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  • Long, Georgina V; Atkinson, Victoria; Ascierto, Paolo A; Brady, Benjamin; Dutriaux, Caroline; Maio, Michele; Mortier, Laurent; Hassel, Jessica C; Rutkowski, Piotr; McNeil, Catriona; Kalinka-Warzocha, Ewa; Savage, Kerry J; Hernberg, Micaela; Lebbé, Celeste; Charles, Julie; Mihalcioiu, Catalin; Chiarion-Sileni, Vanna; Mauch, Cornelia; Schmidt, Henrik; Schadendorf, Dirk; Gogas, Helen; Horak, Christine; Sharkey, Brian; Waxman, Ian M; Robert, Caroline (BioMed Central Ltd, 2015)
  • Antonios, Gregory; Saiepour, Nasrin; Bouter, Yvonne; Richard, Bernhard C; Paetau, Anders; Verkkoniemi-Ahola, Auli; Lannfelt, Lars; Ingelsson, Martin; Kovacs, Gabor G; Pillot, Thierry; Wirths, Oliver; Bayer, Thomas A (BioMed Central, 2013)
    Abstract Background The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1–42 and Aβ1–40, N-truncated AβpE3-42 and Aβ4–42 are major variants in AD brain. Although Aβ4–42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4–42 may precede the other in Alzheimer’s disease pathology. Results Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4–42 toxicity in vitro no beneficial effect was observed against Aβ1–42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD. Conclusions Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research.
  • Tabassum, Rubina; Sivadas, Ambily; Agrawal, Vartika; Tian, Haozheng; Arafat, Dalia; Gibson, Greg (BioMed Central, 2015)
    Abstract Background Personalized medicine is predicated on the notion that individual biochemical and genomic profiles are relatively constant in times of good health and to some extent predictive of disease or therapeutic response. We report a pilot study quantifying gene expression and methylation profile consistency over time, addressing the reasons for individual uniqueness, and its relation to N = 1 phenotypes. Methods Whole blood samples from four African American women, four Caucasian women, and four Caucasian men drawn from the Atlanta Center for Health Discovery and Well Being study at three successive 6-month intervals were profiled by RNA-Seq, miRNA-Seq, and Illumina Methylation 450 K arrays. Standard regression approaches were used to evaluate the proportion of variance for each type of omic measure among individuals, and to quantify correlations among measures and with clinical attributes related to wellness. Results Longitudinal omic profiles were in general highly consistent over time, with an average of 67 % variance in transcript abundance, 42 % in CpG methylation level (but 88 % for the most differentiated CpG per gene), and 50 % in miRNA abundance among individuals, which are all comparable to 74 % variance among individuals for 74 clinical traits. One third of the variance could be attributed to differential blood cell type abundance, which was also fairly stable over time, and a lesser amount to expression quantitative trait loci (eQTL) effects. Seven conserved axes of covariance that capture diverse aspects of immune function explained over half of the variance. These axes also explained a considerable proportion of individually extreme transcript abundance, namely approximately 100 genes that were significantly up-regulated or down-regulated in each person and were in some cases enriched for relevant gene activities that plausibly associate with clinical attributes. A similar fraction of genes had individually divergent methylation levels, but these did not overlap with the transcripts, and fewer than 20 % of genes had significantly correlated methylation and gene expression. Conclusions People express an “omic personality” consisting of peripheral blood transcriptional and epigenetic profiles that are constant over the course of a year and reflect various types of immune activity. Baseline genomic profiles can provide a window into the molecular basis of traits that might be useful for explaining medical conditions or guiding personalized health decisions.
  • Virtanen, Jorma I; Vehkalahti, Kimmo I; Vehkalahti, Miira M (BioMed Central, 2015)
    Abstract Background Health behaviors play a major role in the prevention of the most common oral diseases. To investigate health behaviors related to the potential transmission of oral bacteria from mother to child using novel multiple correspondence analysis (MCA). Methods Mothers (n = 313) with children under three years attending two municipal child health clinics in Finland completed a self-administered questionnaire on health knowledge and behaviors such as sharing a spoon with their child, kissing on the lips, and the mothers’ tooth brushing, smoking, age, and level of education. We used MCA to reveal the relationships between the mothers’ behaviors and background factors, along with unconditional, binary, multivariable logistic regression models, odds ratios (OR) and their 95 % confidence intervals (95 %CI). Results Of the mothers, 38 % kissed their child on the lips and 14 % shared a spoon with their child; 11 % believed that oral bacteria cannot be transmitted from mother to child. Two-thirds (68 %) of them reported tooth brushing twice daily, and 80 % were non-smokers. MCA revealed two diverging dimensions of the mothers’ behaviors: a ‘horizontal’ one showing clear evidence of relationships between tooth brushing, smoking, age and education, whereas the ‘vertical’ one revealed the mothers’ habits of kissing the child on the lips and sharing a spoon related to each other. Spoon sharing was related to the kissing on lips (OR 10.3), a higher level of education (OR 3.1), and, inversely, older age (OR 0.1), whereas kissing on lips behavior was inversely related to a higher level of education (OR 0.5). Conclusion The study revealed two diverging dimensions of the mothers’ health behaviors. More emphasis in health education ought to be put to how to avoid bacterial transmission from caregiver to child during feeding.
  • Castrén, Eeva; Sillat, Tarvo; Oja, Sofia; Noro, Ariel; Laitinen, Anita; Konttinen, Yrjö T; Lehenkari, Petri; Hukkanen, Mika; Korhonen, Matti (BioMed Central, 2015)
    Abstract Introduction Bone marrow-derived mesenchymal stromal cells (MSCs) have been intensely studied for the purpose of developing solutions for clinical tissue engineering. Autologous MSCs can potentially be used to replace tissue defects, but the procedure also carries risks such as immunization and xenogeneic infection. Replacement of the commonly used fetal calf serum (FCS) with human platelet lysate and plasma (PLP) to support cell growth may reduce some of these risks. Altered media could, however, influence stem cell differentiation and we address this experimentally. Methods We examined human MSC differentiation into the osteoblast lineage using in vitro two- and three-dimensional cultures with PLP or FCS as cell culture medium supplements. Differentiation was followed by quantitative polymerase chain reaction, and alkaline phosphatase activity, matrix formation and matrix calcium content were quantified. Results Three-dimensional culture, where human MSCs were grown on collagen sponges, markedly stimulated osteoblast differentiation; a fourfold increase in calcium deposition could be observed in both PLP and FCS groups. PLP-grown cells showed robust osteogenic differentiation both in two- and three-dimensional MSC cultures. The calcium content of the matrix in the two-dimensional PLP group at day 14 was 2.2-fold higher in comparison to the FCS group (p < 0.0001), and at day 21 it was still 1.3-fold higher (p < 0.001), suggesting earlier calcium accumulation to the matrix in the PLP group. This was supported by stronger Alizarin Red staining in the PLP group at day 14. In two-dimesional PLP cultures, cellular proliferation appeared to decrease during later stages of differentiation, while in the FCS group the number of cells increased throughout the experiment. In three-dimensional experiments, the PLP and FCS groups behaved more congruently, except for the alkaline phosphatase activity and mRNA levels which were markedly increased by PLP. Conclusions Human PLP was at least equal to FCS in supporting osteogenic differentiation of human MSCs in two- and three-dimensional conditions; however, proliferation was inferior. As PLP is free of animal components, and thus represents reduced risk for xenogeneic infection, its use for human MSC-induced bone repair in the clinic by the three-dimensional live implants presented here appears a promising therapy option.
  • Rahmanian, Abdolkarim; Seifzadeh, Babak; Razmkon, Ali; Petramfar, Peyman; Kivelev, Juri; Alibai, Ehsan-Ali; Hernesniemi, Juha (Springer, 2014)
    Abstract Background Malignant cerebral infarction is a well-recognized disease, comprising 10-15% of all cases with cerebral infarction and causing herniation and death in 80% of cases. In this study, we compare the effects of decompressive craniectomy versus conventional medical treatment on mortality rate and functional and neurological outcome in patients with malignant MCA infarction. Methods We performed a prospective case&#8211;control study on 60 patients younger than 80years of age suffering malignant MCA cerebral infarction. The case group underwent decompressive craniectomy in addition to routine aggressive medical care; while the control group received routine medical treatment. Patient outcome was assessed using Glasgow outcome scale and modified Rankin scale within three months of follow-up. The data were analyzed by SPSS version 16.0 software using Chi Square, One-way ANOVA and Mann&#8211;Whitney tests. Results There were 27 male and 33 female patients with a mean age of 60.6&#160;years (SD&#8201;=&#8201;12.3). Glasgow outcome scale score averaged 2.93 in the surgical versus 1.53 in the medical group; this difference was significant (p&#8201;=&#8201;0.001). Outcome in modified Rankin scale was also significantly lower in the surgical (3.27) versus medical (5.27) group (p&#8201;&lt;&#8201;0.001). Surgery could decrease the mortality rate about 47%. Conclusion In this study, decompressive craniectomy could decrease mortality rate, and improve neurological and functional outcome, and decrease long-term disability in patients with malignant MCA infarction.
  • Calteau, Alexandra; Fewer, David P; Latifi, Amel; Coursin, Thérèse; Laurent, Thierry; Jokela, Jouni; Kerfeld, Cheryl A; Sivonen, Kaarina; Piel, Jörn; Gugger, Muriel (BioMed Central Ltd, 2014)
    Abstract Background Cyanobacteria are an ancient lineage of photosynthetic bacteria from which hundreds of natural products have been described, including many notorious toxins but also potent natural products of interest to the pharmaceutical and biotechnological industries. Many of these compounds are the products of non-ribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) pathways. However, current understanding of the diversification of these pathways is largely based on the chemical structure of the bioactive compounds, while the evolutionary forces driving their remarkable chemical diversity are poorly understood. Results We carried out a phylum-wide investigation of genetic diversification of the cyanobacterial NRPS and PKS pathways for the production of bioactive compounds. 452 NRPS and PKS gene clusters were identified from 89 cyanobacterial genomes, revealing a clear burst in late-branching lineages. Our genomic analysis further grouped the clusters into 286 highly diversified cluster families (CF) of pathways. Some CFs appeared vertically inherited, while others presented a more complex evolutionary history. Only a few horizontal gene transfers were evidenced amongst strongly conserved CFs in the phylum, while several others have undergone drastic gene shuffling events, which could result in the observed diversification of the pathways. Conclusions Therefore, in addition to toxin production, several NRPS and PKS gene clusters are devoted to important cellular processes of these bacteria such as nitrogen fixation and iron uptake. The majority of the biosynthetic clusters identified here have unknown end products, highlighting the power of genome mining for the discovery of new natural products.
  • Guo, Baocheng; DeFaveri, Jacquelin; Sotelo, Graciela; Nair, Abhilash; Merilä, Juha (BioMed Central, 2015)
    Abstract Background The degree of genetic differentiation among populations experiencing high levels of gene flow is expected to be low for neutral genomic sites, but substantial divergence can occur in sites subject to directional selection. Studies of highly mobile marine fish populations provide an opportunity to investigate this kind of heterogeneous genomic differentiation, but most studies to this effect have focused on a relatively low number of genetic markers and/or few populations. Hence, the patterns and extent of genomic divergence in high-gene-flow marine fish populations remain poorly understood. Results We here investigated genome-wide patterns of genetic variability and differentiation in ten marine populations of three-spined stickleback (Gasterosteus aculeatus) distributed across a steep salinity and temperature gradient in the Baltic Sea, by utilizing >30,000 single nucleotide polymorphisms obtained with a pooled RAD-seq approach. We found that genetic diversity and differentiation varied widely across the genome, and identified numerous fairly narrow genomic regions exhibiting signatures of both divergent and balancing selection. Evidence was uncovered for substantial genetic differentiation associated with both salinity and temperature gradients, and many candidate genes associated with local adaptation in the Baltic Sea were identified. Conclusions The patterns of genetic diversity and differentiation, as well as candidate genes associated with adaptation, in Baltic Sea sticklebacks were similar to those observed in earlier comparisons between marine and freshwater populations, suggesting that similar processes may be driving adaptation to brackish and freshwater environments. Taken together, our results provide strong evidence for heterogenic genomic divergence driven by local adaptation in the face of gene flow along an environmental gradient in the post-glacially formed Baltic Sea.
  • Skrifvars, MB; Raj, R; Bendel, S; Selander, T; Kivisaari, R; Siironen, J; Reinikainen, M (BioMed Central Ltd, 2014)
  • Traoré, Oumar; Nyholm, Outi; Siitonen, Anja; Bonkoungou, Isidore J O; Traoré, Alfred S; Barro, Nicolas; Haukka, Kaisa (BioMed Central, 2015)
    Abstract Background This study investigated the prevalence, serotypes and antimicrobial sensitivity patterns of Salmonella enterica in environment in Ouagadougou, Burkina Faso. A total of 476 samples, consisting of 36 samples of tap water, 51 samples of well water, 87 samples of channel water, 44 samples of reservoir water, 238 samples of fish, and 20 samples of lettuce were examined using standard bacteriological procedures for Salmonella. Results Salmonella were isolated from 98 samples. Salmonella were rare in drinking water, since they were not found at all from the tap water, and only in 2 % of well water. Salmonella were more common in the water of reservoir of Tanghin (15 %), reservoir of Yamtenga (20 %), and in the water channels in the city (from 20 to 31 %). Salmonella were commonly isolated from the fish (24 %) caught from the reservoir of Tanghin and from the lettuce (50 %) irrigated with water from Tanghin. The Salmonella isolates were found to represent 50 different serotypes. The 11 most common serotypes were Salmonella Bredeney and S. Colindale (both 8.2 %), S. Muenster (6.1 %), S. Korlebu (5.1 %), S. Eastbourne and S. Poona (both 4.1 %), and S. Agona, S. Derby, S. Drac, S. Senftenberg, S. Waycross (each 3.1 %), accounting for 51.3 % of all the isolates. In general, the Salmonella strains were sensitive to the antimicrobials tested, but two strains were resistant to streptomycin and many more intermediate to streptomycin or sulphonamide. Conclusion This study highlights the common prevalence of Salmonella and the high diversity of Salmonella serotypes in aquatic environment in Ouagadougou, Burkina Faso. Therefore, various human activities linked to water and consumption of water-related products, such as fish and lettuce, can lead to human Salmonella infections.
  • Örmälä-Odegrip, Anni-Maria; Ojala, Ville; Hiltunen, Teppo; Zhang, Ji; Bamford, Jaana K; Laakso, Jouni (BioMed Central, 2015)
    Abstract Background Consumer-resource interactions constitute one of the most common types of interspecific antagonistic interaction. In natural communities, complex species interactions are likely to affect the outcomes of reciprocal co-evolution between consumers and their resource species. Individuals face multiple enemies simultaneously, and consequently they need to adapt to several different types of enemy pressures. In this study, we assessed how protist predation affects the susceptibility of bacterial populations to infection by viral parasites, and whether there is an associated cost of defence on the competitive ability of the bacteria. As a study system we used Serratia marcescens and its lytic bacteriophage, along with two bacteriovorous protists with distinct feeding modes: Tetrahymena thermophila (particle feeder) and Acanthamoeba castellanii (surface feeder). The results were further confirmed with another study system with Pseudomonas and Tetrahymena thermophila. Results We found that selection by protist predators lowered the susceptibility to infections by lytic phages in Serratia and Pseudomonas. In Serratia, concurrent selection by phages and protists led to lowered susceptibility to phage infections and this effect was independent from whether the bacteria shared a co-evolutionary history with the phage population or not. Bacteria that had evolved with phages were overall more susceptible to phage infection (compared to bacteria with history with multiple enemies) but they were less vulnerable to the phages they had co-evolved with than ancestral phages. Selection by bacterial enemies was costly in general and was seen as a lowered fitness in absence of phages, measured as a biomass yield. Conclusions Our results show the significance of multiple species interactions on pairwise consumer-resource interaction, and suggest potential overlap in defending against predatory and parasitic enemies in microbial consumer-resource communities. Ultimately, our results could have larger scale effects on eco-evolutionary community dynamics.
  • Pohjola, Leena; Rossow, Laila; Huovilainen, Anita; Soveri, Timo; Hänninen, Marja-Liisa; Fredriksson-Ahomaa, Maria (BioMed Central Ltd, 2015)
    Abstract Background Although modern commercial poultry production today is based on large farms and intensive husbandry, keeping backyard poultry has regained popularity in industrialized countries. However, the health status of backyard flocks is still relatively poorly documented. A questionnaire was sent to the owners of 376 backyard poultry flocks (&lt;500 birds) in order to study health management procedures and characterize backyard poultry populations in Finland. Information was also collected on the postmortem findings from non-commercial flocks using necropsy data from the Finnish Food Safety Authority (Evira). Results Backyard flocks in Finland are small in size (&lt;50 birds), comprising mainly chickens. Based on the results of the questionnaire, the health of such flocks is good, mortality low and vaccinations are not commonly used. Most of the flocks were registered in the national poultry register. The standard biosecurity practices are not generally applied and contact with wild birds, pets and farm animals is frequent, which can make the flocks more prone to infectious diseases. We conducted an 11-year retrospective study of the postmortem necropsy findings of the Evira in order to document the diseases, which caused mortality in backyard chickens in Finland. Necropsy was performed on a total of 132 non-commercial laying hens during 2000 &#8211; 2011. The most common postmortem findings were Marek&#8217;s disease (27%) and colibacillosis (17%). Conclusions This study is the first to report data on characteristics of and management practices for backyard chicken flocks in Finland. Close connections with commercial flocks are rare and farms are usually distantly located suggesting that the risk that these backyard flocks pose to commercial poultry is low.
  • Kaunisto, Jaana; Kelloniemi, K.; Sutinen, E.; Hodgson, U.; Piilonen, A.; Kaarteenaho, R.; Mäkitaro, R.; Purokivi, M.; Lappi-Blanco, E.; Saarelainen, S.; Kankaanranta, H.; Mursu, A.; Kanervisto, M.; Salomaa, E-R.; Myllärniemi, M. (BioMed Central, 2015)
    Abstract Background The FinnishIPF registry is a prospective, longitudinal national registry study on the epidemiology of idiopathic pulmonary fibrosis (IPF). It was designed to describe the characteristics, management and prognosis of prevalent and incident IPF patients. The study was initiated in 2012. Methods We present here results limited to five university hospitals. Patients with IPF were screened from hospital registries using ICD-10 diagnosis codes J84.1 and J84.9. All patients who gave informed consent were included and evaluated using novel diagnostic criteria. Point prevalence on the 31st of December in 2012 was calculated using the reported population in each university hospital city as the denominator. Results Patients with ICD-10 codes J84.1 and J84.9 yielded a heterogeneous group – on the basis of patient records assessed by pulmonologists only 20–30 % of the cases were IPF. After clinical, radiological and histological re-evaluation 111 of 123 (90 %) of patients fulfilled the clinical criteria of IPF. The estimated prevalence of IPF was 8.6 cases/100 000. 60.4 % were men. Forty four percent of the patients were never-smokers. At diagnosis, the patients’ mean age was 73.5 years and mean FVC was 80.4 % and DLCO 57.3 % of predicted. Conclusions Our results suggest that hospital registries are inaccurate for epidemiological studies unless patients are carefully re-evaluated. IPF is diagnosed in Finland at a stage when lung function is still quite well preserved. Smoking in patients with IPF was less common than in previous reports.
  • Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T; McGuffog, Lesley; Barrowdale, Daniel; Bolla, Manjeet K; Wang, Qin; Healey, Sue; Schmutzler, Rita K; Wappenschmidt, Barbara; Rhiem, Kerstin; Hahnen, Eric; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Ellis, Steve; Frost, Debra; Platte, Radka; Perkins, Jo; Evans, D G; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Scuvera, Giulietta; Manoukian, Siranoush; Bonanni, Bernardo; Mariette, Frederique; Fortuzzi, Stefano; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Varesco, Liliana; Balleine, Rosemary; Nathanson, Katherine L; Domchek, Susan M; Offitt, Kenneth; Jakubowska, Anna; Lindor, Noralane; Thomassen, Mads; Jensen, Uffe B; Rantala, Johanna; Borg, Åke; Andrulis, Irene L; Miron, Alexander; Hansen, Thomas V; Caldes, Trinidad; Neuhausen, Susan L; Toland, Amanda E; Nevanlinna, Heli; Montagna, Marco; Garber, Judy; Godwin, Andrew K; Osorio, Ana; Factor, Rachel E; Terry, Mary B; Rebbeck, Timothy R; Karlan, Beth Y; Southey, Melissa; Rashid, Muhammad U; Tung, Nadine; Pharoah, Paul D; Blows, Fiona M; Dunning, Alison M; Provenzano, Elena; Hall, Per; Czene, Kamila; Schmidt, Marjanka K; Broeks, Annegien; Cornelissen, Sten; Verhoef, Senno; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Slamon, Dennis J; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Aittomäki, Kristiina; Muranen, Taru A; Heikkilä, Päivi; Blomqvist, Carl; Figueroa, Jonine; Chanock, Stephen J; Brinton, Louise; Lissowska, Jolanta; Olson, Janet E; Pankratz, Vernon S; John, Esther M; Whittemore, Alice S; West, Dee W; Hamann, Ute; Torres, Diana; Ulmer, Hans U; Rüdiger, Thomas; Devilee, Peter; Tollenaar, Robert A; Seynaeve, Caroline; Van Asperen, Christi J; Eccles, Diana M; Tapper, William J; Durcan, Lorraine; Jones, Louise; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Dwek, Miriam; Swann, Ruth; Bane, Anita L; Glendon, Gord; Mulligan, Anna M; Giles, Graham G; Milne, Roger L; Baglietto, Laura; McLean, Catriona; Carpenter, Jane; Clarke, Christine; Scott, Rodney; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Cox, Angela; Cross, Simon S; Reed, Malcolm W; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Dörk, Thilo; Bogdanova, Natalia; Park-Simon, Tjoung-Won; Hillemanns, Peter; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Burwinkel, Barbara; Marme, Frederik; Surovy, Harald; Yang, Rongxi; Anton-Culver, Hoda; Ziogas, Argyrios; Hooning, Maartje J; Collée, J M; Martens, John W; Tilanus-Linthorst, Madeleine M; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volke; Stegmaier, Christa; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Lindblom, Annika; Margolin, Sara; Joseph, Vijai; Robson, Mark; Rau-Murthy, Rohini; González-Neira, Anna; Arias, José I; Zamora, Pilar; Benítez, Javier; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Peterlongo, Paolo; Zaffaroni, Daniela; Barile, Monica; Capra, Fabio; Radice, Paolo; Teo, Soo H; Easton, Douglas F; Antoniou, Antonis C; Chenevix-Trench, Georgia; Goldgar, David E (BioMed Central, 2014)
    Abstract Introduction The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
  • Hemilä, Harri; Al-Biltagi, Mohammed; Baset, Ahmed A (BioMed Central Ltd, 2012)
    AbstractWe reported that the effect of vitamin C on asthma in Egyptian children was modified by age, exposure to dampness and the severity of asthma, Clinical &amp; Translational Allergy 2011, 1:9. After our paper was published, we found out severe problems in the data set. There were 60 children in the study. The ages were by accident duplicated between the upper and lower halves of the database. Thus, the ages for the first 30 children in the data set were identical and in the same order with the ages for the second set of 30 children. Similar duplication was also found for C-ACT and FEV1 measurements after vitamin C supplementation and for exposure to dampness. This duplication thus directly invalidates the second part of the data set, and thus the reported outcome. We have not been able to sort out the reason for this duplication. The files with the original data are not available any more, making it impossible to reconstruct a valid data set for reanalysis. Therefore we have to retract our paper. The authors deeply regret the inconvenience this has caused to the journal and the scientific community.
  • Castellsagué, Xavier; Paavonen, Jorma; Jaisamrarn, Unnop; Wheeler, Cosette M; Skinner, S Rachel; Lehtinen, Matti; Naud, Paulo; Chow, Song-Nan; Del Rosario-Raymundo, Maria R; Teixeira, Julio C; Palmroth, Johanna; de Carvalho, Newton S; Germar, Maria JV; Peters, Klaus; Garland, Suzanne M; Szarewski, Anne; Poppe, Willy AJ; Romanowski, Barbara; Schwarz, Tino F; Tjalma, Wiebren AA; Bosch, F X; Bozonnat, Marie-Cecile; Struyf, Frank; Dubin, Gary; Rosillon, Dominique; Baril, Laurence; for the HPV PATRICIA Study Group (BioMed Central Ltd, 2014)
    Abstract Background More information is needed about time between sexual initiation and human papillomavirus (HPV) infection and development of cervical precancer. Methods The objectives were to investigate the time between first sexual activity and detection of first cervical HPV infection or development of first cervical intraepithelial neoplasia (CIN), and associated factors in women from the double-blind, multinational, 4-year PATRICIA trial. PATRICIA enroled women aged 15&#8211;25 years with no more than 6 lifetime sexual partners. Women were randomized 1:1 to the HPV-16/18 AS04-adjuvanted vaccine or to control, but only women from the control arm who began sexual intercourse during the study or within 6&#160;months before enrolment, and had no HPV infection detected before the recorded date of their first sexual intercourse, were included in the present analysis. The time between onset of sexual activity and detection of the first cervical HPV infection or development of the first CIN lesion was analyzed using Kaplan-Meier and univariate and multivariable Cox proportional-hazards models. Results A total of 9337 women were enroled in the control arm of PATRICIA of whom 982 fulfilled the required inclusion criteria for analysis. A cumulative total of 28%, 44%, and 62% of the subjects had HPV infection within 12, 24, and 48&#160;months, respectively. The overall incidence rate was 27.08 per 100 person-years. The most common oncogenic types associated with 6-month persistent infection were HPV-16 (incidence rate: 2.74 per 100 person-years), HPV-51 (2.70), HPV-52 (1.66), HPV-66 (1.14), and HPV-18 (1.09). Increased infection risk was associated with more lifetime sexual partners, being single, Chlamydia trachomatis history, and duration of hormone use. CIN1+ and CIN2+ lesions were most commonly associated with HPV-16, with an overall incidence rate of 1.87 and 1.07 per 100 person-years, respectively. Previous cervical HPV infection was most strongly associated with CIN development. Conclusions More than 25% of women were infected with HPV within 1&#160;year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation. Trial registration NCT00122681.
  • Sidoroff, Marianne; Kolho, Kaija-Leena (BioMed Central Ltd, 2014)
    Abstract Background Pharmacological doses of corticoids may result in adrenal suppression but with individual sensitivity. In paediatric inflammatory bowel disease (IBD), glucocorticoids are needed in the majority of the patients but there are less studies related to tapering off the drugs. The objective of this study was to estimate the frequency of adrenal insufficiency in children with IBD that were at the end of their systemic glucocorticoid therapy course. Methods The study was a retrospective case series of 59 consecutive paediatric IBD patients (median age 14.1&#160;years; Crohn&#8217;s disease n&#8201;=&#8201;22, ulcerative colitis n&#8201;=&#8201;26, unclassified colitis n&#8201;=&#8201;11) that were on oral prednisolone therapy about to be discontinued. The study patients were treated in a tertiary university hospital setting. Serum morning cortisol was measured with Immulite 2000 cortisol kit. Values&#8201;&lt;&#8201;20&#160;nmol/l are undetectable and indicate adrenal suppression, values&#8201;&gt;&#8201;69&#160;nmol/l are considered to represent normal basal secretion. Results The morning cortisol was below the reference range in 20% of the patients and undetectable in 10%. Low cortisol levels associated with higher daily glucocorticoid doses (median 7.2&#160;mg/m2 vs. 3.0&#160;mg/m2 in patients with normal cortisol levels, p&#8201;&lt;&#8201;0.05) and with the long duration of the treatment (median 11&#160;months vs. 4&#160;months, p&#8201;&lt;&#8201;0.05). Patients with undetectable cortisol levels recovered within few weeks (median 5.6&#160;weeks). Conclusions In paediatric IBD prolonged courses of glucocorticoids are frequent due to the steroid-dependent nature of the disease in a considerable proportion of patients. Adrenal suppression may occur in at least one fifth of the patients despite slowly tapering off the glucocorticoids. Notably, this is based on a set of serum cortisol measurements by request of experienced clinicians. All paediatric IBD patients receiving conventional doses of oral glucocorticoids should be subjected to screening for adrenal suppression when anticipated discontinuation of the drug.
  • Ahola, Tero; Karlin, David G (BioMed Central, 2015)
    Abstract Background Members of the alphavirus supergroup include human pathogens such as chikungunya virus, hepatitis E virus and rubella virus. They encode a capping enzyme with methyltransferase-guanylyltransferase (MTase-GTase) activity, which is an attractive drug target owing to its unique mechanism. However, its experimental study has proven very difficult. Results We examined over 50 genera of viruses by sequence analyses. Earlier studies showed that the MTase-GTase contains a “Core” region conserved in sequence. We show that it is followed by a long extension, which we termed “Iceberg” region, whose secondary structure, but not sequence, is strikingly conserved throughout the alphavirus supergroup. Sequence analyses strongly suggest that the minimal capping domain corresponds to the Core and Iceberg regions combined, which is supported by earlier experimental data. The Iceberg region contains all known membrane association sites that contribute to the assembly of viral replication factories. We predict that it may also contain an overlooked, widely conserved membrane-binding amphipathic helix. Unexpectedly, we detected a sequence homolog of the alphavirus MTase-GTase in taxa related to nodaviruses and to chronic bee paralysis virus. The presence of a capping enzyme in nodaviruses is biologically consistent, since they have capped genomes but replicate in the cytoplasm, where no cellular capping enzyme is present. The putative MTase-GTase domain of nodaviruses also contains membrane-binding sites that may drive the assembly of viral replication factories, revealing an unsuspected parallel with the alphavirus supergroup. Conclusions Our work will guide the functional analysis of the alphaviral MTase-GTase and the production of domains for structure determination. The identification of a homologous domain in a simple model system, nodaviruses, which replicate in numerous eukaryotic cell systems (yeast, flies, worms, mammals, and plants), can further help crack the function and structure of the enzyme. Reviewers This article was reviewed by Valerian Dolja, Eugene Koonin and Sebastian Maurer-Stroh.
  • Kim, Jinsil; Stirling, Kara J; Cooper, Margaret E; Ascoli, Mario; Momany, Allison M; McDonald, Erin L; Ryckman, Kelli K; Rhea, Lindsey; Schaa, Kendra L; Cosentino, Viviana; Gadow, Enrique; Saleme, Cesar; Shi, Min; Hallman, Mikko; Plunkett, Jevon; Teramo, Kari A; Muglia, Louis J; Feenstra, Bjarke; Geller, Frank; Boyd, Heather A; Melbye, Mads; Marazita, Mary L; Dagle, John M; Murray, Jeffrey C (BioMed Central Ltd, 2013)
    Abstract Background Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. Methods To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. Results Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case&#8211;control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. Conclusions Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.
  • Jokelainen, Pikka; Velström, Kaisa; Lassen, Brian (BioMed Central, 2015)
    Abstract Background Although the prevalence of human Toxoplasma gondii infections is high in Estonia, no information is available on the prevalence of infections in the local animal populations. Wild boars are a good indicator species for estimating the prevalence and spread of T. gondii and were thus investigated in this nationwide cross-sectional study. Volunteer hunters sampled cardiac or skeletal muscle of 471 wild boars legally hunted for human consumption in Estonia during the hunting season of 2012–2013. Serosanguineous meat juice samples were obtained from thawed tissue samples, diluted 1:40, and screened for specific anti-T. gondii IgG antibodies with a commercial direct agglutination test. Results Almost one-quarter (113; 24%) of the wild boars examined were seropositive for T. gondii. The seroprevalence did not differ significantly between age groups or sexes. The seroprevalence was lowest in Viljandimaa, which is located in the southern part of Estonia. In other counties, the infection was evenly prevalent. Conclusions In Estonia, wild boars are commonly exposed to T. gondii, which is endemic and widespread. The consumption of raw or undercooked meat of Estonian wild boars may pose an infection risk to humans and other hosts.