää, Pirjo; Erkkilä, Maria; Kalendar, Ruslan; Schulman, Alan H; Manninen, Outi (BioMed Central, 2016)
    Abstract Background Timothy (Phleum pratense L.), a cool-season hexaploid perennial, is the most important forage grass species in Nordic countries. Earlier analyses of genetic diversity in a collection of 96 genebank accessions of timothy with SSR markers demonstrated high levels of diversity but could not resolve population structure. Therefore, we examined a subset of 51 accessions with REMAP markers, which are based on retrotransposons, and compared the diversity results with those obtained with SSR markers. Results Using four primer combinations, 533 REMAP markers were analyzed, compared with 464 polymorphic alleles in the 13 SSR loci previously. The average marker index, which describes information obtained per experiment (per primer combination or locus) was over six times higher with REMAPs. Most of the variation found was within accessions, with somewhat less, 89 %, for REMAPs, than for SSR, with 93 %. Conclusions SSRs revealed differences in the level of diversity slightly better than REMAPs but neither marker type could reveal any clear clustering of accessions based on countries, vegetation zones, or different cultivar types. In our study, reliable evaluation of SSR allele dosages was not possible, so each allele had to be handled as a dominant marker. SSR and REMAP, which report from different mechanisms of generating genetic diversity and from different genomic regions, together indicate a lack of population structure. Taken together, this likely reflects the outcrossing and hexaploid nature of timothy rather than failures of either marker system.
  • Mäkeläinen, Sanna; de Knegt, Henrik J; Ovaskainen, Otso; Hanski, Ilpo K (BioMed Central, 2016)
  • Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J (BioMed Central, 2016)
    Abstract Background New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Methods and Results Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). Conclusions This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0–2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.
  • Lehikoinen, Markku; Arffman, Martti; Manderbacka, Kristiina; Elovainio, Marko; Keskimäki, Ilmo (BioMed Central, 2016)
    Abstract Background Large cities are often claimed to display more distinct geographical and socioeconomic health inequalities than other areas due to increasing residential differentiation. Our aim was to assess whether geographical inequalities in mortality within the capital (City of Helsinki) both exceeded that in other types of geographical areas in Finland, and whether those differences were dependent on socioeconomic inequalities. Methods We analysed the inequality of distribution separately for overall, ischemic heart disease and alcohol-related mortality, and mortality amenable (AM) to health care interventions in 1992–2008 in three types of geographical areas in Finland: City of Helsinki, other large cities, and small towns and rural areas. Mortality data were acquired as secondary data from the Causes of Death statistics from Statistics Finland. The assessment of changing geographical differences over time, that is geographical inequalities, was performed using Gini coefficients. As some of these differences might arise from socioeconomic factors, we assessed socioeconomic differences with concentration indices in parallel to an analysis of geographical differences. To conclude the analysis, we compared the changes over time of these inequalities between the three geographical areas. Results While mortality rates mainly decreased, alcohol-related mortality in the lowest income quintile increased. Statistically significant differences over time were found in all mortality groups, varying between geographical areas. Socioeconomic differences existed in all mortality groups and geographical areas. In the study period, geographical differences in mortality remained relatively stable but income differences increased substantially. For instance, the values of concentration indices for AM changed by 54 % in men (p < 0.027) and by 62 % in women (p < 0.016). Only slight differences existed in the time trends of Gini or in the concentration indices between the geographical areas. Conclusions No geographical or income-related differences in the distribution of mortality existed between Helsinki and other urban or rural areas of Finland. This suggests that the effect of increasing residential differentiation in the capital may have been mitigated by the policies of positive discrimination and social mixing. One of the main reasons for the increase in health inequalities was growth of alcohol-related mortality, especially among those with the lowest incomes.
  • Koskinen, Jyri-Pekka; Kiviranta, Hannu; Vartiainen, Erkki; Jousilahti, Pekka; Vlasoff, Tiina; von Hertzen, Leena; Mäkelä, Mika; Laatikainen, Tiina; Haahtela, Tari (BioMed Central, 2016)
    Abstract Background Atopic allergy is much more common in Finnish compared with Russian Karelia, although these areas are geographically and genetically close. To explore the role of environmental chemicals on the atopy difference a random sample of 200 individuals, 25 atopic and 25 non-atopic school-aged children and their mothers, were studied. Atopy was defined as having at least one positive skin prick test response to 14 common inhalant and food allergens tested. Concentrations of 11 common environmental pollutants were measured in blood samples. Results Overall, the chemical levels were much higher in Russia than in Finland, except for 2,2′,4,4′-tetra-bromodiphenyl ether (BDE47). In Finland but not in Russia, the atopic children had higher concentrations of polychlorinated biphenyls and 1,1-Dichloro-2,2-bis-(p-chlorophenyl)-ethylene (DDE) than the non-atopic children. In Russia but not in Finland, the atopic mothers had higher DDE concentrations than the non-atopic mothers. Conclusions Higher concentrations of common environmental chemicals were measured in Russian compared with Finnish Karelian children and mothers. The chemicals did not explain the higher prevalence of atopy on the Finnish side.
  • Niemelä, Tytti M; Tulamo, Riitta-Mari; Hielm-Björkman, Anna K (BioMed Central, 2016)
    Abstract Background Intra-articular inflammation resulting in lameness is a common health problem in horses. Exogenous intra-articular hyaluronic acid has been shown to provide an analgesic effect and reduce pain in equine and human osteoarthritis. High molecular weight non-animal stabilized hyaluronic acid (NASHA) has gained popularity in the treatment of human arthritic conditions due to its long-acting pain-relieving effects. The aim of this study was to compare the response to treatment of lameness localized in the equine metacarpophalangeal joint injected with non-animal stabilized hyaluronic acid (NASHA) and placebo (saline). Twenty-seven clinically lame horses with a positive response to diagnostic intra-articular anaesthesia of the metacarpophalangeal joint and with no, or at most mild, radiographic changes in this joint were included in the study. Horses in the treatment group (n = 14) received 3 mL of a NASHA product intra-articularly, and those in the placebo group (n = 13) received an equivalent volume of sterile 0.9 % saline solution. Results The change in the lameness score did not significantly differ between NASHA and placebo groups (P = 0.94). Scores in the flexion test improved more in the NASHA group compared with placebo (P = 0.01). The changes in effusion and pain in flexion were similar (P = 0.94 and P = 0.27, respectively) when NASHA and placebo groups were compared. A telephone interview follow-up of the owners three months post-treatment revealed that 14 of the 21 horses (67 %) were able to perform at their previous level of exercise. Conclusions In the present study, a single IA NASHA injection was not better than a single saline injection for reducing lameness in horses with synovitis or mild osteoarthritis. However, the results of this study indicate that IA NASHA may have some beneficial effects in modifying mild clinical signs but more research is needed to evaluate whether the positive effect documented ie. reduced response in the flexion test is a true treatment effect.
  • Sormunen, Jani J; Penttinen, Ritva; Klemola, Tero; Hänninen, Jari; Vuorinen, Ilppo; Laaksonen, Maija; Sääksjärvi, Ilari E; Ruohomäki, Kai; Vesterinen, Eero J (BioMed Central, 2016)
    Abstract Background Ixodes ricinus and Ixodes persulcatus are the main vectors of Lyme borreliosis spirochetes and several other zoonotic bacteria in northern Europe and Russia. However, few studies screening bacterial pathogens in Finnish ticks have been conducted. Therefore, reports on the occurrence and prevalence of several bacterial pathogens detected from ticks elsewhere in Europe and Russia are altogether missing from Finland. The main aim of the current study was to produce novel data on the occurrence and prevalence of several tick-borne bacterial pathogens in ticks collected from southwestern Finland. Methods Ticks were collected in 2013–2014 by blanket dragging from 25 localities around southwestern Finland, and additionally from a dog in Lempäälä. Collected ticks were molecularly identified and screened for Borrelia burgdorferi s.l., Borrelia miyamotoi, Rickettsia, Bartonella and Candidatus Neoehrlichia mikurensis using quantitative PCR. Furthermore, detected Rickettsia spp. were sequenced using conventional PCR to determine species. Results A total of 3169 ticks in 1174 DNA samples were screened for the listed pathogens. The most common bacteria detected was B. burgdorferi (s.l.) (18.5 % nymphal and 23.5 % adult ticks), followed by Rickettsia spp. (1.1 %; 5.1 %) and B. miyamotoi (0.51 %; 1.02 %). B. miyamotoi and Rickettsia spp. were also detected in larval samples (minimum infection rates 0.31 % and 0.21 %, respectively). Detected Rickettsia spp. were identified by sequencing as R. helvetica and R. monacensis. All screened samples were negative for Bartonella spp. and Ca. N. mikurensis. Conclusions In the current study we report for the first time the presence of Rickettsia in Finnish ticks. Furthermore, Rickettsia spp. and B. miyamotoi were found from larval tick samples, emphasizing the importance they may have as vectors of these pathogens. Comparisons of tick density estimates and B. burgdorferi (s.l.) prevalence made between the current study and a previous study conducted in 2000 in ten out of the 25 study localities suggest that an increase in tick abundance and B. burgdorferi (s.l.) prevalence has occurred in at least some of the study localities.
  • Ranki, Tuuli; Pesonen, Sari; Hemminki, Akseli; Partanen, Kaarina; Kairemo, Kalevi; Alanko, Tuomo; Lundin, Johan; Linder, Nina; Turkki, Riku; Ristimäki, Ari; Jäger, Elke; Karbach, Julia; Wahle, Claudia; Kankainen, Matti; Backman, Charlotta; von Euler, Mikael; Haavisto, Elina; Hakonen, Tiina; Heiskanen, Raita; Jaderberg, Magnus; Juhila, Juuso; Priha, Petri; Suoranta, Laura; Vassilev, Lotta; Vuolanto, Antti; Joensuu, Timo (BioMed Central, 2016)
    Abstract Background We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined. Methods The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT). Results No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients. Conclusions ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors. Trial registration NCT01598129 . Registered 19/04/2012
  • Karjalainen, Liisa; Anttila, Ahti; Nieminen, Pekka; Luostarinen, Tapio; Virtanen, Anni (BioMed Central, 2016)
    Abstract Background High coverage and attendance is essential for cervical cancer screening success. We investigated whether the previous positive experiences on increasing screening attendance by self-sampling in Finland are sampler device dependent. Methods All women identified to cervical cancer screening in 2013 in 28 Finnish municipalities were randomised to receive a lavage- (n = 6030) or a brush type of self-sampling device (n = 6045) in case of non-attendance after two invitation letters. Seven hundred seventy non-attending women in the lavage device group and 734 in the brush group received the self-sampling offer. Women’s experiences were enquired with an enclosed questionnaire. Results Total attendance in the lavage group increased from 71.0 to 77.7 % by reminder letters and further to 80.5 % by self-sampling. Respective increase in the brush group was from 72.2 to 78.6 % and then to 81.5 %. The participation by self-sampling was 21.7 % (95 % CI 18.8–24.6) in the lavage group and 23.8 % (95 % CI 20.8–26.9) in the brush group. Women’s self-sampling experiences were mainly positive and the sampler devices were equally well accepted by the women. Conclusion Our study shows that the lavage device and brush device perform similarly in terms of uptake by non-attending women and user comfort. If self-sampling is integrated to the routine screening program in Finland, either of the devices can be chosen without the fear of losing participants due to a less acceptable device.
  • Oghenekaro, Abbot O; Raffaello, Tommaso; Kovalchuk, Andriy; Asiegbu, Fred O (BioMed Central, 2016)
    Abstract Background The basidiomycete Rigidoporus microporus is a fungus that causes the white rot disease of the tropical rubber tree, Hevea brasiliensis, the major source of commercial natural rubber. Besides its lifestyle as a pathogen, the fungus is known to switch to saprotrophic growth on wood with the ability to degrade both lignin and cellulose. There is almost no genomic or transcriptomic information on the saprotrophic abilities of this fungus. In this study, we present the fungal transcriptomic profiles during saprotrophic growth on rubber wood. Results A total of 266.6 million RNA-Seq reads were generated from six libraries of the fungus growing either on rubber wood or without wood. De novo assembly produced 34, 518 unigenes with an average length of 2179 bp. Annotation of unigenes using public databases; GenBank, Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), Cluster of Orthologous Groups (COG) and Gene Ontology (GO) produced 25, 880 annotated unigenes. Transcriptomic profiling analysis revealed that the fungus expressed over 300 genes encoding lignocellulolytic enzymes. Among these, 175 genes were up-regulated in rubber wood. These include three members of the glycoside hydrolase family 43, as well as various glycosyl transferases, carbohydrate esterases and polysaccharide lyases. A large number of oxidoreductases which includes nine manganese peroxidases were also significantly up-regulated in rubber wood. Several genes involved in fatty acid metabolism and degradation as well as natural rubber degradation were expressed in the transcriptome. Four genes (acyl-CoA synthetase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and acyl-CoA acetyltransferase) potentially involved in rubber latex degradation pathway were also induced. A number of ATP binding cassette (ABC) transporters and hydrophobin genes were significantly expressed in the transcriptome during saprotrophic growth. Some genes related to energy metabolism were also induced. Conclusions The analysed data gives an insight into the activation of lignocellulose breakdown machinery of R. microporus. This study also revealed genes with relevance in antibiotic metabolism (e.g. cephalosporin esterase) as well as those with potential applications in fatty acid degradation. This is the first study on the transcriptomic analysis of R. microporus on rubber wood and should serve as a pioneering resource for future studies of the fungus at the genomic or transcriptomic level.
  • Kasteenpohja, Teija; Marttunen, Mauri; Aalto-Setälä, Terhi; Perälä, Jonna; Saarni, Samuli I; Suvisaari, Jaana (BioMed Central, 2016)
    Abstract Background Anxiety disorders are common in early adulthood, but general population studies concerning the treatment adequacy of anxiety disorders taking into account appropriate pharmacological and psychological treatment are scarce. The aims of this study were to examine treatments received for anxiety disorders in a Finnish general population sample of young adults, and to define factors associated with receiving minimally adequate treatment and with dropping out from treatment. Methods A questionnaire containing several mental health screens was sent to a nationally representative two-stage cluster sample of 1894 Finns aged 19 to 34 years. All screen positives and a random sample of screen negatives were invited to a mental health assessment including a SCID interview. For the final diagnostic assessment, case records from mental health treatments for the same sample were obtained. This article investigates treatment received, treatment adequacy and dropouts from treatment of 79 participants with a lifetime anxiety disorder (excluding those with a single specific phobia). Based on all available information, receiving antidepressant or buspirone medication for at least 2 months with at least four visits with any type of physician or at least eight sessions of psychotherapy within 12 months or at least 4 days of hospitalization were regarded as minimally adequate treatment for anxiety disorders. Treatment dropout was rated if the patient discontinued the visits by his own decision despite having an adequate treatment strategy according to the case records. Results Of participants with anxiety disorders (excluding those with a single specific phobia), 41.8 % had received minimally adequate treatment. In the multivariate analysis, comorbid substance use disorder was associated with antidepressant or buspirone medication lasting at least 2 months. Those who were currently married or cohabiting had lower odds of having at least four visits with a physician a year. None of these factors were associated with the final outcome of minimally adequate treatment or treatment dropout. Participants with comorbid personality disorders received and misused benzodiazepines more often than others. Conclusions More efforts are needed to provide adequate treatment for young adults with anxiety disorders. Attention should be paid to benzodiazepine prescribing to individuals with personality disorders.
  • Morandin, Claire; Tin, Mandy M Y; Abril, Sílvia; Gómez, Crisanto; Pontieri, Luigi; Schiøtt, Morten; Sundström, Liselotte; Tsuji, Kazuki; Pedersen, Jes S; Helanterä, Heikki; Mikheyev, Alexander S (BioMed Central, 2016)
    Abstract Background Reproductive division of labor in eusocial insects is a striking example of a shared genetic background giving rise to alternative phenotypes, namely queen and worker castes. Queen and worker phenotypes play major roles in the evolution of eusocial insects. Their behavior, morphology and physiology underpin many ecologically relevant colony-level traits, which evolved in parallel in multiple species. Results Using queen and worker transcriptomic data from 16 ant species we tested the hypothesis that conserved sets of genes are involved in ant reproductive division of labor. We further hypothesized that such sets of genes should also be involved in the parallel evolution of other key traits. We applied weighted gene co-expression network analysis, which clusters co-expressed genes into modules, whose expression levels can be summarized by their ‘eigengenes’. Eigengenes of most modules were correlated with phenotypic differentiation between queens and workers. Furthermore, eigengenes of some modules were correlated with repeated evolution of key phenotypes such as complete worker sterility, the number of queens per colony, and even invasiveness. Finally, connectivity and expression levels of genes within the co-expressed network were strongly associated with the strength of selection. Although caste-associated sets of genes evolve faster than non-caste-associated, we found no evidence for queen- or worker-associated co-expressed genes evolving faster than one another. Conclusions These results identify conserved functionally important genomic units that likely serve as building blocks of phenotypic innovation, and allow the remarkable breadth of parallel evolution seen in ants, and possibly other eusocial insects as well.
  • Lilley, Thomas M; Johnson, Joseph S; Ruokolainen, Lasse; Rogers, Elisabeth J; Wilson, Cali A; Schell, Spencer M; Field, Kenneth A; Reeder, DeeAnn M (BioMed Central, 2016)
    Abstract Background White-nose syndrome (WNS) has devastated bat populations in North America, with millions of bats dead. WNS is associated with physiological changes in hibernating bats, leading to increased arousals from hibernation and premature consumption of fat reserves. However, there is evidence of surviving populations of little brown myotis (Myotis lucifugus) close to where the fungus was first detected nearly ten years ago. Results We examined the hibernation patterns of a surviving population of little brown myotis and compared them to patterns in populations before the arrival of WNS and populations at the peak of WNS mortality. Despite infection with Pseudogymnoascus destructans, the causative fungal agent, the remnant population displayed less frequent arousals from torpor and lower torpid body temperatures than bats that died from WNS during the peak of mortality. The hibernation patterns of the remnant population resembled pre-WNS patterns with some modifications. Conclusions These data show that remnant populations of little brown myotis do not experience the increase in periodic arousals from hibernation typified by bats dying from WNS, despite the presence of the fungal pathogen on their skin. These patterns may reflect the use of colder hibernacula microclimates by WNS survivors, and/or may reflect differences in how these bats respond to the disease.
  • Williamson, Charles H D; Sahl, Jason W; Smith, Theresa J; Xie, Gary; Foley, Brian T; Smith, Leonard A; Fernández, Rafael A; Lindström, Miia; Korkeala, Hannu; Keim, Paul; Foster, Jeffrey; Hill, Karen (BioMed Central, 2016)
    Abstract Background Clostridium botulinum is a diverse group of bacteria characterized by the production of botulinum neurotoxin. Botulinum neurotoxins are classified into serotypes (BoNT/A–G), which are produced by six species/Groups of Clostridia, but the genetic background of the bacteria remains poorly understood. The purpose of this study was to use comparative genomics to provide insights into the genetic diversity and evolutionary history of bacteria that produce the potent botulinum neurotoxin. Results Comparative genomic analyses of over 170 Clostridia genomes, including our draft genome assemblies for 59 newly sequenced Clostridia strains from six continents and publicly available genomic data, provided in-depth insights into the diversity and distribution of BoNT-producing bacteria. These newly sequenced strains included Group I and II strains that express BoNT/A,/B,/E, or/F as well as bivalent strains. BoNT-producing Clostridia and closely related Clostridia species were delineated with a variety of methods including 16S rRNA gene, concatenated marker genes, core genome and concatenated multi-locus sequencing typing (MLST) gene phylogenies that related whole genome sequenced strains to publicly available strains and sequence types. These analyses illustrated the phylogenetic diversity in each Group and the diversity of genomic backgrounds that express the same toxin type or subtype. Comparisons of the botulinum neurotoxin genes did not identify novel toxin types or variants. Conclusions This study represents one of the most comprehensive analyses of whole genome sequence data for Group I and II BoNT-producing strains. Read data and draft genome assemblies generated for 59 isolates will be a resource to the research community. Core genome phylogenies proved to be a powerful tool for differentiating BoNT-producing strains and can provide a framework for the study of these bacteria. Comparative genomic analyses of Clostridia species illustrate the diversity of botulinum-neurotoxin-producing strains and the plasticity of the genomic backgrounds in which bont genes are found.
  • Heikinheimo, Annamari; Johler, Sophia; Karvonen, Laura; Julmi, Jérôme; Fredriksson-Ahomaa, Maria; Stephan, Roger (BioMed Central, 2016)
    Abstract Background The emergence of livestock-associated MRSA has become a growing public health concern worldwide. Studies elucidating the population structure, as well as resistance phenotypes and virulence gene profiles of livestock-associated MRSA strains are needed to improve risk assessment and to develop effective control measures. The objective of this study therefore was to determine i) clonal complexes and spa types, as well as ii) resistance phenotypes and iii) virulence and resistance gene profiles of livestock-associated MRSA isolated from Finnish fattening pigs at slaughter. Methods Fifty MRSA isolates collected from Finnish fattening pigs at slaughter were characterized by spa typing and DNA microarray profiling. In addition, antimicrobial susceptibility testing was performed using the Kirby Bauer disk diffusion method. Results MRSA isolates were assigned to clonal complexes CC1 (n = 4) and CC398 (n = 46). One dominant spa type (t2741) was present in 33 out of 50 investigated isolates, originating from 15 out of 18 farms. The remaining isolates were assigned to spa types t034 (n = 7), t108 (n = 5), and t011 (n = 1). Although each herd exhibited isolates assigned to one clonal complex only, five herds harbored MRSA isolates of either two or three different spa types. All tested MRSA isolates were phenotypically resistant to penicillin, oxacillin, cefoxitin, and tetracycline. With the exception of the isolates assigned to t108, all isolates exhibited resistance to clindamycin. On the genomic level, all isolates exhibited mecA, blaZ/I/R, and tetK, and were assigned to SCCmec type V. Many isolates also harbored tetM (46/50 isolates), lnuB (41/50 isolates), ermB (26/50 isolates), and one isolate was positive for aadD. DNA microarray profiling showed that all isolates of the dominant CC398/t2741 MRSA-V type belonged to agr type I, capsule type 5, and were negative for fnbB. Interestingly, one isolate of CC398/t2741 MRSA-V was agr negative and also lacked hld. Conclusions A new dominant LA-MRSA clone (CC398/t2741, SCCmec type V) was identified among fattening pigs in Finland. This is the first study identifying t2741 as a common spa type in LA-MRSA in pigs.
  • Kuusela, Jukka; Kujala, Ville J; Kiviaho, Anna; Ojala, Marisa; Swan, Heikki; Kontula, Kimmo; Aalto-Setälä, Katriina (Springer International Publishing, 2016)
    Abstract Human induced pluripotent stem cells (hiPSC) have enabled a major step forward in pathophysiologic studies of inherited diseases and may also prove to be valuable in in vitro drug testing. Long QT syndrome (LQTS), characterized by prolonged cardiac repolarization and risk of sudden death, may be inherited or result from adverse drug effects. Using a microelectrode array platform, we investigated the effects of six different drugs on the electrophysiological characteristics of human embryonic stem cell-derived cardiomyocytes as well as hiPSC-derived cardiomyocytes from control subjects and from patients with type 1 (LQT1) and type 2 (LQT2) of LQTS. At baseline the repolarization time was significantly longer in LQTS cells compared to controls. Isoprenaline increased the beating rate of all cell lines by 10–73 % but did not show any arrhythmic effects in any cell type. Different QT-interval prolonging drugs caused prolongation of cardiac repolarization by 3–13 % (cisapride), 10–20 % (erythromycin), 8–23 % (sotalol), 16–42 % (quinidine) and 12–27 % (E-4031), but we did not find any systematic differences in sensitivity between the control, LQT1 and LQT2 cell lines. Sotalol, quinidine and E-4031 also caused arrhythmic beats and beating arrests in some cases. In summary, the drug effects on these patient-specific cardiomyocytes appear to recapitulate clinical observations and provide further evidence that these cells can be applied for in vitro drug testing to probe their vulnerability to arrhythmia.
  • Pausch, Hubert; Venhoranta, Heli; Wurmser, Christine; Hakala, Kalle; Iso-Touru, Terhi; Sironen, Anu; Vingborg, Rikke K; Lohi, Hannes; Söderquist, Lennart; Fries, Ruedi; Andersson, Magnus (BioMed Central, 2016)
    Abstract Background Artificial insemination is widely used in many cattle breeding programs. Semen samples of breeding bulls are collected and closely examined immediately after collection at artificial insemination centers. Only ejaculates without anomalous findings are retained for artificial insemination. Although morphological aberrations of the spermatozoa are a frequent reason for discarding ejaculates, the genetic determinants underlying poor semen quality are scarcely understood. Results A tail stump sperm defect was observed in three bulls of the Swedish Red cattle breed. The spermatozoa of affected bulls were immotile because of severely disorganized tails indicating disturbed spermatogenesis. We genotyped three affected bulls and 18 unaffected male half-sibs at 46,035 SNPs and performed homozygosity mapping to map the fertility disorder to an 8.42 Mb interval on bovine chromosome 13. The analysis of whole-genome re-sequencing data of an affected bull and 300 unaffected animals from eleven cattle breeds other than Swedish Red revealed a 1 bp deletion (Chr13: 24,301,425 bp, ss1815612719) in the eleventh exon of the armadillo repeat containing 3-encoding gene (ARMC3) that was compatible with the supposed recessive mode of inheritance. The deletion is expected to alter the reading frame and to induce premature translation termination (p.A451fs26). The mutated protein is shortened by 401 amino acids (46 %) and lacks domains that are likely essential for normal protein function. Conclusions We report the phenotypic and genetic characterization of a sterilizing tail stump sperm defect in the Swedish Red cattle breed. Exploiting high-density genotypes and massive re-sequencing data enabled us to identify the most likely causal mutation for the fertility disorder in bovine ARMC3. Our results provide the basis for monitoring the mutated variant in the Swedish Red cattle population and for the early identification of infertile animals.
  • Eranti, Antti; Kerola, Tuomas; Aro, Aapo L; Tikkanen, Jani T; Rissanen, Harri A; Anttonen, Olli; Junttila, M. J; Knekt, Paul; Huikuri, Heikki V (BioMed Central, 2016)
    Abstract Background Diabetes predisposes to sudden cardiac death (SCD). However, it is uncertain whether greater proportion of cardiac deaths are sudden among diabetes patients than other subjects. It is also unclear whether the risk of SCD is pronounced already early in the course of the disease. The relationship of impaired glucose tolerance (IGT) and SCD is scarcely documented. Methods A general population cohort of 10594 middle-aged subjects (mean age 44 years, 52.6 % male, follow-up duration 35–41 years) was divided into diabetes patients (n = 82), subjects with IGT (n = 3806, plasma glucose ≥9.58 mmol/l in one-hour glucose tolerance test), and controls (n = 6706). Results Diabetes patients had an increased risk of SCD after adjustment confounders (hazard ratio 2.62, 95 % confidence interval 1.46–4.70, p = 0.001) but risk for non-sudden cardiac death was similarly increased and the proportion of SCD of cardiac deaths was not increased. The SCD risk persisted after exclusion of subjects with baseline cardiac disease or non-fatal cardiac events during the follow-up. Subjects with IGT were at increased risk for SCD (univariate hazard ratio 1.51; 95 % confidence interval 1.31–1.74; p < 0.001) and also for non-sudden cardiac deaths and non-fatal cardiac events but adjustments for other risk factors attenuated these effects. Conclusions Diabetes was associated with increased risk of SCD but also the risk of non-sudden cardiac death was similarly increased. The proportion of cardiac deaths being sudden in subjects with diabetes was not increased. The higher SCD risk in diabetes patients was independent of known cardiac disease at baseline or occurrence of non-fatal cardiac event during the follow-up.
  • Roine, Johanna; Uusitalo, Liisa; Hielm-Björkman, Anna (BioMed Central, 2016)
    Abstract Background The DOGRISK questionnaire is an internet-based ongoing study of canine nutrition, living environment, and disease. Here we aim to assess the performance of the questionnaire using data from the first three years in relation to some descriptive and disease variables. We used associated questions, official register records, test-retest repeatability, and email/mail contact with questionnaire respondents. Results Reliability against an official register of gender, season of birth, breed, and results of hip radiography was tested and Cohen’s Kappa was between 0.95–0.99. Internal consistencies of hypothyroidism status and dog’s age were calculated using Cronbach’s Alpha (α = 0.95 and α = 0.99, respectively). Test-retest repeatability of ten variables among 224 participants was analyzed. Gender, season of birth, and born in owner family had Cohen’s Kappa > 0.86, color of coat, vaccination status as an adult, other dogs in household, and vaccination status as a puppy had Cohen’s Kappa between 0.67–0.80, and body condition score under two months of age and tidiness of household, had Cohen’s kappa of 0.45 and 0.42, respectively. In addition, time spent outside had Cohen’s kappa of 0.37. Of the owners contacted by email/mail to confirm their dog’s atopy/allergy (skin symptoms), 8.9 % reported that they had given an incorrect answer (positive predicted value 91 %), but only 69 % of all reaffirmed positive answers had a diagnosis set by a veterinarian. Conclusions Our study showed that owners were diligent with basic information and with the status of three diseases. Cohen’s Kappa in the reliability of the test-retest was in most variables at least 0.67. We propose that the descriptive variables and the disease variables be used as such when we generate hypotheses from the DOGRISK data.
  • Hippeläinen, Eero; Tenhunen, Mikko; Mäenpää, Hanna; Sohlberg, Antti (Springer Berlin Heidelberg, 2016)
    Abstract Background In targeted radionuclide therapy (TRT), accurate quantification using SPECT/CT images is important for optimizing radiation dose delivered to both the tumour and healthy tissue. Quantitative SPECT images are regularly reconstructed using the ordered subset expectation maximization (OSEM) algorithm with various compensation methods such as attenuation (A), scatter (S) and detector and collimator response (R). In this study, different combinations of the compensation methods are applied during OSEM reconstruction and the effect on the 177Lu quantification accuracy is studied in an anthropomorphic torso phantom. In addition, the phantom results are reflected to (177)Lu-DOTA-Tyr3-octreotate (177Lu-DOTATATE)-treated patient data and kidney absorbed dose estimates. Methods The torso phantom was imaged with nine various sized (0.4–104.4 cm3) spherical inserts, filled with known 177Lu activity ranging from 0.5 to 105.5 MBq. Images were reconstructed using OSEM algorithm using A, AR and ARS compensation method combinations. The compensation method combinations were compared by calculating the concentration recovery coefficient (cRC) for each insert. In addition, ten 177Lu-DOTATATE-treated patient’s post-therapy dosimetry acquisitions were reconstructed, and the absorbed dose to kidneys was estimated. Results cRC values depend on the insert size for all compensation methods. AR and ARS produced significantly higher cRC values than attenuation correction alone. There were no cRC value differences between the methods for the smallest 1-cm-diameter insert, cRC being 0.18. However, the collimator and detector response compensation method (R) made the 1.3-cm-diameter insert clearly visible and improved cRC estimate from 0.19 to 0.43. ARS produced slightly higher cRC values for small- and medium-sized inserts than AR. On the patient data, a similar trend could be seen. AR and ARS produced higher kidney activities than using attenuation correction alone; the total absorbed doses to the right and left kidneys were on average 15 and 20 % higher for AR and 19 and 25 % higher for ARS, respectively. The effective half-life decay estimated from time-activity curves however showed no notable difference between the compensation methods. Conclusions The highest cRC values were achieved by applying ARS compensation during reconstruction. The results were notably higher than those using attenuation correction alone. Similarly, higher activity estimates and thus higher absorbed dose estimates were found in patient data when all compensation methods were applied. ARS improved cRC especially in small-sized sources, and it thus might aid tumour dosimetry for 177Lu PRRT treatments.