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  • 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 (<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 (<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 – 2011. The most common postmortem findings were Marek’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.
  • 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 & 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 15–25 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 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 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 year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation. Trial registration clinicaltrials.gov: 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 years; Crohn’s disease n = 22, ulcerative colitis n = 26, unclassified colitis n = 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 < 20 nmol/l are undetectable and indicate adrenal suppression, values > 69 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 mg/m2 vs. 3.0 mg/m2 in patients with normal cortisol levels, p < 0.05) and with the long duration of the treatment (median 11 months vs. 4 months, p < 0.05). Patients with undetectable cortisol levels recovered within few weeks (median 5.6 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–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.
  • Werner, Stefan; Apolinário, José A Jr.; Diniz, Paulo SR (Springer, 2007)
    Proportionate adaptive filters can improve the convergence speed for the identification of sparse systems as compared to their conventional counterparts. In this paper, the idea of proportionate adaptation is combined with the framework of set-membership filtering (SMF) in an attempt to derive novel computationally efficient algorithms. The resulting algorithms attain an attractive faster converge for both situations of sparse and dispersive channels while decreasing the average computational complexity due to the data discerning feature of the SMF approach. In addition, we propose a rule that allows us to automatically adjust the number of past data pairs employed in the update. This leads to a set-membership proportionate affine projection algorithm (SM-PAPA) having a variable data-reuse factor allowing a significant reduction in the overall complexity when compared with a fixed data-reuse factor. Reduced-complexity implementations of the proposed algorithms are also considered that reduce the dimensions of the matrix inversions involved in the update. Simulations show good results in terms of reduced number of updates, speed of convergence, and final mean-squared error.
  • Kondadi, Pradeep K; Revez, Joana; Hänninen, Marja-Liisa; Rossi, Mirko (BioMed Central Ltd, 2015)
    Abstract Sialic acid in lipopolysaccharides (LPS) of mucosal pathogens is known to be an important virulence factor. Few strains of Helicobacter pylori express sialyl-Lewis-X and we have reported that human and canine Helicobacter bizzozeronii strains express sialyl-lactoseamine in their LPS. However, the role of sialyation of Helicobacter LPS in the interaction with the host cells is still unknown. In this study H. bizzozeronii LPS is shown to activate the TLR2 in a dose and strain dependent manner in the in vitro HEK-293 cells model expressing TLR2, but not the cells expressing TLR4. These results indicate that TLR2 is the specific receptor for H. bizzozzeronii LPS, as previously described for H. pylori. To further explore the role of sialylation of H. bizzozeronii LPS on TLR2 response, H. bizzozeronii Δhbs2 mutant strains deficient in sialyltransferase activity were constructed by homologous recombination. LPS from H. bizzozeronii Δhbs2 strains enhanced the NF-ĸB induction via TLR2 compared to the respective wild types, leading to the conclusion that the sialylation of H. bizzozeronii LPS in wild-type strains may modulate host immune response.
  • Hoffmann, Rasmus; Borsboom, Gerard; Saez, Marc; Mari Dell’Olmo, Marc; Burström, Bo; Corman, Diana; Costa, Claudia; Deboosere, Patrick; Domínguez-Berjón, M F; Dzúrová, Dagmar; Gandarillas, Ana; Gotsens, Mercè; Kovács, Katalin; Mackenbach, Johan; Martikainen, Pekka; Maynou, Laia; Morrison, Joana; Palència, Laia; Pérez, Gloria; Pikhart, Hynek; Rodríguez-Sanz, Maica; Santana, Paula; Saurina, Carme; Tarkiainen, Lasse; Borrell, Carme (BioMed Central, 2014)
    Abstract Background Health and inequalities in health among inhabitants of European cities are of major importance for European public health and there is great interest in how different health care systems in Europe perform in the reduction of health inequalities. However, evidence on the spatial distribution of cause-specific mortality across neighbourhoods of European cities is scarce. This study presents maps of avoidable mortality in European cities and analyses differences in avoidable mortality between neighbourhoods with different levels of deprivation. Methods We determined the level of mortality from 14 avoidable causes of death for each neighbourhood of 15 large cities in different European regions. To address the problems associated with Standardised Mortality Ratios for small areas we smooth them using the Bayesian model proposed by Besag, York and Mollié. Ecological regression analysis was used to assess the association between social deprivation and mortality. Results Mortality from avoidable causes of death is higher in deprived neighbourhoods and mortality rate ratios between areas with different levels of deprivation differ between gender and cities. In most cases rate ratios are lower among women. While Eastern and Southern European cities show higher levels of avoidable mortality, the association of mortality with social deprivation tends to be higher in Northern and lower in Southern Europe. Conclusions There are marked differences in the level of avoidable mortality between neighbourhoods of European cities and the level of avoidable mortality is associated with social deprivation. There is no systematic difference in the magnitude of this association between European cities or regions. Spatial patterns of avoidable mortality across small city areas can point to possible local problems and specific strategies to reduce health inequality which is important for the development of urban areas and the well-being of their inhabitants.
  • Kulhánová, Ivana; Menvielle, Gwenn; Bopp, Matthias; Borrell, Carme; Deboosere, Patrick; Eikemo, Terje A; Hoffmann, Rasmus; Leinsalu, Mall; Martikainen, Pekka; Regidor, Enrique; Rodríguez-Sanz, Maica; Rychtaříková, Jitka; Wojtyniak, Bogdan; Mackenbach, Johan P (BioMed Central Ltd, 2014)
    Abstract Background Cause-of-death data linked to information on socioeconomic position form one of the most important sources of information about health inequalities in many countries. The proportion of deaths from ill-defined conditions is one of the indicators of the quality of cause-of-death data. We investigated educational differences in the use of ill-defined causes of death in official mortality statistics. Methods Using age-standardized mortality rates from 16 European countries, we calculated the proportion of all deaths in each educational group that were classified as due to “Symptoms, signs and ill-defined conditions”. We tested if this proportion differed across educational groups using Chi-square tests. Results The proportion of ill-defined causes of death was lower than 6.5% among men and 4.5% among women in all European countries, without any clear geographical pattern. This proportion statistically significantly differed by educational groups in several countries with in most cases a higher proportion among less than secondary educated people compared with tertiary educated people. Conclusions We found evidence for educational differences in the distribution of ill-defined causes of death. However, the differences between educational groups were small suggesting that socioeconomic inequalities in cause-specific mortality in Europe are not likely to be biased.
  • Kulhánová, Ivana; Menvielle, Gwenn; Bopp, Matthias; Borrell, Carme; Deboosere, Patrick; Eikemo, Terje A; Hoffmann, Rasmus; Leinsalu, Mall; Martikainen, Pekka; Regidor, Enrique; Rodríguez-Sanz, Maica; Rychtaříková, Jitka; Wojtyniak, Bogdan; Mackenbach, Johan P (BioMed Central, 2014)
    Abstract Background Cause-of-death data linked to information on socioeconomic position form one of the most important sources of information about health inequalities in many countries. The proportion of deaths from ill-defined conditions is one of the indicators of the quality of cause-of-death data. We investigated educational differences in the use of ill-defined causes of death in official mortality statistics. Methods Using age-standardized mortality rates from 16 European countries, we calculated the proportion of all deaths in each educational group that were classified as due to “Symptoms, signs and ill-defined conditions”. We tested if this proportion differed across educational groups using Chi-square tests. Results The proportion of ill-defined causes of death was lower than 6.5% among men and 4.5% among women in all European countries, without any clear geographical pattern. This proportion statistically significantly differed by educational groups in several countries with in most cases a higher proportion among less than secondary educated people compared with tertiary educated people. Conclusions We found evidence for educational differences in the distribution of ill-defined causes of death. However, the differences between educational groups were small suggesting that socioeconomic inequalities in cause-specific mortality in Europe are not likely to be biased.
  • Plug, Iris; Hoffmann, Rasmus; Artnik, Barbara; Bopp, Matthias; Borrell, Carme; Costa, Giuseppe; Deboosere, Patrick; Esnaola, Santi; Kalediene, Ramune; Leinsalu, Mall; Lundberg, Olle; Martikainen, Pekka; Regidor, Enrique; Rychtarikova, Jitka; Strand, Björn H; Wojtyniak, Bogdan; Mackenbach, Johan P (BioMed Central Ltd, 2012)
    AbstractBackgroundPrevious studies have reported large socioeconomic inequalities in mortality from conditions amenable to medical intervention, but it is unclear whether these can be attributed to inequalities in access or quality of health care, or to confounding influences such as inequalities in background risk of diseases. We therefore studied whether inequalities in mortality from conditions amenable to medical intervention vary between countries in patterns which differ from those observed for other (non-amenable) causes of death. More specifically, we hypothesized that, as compared to non-amenable causes, inequalities in mortality from amenable causes are more strongly associated with inequalities in health care use and less strongly with inequalities in common risk factors for disease such as smoking.MethodsCause-specific mortality data for people aged 30–74 years were obtained for 14 countries, and were analysed by calculating age-standardized mortality rates and relative risks comparing a lower with a higher educational group. Survey data on health care use and behavioural risk factors for people aged 30–74 years were obtained for 12 countries, and were analysed by calculating age-and sex-adjusted odds ratios comparing a low with a higher educational group. Patterns of association were explored by calculating correlation coefficients.ResultsIn most countries and for most amenable causes of death substantial inequalities in mortality were observed, but inequalities in mortality from amenable causes did not vary between countries in patterns that are different from those seen for inequalities in non-amenable mortality. As compared to non-amenable causes, inequalities in mortality from amenable causes are not more strongly associated with inequalities in health care use. Inequalities in mortality from amenable causes are also not less strongly associated with common risk factors such as smoking.ConclusionsWe did not find evidence that inequalities in mortality from amenable conditions are related to inequalities in access or quality of health care. Further research is needed to find the causes of socio-economic inequalities in mortality from amenable conditions, and caution should be exercised in interpreting these inequalities as indicating health care deficiencies.
  • Rosti, Katja; Goldman, Adrian; Kajander, Tommi (BioMed Central, 2015)
    Abstract Background The protein growth arrest specific-1 (GAS1) was discovered based on its ability to stop the cell cycle. During development it is involved in embryonic patterning, inhibits cell proliferation and mediates cell death, and has therefore been considered as a tumor suppressor. GAS1 is known to signal through two different cell membrane receptors: Rearranged during transformation (RET), and the sonic hedgehog receptor Patched-1. Sonic Hedgehog signalling is important in stem cell renewal and RET mediated signalling in neuronal survival. Disorders in both sonic hedgehog and RET signalling are connected to cancer progression. The neuroprotective effect of RET is controlled by glial cell-derived neurotrophic factor family ligands and glial cell-derived neurotrophic factor receptor alphas (GFRαs). Human Growth arrest specific-1 is a distant homolog of the GFRαs. Results We have produced and purified recombinant human GAS1 protein, and confirmed that GAS1 is a monomer in solution by static light scattering and small angle X-ray scattering analysis. The low resolution solution structure reveals that GAS1 is more elongated and flexible than the GFRαs, and the homology modelling of the individual domains show that they differ from GFRαs by lacking the amino acids for neurotrophic factor binding. In addition, GAS1 has an extended loop in the N-terminal domain that is conserved in vertebrates after the divergence of fishes and amphibians. Conclusions We conclude that GAS1 most likely differs from GFRαs functionally, based on comparative structural analysis, while it is able to bind the extracellular part of RET in a neurotrophic factor independent manner, although with low affinity in solution. Our structural characterization indicates that GAS1 differs from GFRα’s significantly also in its conformation, which probably reflects the functional differences between GAS1 and the GFRαs.
  • Lülf, Sebastian; Matz, Julie; Rouyez, Marie-Christine; Järviluoma, Annika; Saksela, Kalle; Benichou, Serge; Geyer, Matthias (BioMed Central, 2014)
    Abstract Background The HIV-1 Nef protein is essential for AIDS pathogenesis by its interaction with host cell surface receptors and signaling factors. Despite its critical role as a virulence factor Nef is not targeted by current antiviral strategies. Results We have determined the crystal structure of the complex formed by a camelid single-domain antibody fragment, termed sdAb19, bound to HIV-1 Nef together with a stabilizing SH3 domain. sdAb19 forms a stoichiometric 1:1 complex with Nef and binds to a conformationally conserved surface at the C-terminus of Nef that overlaps with functionally important interaction sites involved in Nef-induced perturbations of signaling and trafficking pathways. The antibody fragment binds Nef with low nanomolar affinity, which could be attenuated to micromolar affinity range by site-directed mutagenesis of key interaction residues in sdAb19. Fusion of the SH3 domain to sdAb19, termed Neffin, leads to a significantly increased affinity for Nef and formation of a stoichiometric 2:2 Nef–Neffin complex. The 19 kDa Neffin protein inhibits all functions of Nef as CD4 and MHC-I downregulation, association with Pak2, and the increase in virus infectivity and replication. Conclusions Together, sdAb19 and Neffin thus represent efficient tools for the rational development of antiviral strategies against HIV-1 Nef.
  • Tikkinen, Kari A; Agarwal, Arnav; Craigie, Samantha; Cartwright, Rufus; Gould, Michael K; Haukka, Jari; Naspro, Richard; Novara, Giacomo; Sandset, Per M; Siemieniuk, Reed A; Violette, Philippe D; Guyatt, Gordon H (BioMed Central, 2014)
    Abstract Background Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery. Methods/design We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors. Discussion This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk (including modeling of timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis. Systematic review registration PROSPERO CRD42014010342 .
  • Tikkinen, Kari AO; Agarwal, Arnav; Craigie, Samantha; Cartwright, Rufus; Gould, Michael K; Haukka, Jari; Naspro, Richard; Novara, Giacomo; Sandset, Per M; Siemieniuk, Reed A; Violette, Philippe D; Guyatt, Gordon H (BioMed Central Ltd, 2014)
    Abstract Background Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery. Methods/design We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors. Discussion This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk (including modeling of timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis. Systematic review registration PROSPERO CRD42014010342.
  • Kainulainen, Veera; Tang, Yurui; Spillmann, Thomas; Kilpinen, Susanne; Reunanen, Justus; Saris, Per E; Satokari, Reetta (BioMed Central, 2015)
    Abstract Background For a good probiotic candidate, the abilities to adhere to intestinal epithelium and to fortify barrier function are considered to be crucial for colonization and functionality of the strain. The strain Lactobacillus acidophilus LAB20 was isolated from the jejunum of a healthy dog, where it was found to be the most pre-dominant lactobacilli. In this study, the adhesion ability of LAB20 to intestinal epithelial cell (IECs) lines, IECs isolated from canine intestinal biopsies, and to canine, porcine and human intestinal mucus was investigated. Further, we studied the ability of LAB20 to fortify the epithelial cell monolayer and to reduce LPS-induced interleukin (IL-8) release from enterocytes. Results We found that LAB20 presented higher adhesion to canine colonic mucus as compared to mucus isolated from porcine colon. LAB20 showed adhesion to HT-29 and Caco-2 cell lines, and importantly also to canine IECs isolated from canine intestinal biopsies. In addition, LAB20 increased the transepithelial electrical resistance (TER) of enterocyte monolayers and thus strengthened the intestinal barrier function. The strain showed also anti-inflammatory capacity in being able to attenuate the LPS-induced IL-8 production of HT-29 cells. Conclusion In conclusion, canine indigenous strain LAB20 is a potential probiotic candidate for dogs adhering to the host epithelium and showing intestinal barrier fortifying and anti-inflammatory effects.
  • Kainulainen, Veera; Tang, Yurui; Spillmann, Thomas; Kilpinen, Susanne; Reunanen, Justus; Saris, Per EJ; Satokari, Reetta (BioMed Central Ltd, 2015)
    Abstract Background For a good probiotic candidate, the abilities to adhere to intestinal epithelium and to fortify barrier function are considered to be crucial for colonization and functionality of the strain. The strain Lactobacillus acidophilus LAB20 was isolated from the jejunum of a healthy dog, where it was found to be the most pre-dominant lactobacilli. In this study, the adhesion ability of LAB20 to intestinal epithelial cell (IECs) lines, IECs isolated from canine intestinal biopsies, and to canine, porcine and human intestinal mucus was investigated. Further, we studied the ability of LAB20 to fortify the epithelial cell monolayer and to reduce LPS-induced interleukin (IL-8) release from enterocytes. Results We found that LAB20 presented higher adhesion to canine colonic mucus as compared to mucus isolated from porcine colon. LAB20 showed adhesion to HT-29 and Caco-2 cell lines, and importantly also to canine IECs isolated from canine intestinal biopsies. In addition, LAB20 increased the transepithelial electrical resistance (TER) of enterocyte monolayers and thus strengthened the intestinal barrier function. The strain showed also anti-inflammatory capacity in being able to attenuate the LPS-induced IL-8 production of HT-29 cells. Conclusion In conclusion, canine indigenous strain LAB20 is a potential probiotic candidate for dogs adhering to the host epithelium and showing intestinal barrier fortifying and anti-inflammatory effects.