Articles from BioMed Central

 

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  • Legehar, Ashenafi; Xhaard, Henri; Ghemtio, Leo (Springer International Publishing, 2016)
    Abstract Background The disposition of a pharmaceutical compound within an organism, i.e. its Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) properties and adverse effects, critically affects late stage failure of drug candidates and has led to the withdrawal of approved drugs. Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and ADMET or adverse effects, but this is limited by the size, quality, and heterogeneity of the data available from individual sources. Thus, large, clean and integrated databases of approved drug data, associated with fast and efficient predictive tools are desirable early in the drug discovery process. Description We have built a relational database (IDAAPM) to integrate available approved drug data such as drug approval information, ADMET and adverse effects, chemical structures and molecular descriptors, targets, bioactivity and related references. The database has been coupled with a searchable web interface and modern data analytics platform (KNIME) to allow data access, data transformation, initial analysis and further predictive modeling. Data were extracted from FDA resources and supplemented from other publicly available databases. Currently, the database contains information regarding about 19,226 FDA approval applications for 31,815 products (small molecules and biologics) with their approval history, 2505 active ingredients, together with as many ADMET properties, 1629 molecular structures, 2.5 million adverse effects and 36,963 experimental drug-target bioactivity data. Conclusion IDAAPM is a unique resource that, in a single relational database, provides detailed information on FDA approved drugs including their ADMET properties and adverse effects, the corresponding targets with bioactivity data, coupled with a data analytics platform. It can be used to perform basic to complex drug-target ADMET or adverse effects analysis and predictive modeling. IDAAPM is freely accessible at http://idaapm.helsinki.fi and can be exploited through a KNIME workflow connected to the database. Graphical abstract FDA approved drug data integration for predictive modeling
  • Andreevskaya, Margarita; Hultman, Jenni; Johansson, Per; Laine, Pia; Paulin, Lars; Auvinen, Petri; Björkroth, Johanna (BioMed Central, 2016)
    Abstract Leuconostoc gelidum subsp. gasicomitatum is a predominant lactic acid bacterium (LAB) in spoilage microbial communities of different kinds of modified-atmosphere packaged (MAP) food products. So far, only one genome sequence of a poultry-originating type strain of this bacterium (LMG 18811T) has been available. In the current study, we present the completely sequenced and functionally annotated genome of strain KG16-1 isolated from a vegetable-based product. In addition, six other vegetable-associated strains were sequenced to study possible “niche” specificity suggested by recent multilocus sequence typing. The genome of strain KG16-1 consisted of one circular chromosome and three plasmids, which together contained 2,035 CDSs. The chromosome carried at least three prophage regions and one of the plasmids encoded a galactan degradation cluster, which might provide a survival advantage in plant-related environments. The genome comparison with LMG 18811T and six other vegetable strains suggests no major differences between the meat- and vegetable-associated strains that would explain their “niche” specificity. Finally, the comparison with the genomes of other leuconostocs highlights the distribution of functionally interesting genes across the L. gelidum strains and the genus Leuconostoc.
  • Åhlgren, Johanna; Uimari, Pekka (BioMed Central, 2016)
    Abstract Background The Hovawart is a working and companion dog breed of German origin. A few hundred Hovawart dogs are registered annually in Finland. The most common disease with a proposed genetic background in Hovawarts is hypothyroidism. The disease is usually caused by lymphocytic thyroiditis, an autoimmune disorder which destroys the thyroid gland. Hypothyroidism can be treated medically with hormone replacement. Its overall incidence could also be reduced through selection, provided that the trait shows an adequate genetic basis. The aim of this study was to estimate the heritability of hypothyroidism in the Finnish Hovawart population. Results The pedigree data for the study were provided by the Finnish Kennel Club and the hypothyroidism data by the Finnish Hovawart Club. The data included 4953 dogs born between 1990 and 2010, of which 107 had hypothyroidism and 4846 were unaffected. Prior to the estimation of heritability, we studied the effects of gender, birth year, birth month, and inbreeding on susceptibility to hypothyroidism. Heritability was estimated with the probit model both via restricted maximum likelihood (REML) and Gibbs sampling, using litter and sire of the dog as random effects. None of the studied systematic effects or level of inbreeding had a significant effect on susceptibility to hypothyroidism. The estimated heritability of hypothyroidism varied from 0.47 (SE = 0.18) using REML to 0.62 (SD = 0.21) using Gibbs sampling. Conclusions Based on our analysis, the heritability of hypothyroidism is moderate to high, suggesting that its prevalence could be decreased through selection. Thus, breeders should notify the breed association of any affected dogs, and their use for breeding should be avoided.
  • Svärd, Anna; Lahti, Jouni; Rahkonen, Ossi; Lahelma, Eero; Lallukka, Tea (BioMed Central, 2016)
    Abstract Background Both obesity and mental health are major public health issues. This study aimed to examine whether overweight and obesity among midlife employees are associated with subsequent psychotropic medication. A further aim was to examine the potential effect of key covariates on the association. Methods The Helsinki Health Study baseline survey was conducted in 2000–2002 among 40–60-year-old employees of the City of Helsinki, Finland (n = 8960). The participants were classified as of normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), obese (30–34.9 kg/m2) or severely obese (≥35 kg/m2) based on self-reported body mass index. Data on psychotropic medication purchases from baseline to 2009 were derived from registers of the Social Insurance Institution of Finland. The final analysis included 4760 women and 1338 men. Antidepressants and sedatives were examined separately. Covariates included socio-demographic factors, workload, health behaviours, physical functioning, somatic ill-health and psychotropic medication prior to baseline. Hazard ratios (HR) for the first psychotropic medication purchase were calculated using Cox regression analysis. Results Third of women and quarter of men made at least one psychotropic medication purchase during the follow-up. Adjusting for age, obese (HR = 1.57; 95 % CI = 1.10–2.24) and severely obese (HR = 2.15; 95 % CI = 1.29–3.56) men were at risk of having psychotropic medication compared to men of normal weight. These associations disappeared after further adjustment. Severe obesity remained associated with subsequent sedative medication among the men even after full adjustment (HR = 2.12; 95 % CI = 1.17–3.84). No associations were found among the women. Conclusions Obese and severely obese men, but not women, were at risk of psychotropic medication. Further studies are needed to deepen understanding of the relationship between obesity and mental ill-health, and the possible protecting effects of age, employment, and living environment.
  • Louhimo, Riku; Laakso, Marko; Belitskin, Denis; Klefström, Juha; Lehtonen, Rainer; Hautaniemi, Sampsa (BioMed Central, 2016)
    Abstract Background Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. Results We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. Conclusions Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/ .
  • Icay, Katherine; Chen, Ping; Cervera, Alejandra; Rantanen, Ville; Lehtonen, Rainer; Hautaniemi, Sampsa (BioMed Central, 2016)
    Abstract Background Large-scale sequencing experiments are complex and require a wide spectrum of computational tools to extract and interpret relevant biological information. This is especially true in projects where individual processing and integrated analysis of both small RNA and complementary RNA data is needed. Such studies would benefit from a computational workflow that is easy to implement and standardizes the processing and analysis of both sequenced data types. Results We developed SePIA (Sequence Processing, Integration, and Analysis), a comprehensive small RNA and RNA workflow. It provides ready execution for over 20 commonly known RNA-seq tools on top of an established workflow engine and provides dynamic pipeline architecture to manage, individually analyze, and integrate both small RNA and RNA data. Implementation with Docker makes SePIA portable and easy to run. We demonstrate the workflow’s extensive utility with two case studies involving three breast cancer datasets. SePIA is straightforward to configure and organizes results into a perusable HTML report. Furthermore, the underlying pipeline engine supports computational resource management for optimal performance. Conclusion SePIA is an open-source workflow introducing standardized processing and analysis of RNA and small RNA data. SePIA’s modular design enables robust customization to a given experiment while maintaining overall workflow structure. It is available at http://anduril.org/sepia .
  • Kareem, Abdul; Radhakrishnan, Dhanya; Wang, Xin; Bagavathiappan, Subhikshaa; Trivedi, Zankhana B; Sugimoto, Kaoru; Xu, Jian; Mähönen, Ari P; Prasad, Kalika (BioMed Central, 2016)
    Abstract Background Plants have the remarkable property to elaborate entire body plan from any tissue part. The conversion of lateral root primordium (LRP) to shoot is an ideal method for plant propagation and for plant researchers to understand the mechanism underlying trans-differentiation. Until now, however, a robust method that allows the efficient conversion of LRP to shoot is lacking. This has limited our ability to study the dynamic phases of reprogramming at cellular and molecular levels. Results Here we present an efficient protocol for the direct conversion of LRP to a complete fertile shoot system. This protocol can be readily applied to the various ecotypes of Arabidopsis. We show that, the conversion process is highly responsive to developmental stages of LRP and changes in external environmental stimuli such as temperature. The entire conversion process can be adequately analyzed by histological and imaging techniques. As a demonstration, using a battery of cell fate specific markers, we show that confocal time-lapse imaging can be employed to uncover the early molecular events, intermediate developmental phases and relative abundance of stem cell regulators during the conversion of LRP to shoot. Conclusion Our method is highly efficient, independent of genotypes tested and suitable to study the reprogramming of LRP to shoot in intact plants as well as in excised roots.
  • 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.
  • 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.
  • 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.
  • 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.