Articles from BioMed Central


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  • Kiiskinen, Jasmi; Merivaara, Arto; Hakkarainen, Tiina; Kääriäinen, Minna; Miettinen, Susanna; Yliperttula, Marjo; Koivuniemi, Raili (BioMed Central, 2019)
    Abstract Background In the field of regenerative medicine, delivery of human adipose-derived mesenchymal stem/stromal cells (hASCs) has shown great promise to promote wound healing. However, a hostile environment of the injured tissue has shown considerably to limit the survival rate of the transplanted cells, and thus, to improve the cell survival and retention towards successful cell transplantation, an optimal cell scaffold is required. The objective of this study was to evaluate the potential use of wood-derived nanofibrillar cellulose (NFC) wound dressing as a cell scaffold material for hASCs in order to develop a cell transplantation method free from animal-derived components for wound treatment. Methods Patient-derived hASCs were cultured on NFC wound dressing without cell adhesion coatings. Cell characteristics, including cell viability, morphology, cytoskeletal structure, proliferation potency, and mesenchymal cell and differentiation marker expression, were analyzed using cell viability assays, electron microscopy, immunocytochemistry, and quantitative or reverse transcriptase PCR. Student’s t test and one-way ANOVA followed by a Tukey honestly significant difference post hoc test were used to determine statistical significance. Results hASCs were able to adhere to NFC dressing and maintained high cell survival without cell adhesion coatings with a cell density-dependent manner for the studied period of 2 weeks. In addition, NFC dressing did not induce any remarkable cytotoxicity towards hASCs or alter the morphology, proliferation potency, filamentous actin structure, the expression of mesenchymal vimentin and extracellular matrix (ECM) proteins collagen I and fibronectin, or the undifferentiated state of hASCs. Conclusions As a result, NFC wound dressing offers a functional cell culture platform for hASCs to be used further for in vivo wound healing studies in the future.
  • Rissanen, Annu-Riikka S; Jernman, Riina M; Gissler, Mika; Nupponen, Irmeli; Nuutila, Mika E (BioMed Central, 2019)
    Abstract Background To investigate the trends and changes in the incidence and overall outcome of twin pregnancies in Finland, a retrospective study was conducted with emphasis on maternal complications, covering a 28-year study period. Methods All 23,498 twin pregnancies with 46,363 live born and 633 stillborn children in Finland during 1987–2014 were included in the study. Data were collected from the national Medical Birth Register and the Care Register on Hospital Care (Finnish Institute for Health and Welfare, Finland) regarding the parturients’ characteristics and incidences of several pregnancy and childbirth complications. The incidences of twin pregnancies and maternal complications during pregnancy and childbirth are the main outcome measures of the study. The results are expressed in percentages, means, medians, ranges and standard deviations (SD), when appropriate. Results Twins comprised 1.4% of all births in Finland in 1987–2014. Parturients’ mean age has remained stable, but the share of over 35 year-old parturients is increasing. The incidences of pre-eclampsia, intrahepatic cholestasis of pregnancy, gestational diabetes and postpartum haemorrhage have risen during the study period. Almost half (44.9%) of twins were born preterm, almost half via Caesarean section (47.1%), and 27.7% of twin labours were induced. Conclusions Several pregnancy complications increased during the study period. Advanced maternal age among twin parturients has risen, enhancing the risks for developing complications in a pregnancy already of a high-risk category, and predisposing to preterm delivery. National and international guidelines are necessary to improve the overall outcome of twin pregnancies.
  • Inkinen, Nina; Pettilä, Ville; Lakkisto, Päivi; Kuitunen, Anne; Jukarainen, Sakari; Bendel, Stepani; Inkinen, Outi; Ala-Kokko, Tero; Vaara, Suvi T (Springer International Publishing, 2019)
    Abstract Background Injury to endothelium and glycocalyx predisposes to vascular leak, which may subsequently lead to increased fluid requirements and worse outcomes. In this post hoc study of the prospective multicenter observational Finnish Acute Kidney Injury (FINNAKI) cohort study conducted in 17 Finnish intensive care units, we studied the association of Syndecan-1 (SDC-1), Angiopoetin-2 (Ang-2), soluble thrombomodulin (sTM), vascular adhesion protein-1 (VAP-1) and interleukin-6 (IL-6) with fluid administration and balance among septic critical care patients and their association with development of acute kidney injury (AKI) and 90-day mortality. Results SDC-1, Ang-2, sTM, VAP-1 and IL-6 levels were measured at ICU admission from 619 patients with sepsis. VAP-1 decreased (p < 0.001) and IL-6 increased (p < 0.001) with increasing amounts of administered fluid, but other biomarkers did not show differences according to fluid administration. In linear regression models adjusted for IL-6, only VAP-1 was significantly associated with fluid administration on day 1 (p < 0.001) and the cumulative fluid balance on day 5/ICU discharge (p = 0.001). Of 415 patients admitted without AKI, altogether 112 patients (27.0%) developed AKI > 12 h from ICU admission (AKI>12 h). They had higher sTM levels than patients without AKI, and after multivariable adjustment log, sTM level was associated with AKI>12 h with OR (95% CI) of 12.71 (2.96–54.67), p = 0.001). Ninety-day non-survivors (n = 180; 29.1%) had higher SDC-1 and sTM levels compared to survivors. After adjustment for known confounders, log SDC-1 (OR [95% CI] 2.13 [1.31–3.49], p = 0.002), log sTM (OR [95% CI] 7.35 [2.29–23.57], p < 0.001), and log Ang-2 (OR [95% CI] 2.47 [1.44–4.14], p = 0.001) associated with an increased risk for 90-day mortality. Finally, patients who had high levels of all three markers, namely, SDC-1, Ang-2 and sTM, had an adjusted OR of 5.61 (95% CI 2.67–11.79; p < 0.001) for 90-day mortality. Conclusions VAP-1 and IL-6 associated with fluid administration on the first ICU day. After adjusting for confounders, sTM was associated with development of AKI after 12 h from ICU admission. SDC-1, Ang-2 and sTM were independently associated with an increased risk for 90-day mortality.
  • Ziemele, Inga; Xu, Man; Vilmane, Anda; Rasa-Dzelzkaleja, Santa; Hedman, Lea; Hedman, Klaus; Söderlund-Venermo, Maria; Nora-Krukle, Zaiga; Murovska, Modra; Gardovska, Dace (BioMed Central, 2019)
    Abstract Background Human bocavirus 1 is a commonly detected human parvovirus. Many studies have shown human bocavirus 1 as a pathogen in association with acute respiratory tract infections in children. However, because human bocavirus 1 persists in the upper airways for extensive time periods after acute infection, the definition and diagnostics of acute human bocavirus 1 infection is challenging. Until now, detection of human bocavirus 1 exclusively, high viral load in respiratory samples, and viremia have been associated with a clinical picture of acute respiratory illness. There are no studies showing detection of human bocavirus 1 messenger ribonucleic acid in the peripheral blood mononuclear cells as a diagnostic marker for acute lower respiratory tract infection. Case presentation We report the case of a 17-month-old Latvian boy who presented in intensive care unit with acute bilateral bronchiolitis, with a history of rhinorrhea and cough for 6 days and fever for the last 2 days prior to admission, followed by severe respiratory distress and tracheal intubation. Human bocavirus 1 was the only respiratory virus detected by a qualitative multiplex polymerase chain reaction panel. For the diagnosis of acute human bocavirus 1 infection, both molecular and serological approaches were used. Human bocavirus 1 deoxyribonucleic acid (DNA) was detected simultaneously in nasopharyngeal aspirate, stool, and blood, as well as in the corresponding cell-free blood plasma by qualitative and quantitative polymerase chain reaction, revealing high DNA-copy numbers in nasopharyngeal aspirate and stool. Despite a low-load viremia, human bocavirus 1 messenger ribonucleic acid was found in the peripheral blood mononuclear cells. For detection of human bocavirus 1-specific antibodies, non-competitive immunoglobulin M and competitive immunoglobulin G enzyme immunoassays were used. The plasma was positive for both human bocavirus 1-specific immunoglobulin M and immunoglobulin G antibodies. Conclusions The presence of human bocavirus 1 genomic DNA in blood plasma and human bocavirus 1 messenger ribonucleic acid in peripheral blood mononuclear cells together with human bocavirus 1-specific immunoglobulin M are markers of acute human bocavirus 1 infection that may cause life-threatening acute bronchiolitis.
  • Glerup, Mia; Thiel, Steffen; Rypdal, Veronika; Arnstad, Ellen D; Ekelund, Maria; Peltoniemi, Suvi; Aalto, Kristiina; Rygg, Marite; Nielsen, Susan; Fasth, Anders; Berntson, Lillemor; Nordal, Ellen; Herlin, Troels (BioMed Central, 2019)
    Abstract Background To determine the serum levels of the lectin pathway proteins early in the disease course and 17 years after disease onset and to correlate the protein levels to markers of disease activity in participants from a population-based Nordic juvenile idiopathic arthritis (JIA) cohort. Additionally, to assess the predictive value of lectin pathway proteins with respect to remission status. Methods A population-based cohort study of consecutive cases of JIA with a disease onset from 1997 to 2000 from defined geographical areas of Finland, Sweden, Norway and Denmark with 17 years of follow-up was performed. Clinical characteristics were registered and H-ficolin, M-ficolin, MASP-1, MASP-3, MBL and CL-K1 levels in serum were analyzed. Results In total, 293 patients with JIA were included (mean age 23.7 ± 4.4 years; mean follow-up 17.2 ± 1.7 years). Concentrations of the lectin protein levels in serum were higher at baseline compared to the levels 17 years after disease onset (p ≤ 0.006, n = 164). At baseline, the highest level of M-ficolin was observed in systemic JIA. Further, high M-ficolin levels at baseline and at 17-year follow-up were correlated to high levels of ESR. In contrast, high MASP-1 and MASP-3 tended to correlate to low ESR. CL-K1 showed a negative correlation to JADAS71 at baseline. None of the protein levels had prognostic abilities for remission status 17 years after disease onset. Conclusion We hypothesize that increased serum M-ficolin levels are associated with higher disease activity in JIA and further, the results indicate that MASP-1, MASP-3 and CL-K1 are markers of inflammation.
  • Danielsson, Maria; Lammi, Anelma; Siitonen, Simo; Ollgren, Jukka; Pylkkänen, Liisa; Vasankari, Tuula (BioMed Central, 2019)
    Abstract Background The consumption of tobacco products has evolved to include more complex combinations of different products. We investigated the tobacco habits of a representative population of young Finnish male conscripts in order to evaluate the prevalence of dual use of cigarettes and snus as well as the transition from one tobacco product to another. In addition, we evaluated the correlation between the level of education and the use of cigarettes and snus. Methods A questionnaire-based survey was carried out in three out of 17 garrisons among conscripts during their first week of service in 2014. A total of 1971 male conscripts were selected by simple random sampling of the 9013 males in the selected garrisons. Of them 1916 participated and filled in the questionnaire. The response rate was 97.2%. The questionnaire consisted of 25 questions including age, gender, basic education, use of tobacco products as well as questions assessing nicotine dependency. Results The amount of dual users of cigarettes and snus was 21%. There was a higher probability of dual use of cigarettes and snus among smokers compared to snus users (p < 0.001). One third (35%) of former smokers reported daily snus use and over 40% of the former snus users smoked daily. One third (34%) of the participants reported snus usage and 14% of the study subjects used snus daily. 40% of the study population were smokers and over 25% smoked daily. Of the participants with basic educational background 57% smoked daily (p < 0.001), however, no association between snus and level of education was found (p = 0.69). Conclusions This study provides better understanding of the complex tobacco habits of young adult males. The simultaneous usage of multiple tobacco products as well as the high tendency to transition from one tobacco product to another should be taken into consideration when planning cessation interventions in health care settings and tobacco control policies at societal levels.
  • Harrois, A.; Anstey, J. R; Taccone, F. S; Udy, A. A; Citerio, G.; Duranteau, J.; Ichai, C.; Badenes, R.; Prowle, J. R; Ercole, A.; Oddo, M.; Schneider, A.; van der Jagt, M.; Wolf, S.; Helbok, R.; Nelson, D. W; Skrifvars, M. B; Cooper, D. J; Bellomo, R. (Springer International Publishing, 2019)
    Abstract Background In traumatic brain injury (TBI) patients desmopressin administration may induce rapid decreases in serum sodium and increase intracranial pressure (ICP). Aim In an international multi-centre study, we aimed to report changes in serum sodium and ICP after desmopressin administration in TBI patients. Methods We obtained data from 14 neurotrauma ICUs in Europe, Australia and UK for severe TBI patients (GCS ≤ 8) requiring ICP monitoring. We identified patients who received any desmopressin and recorded daily dose, 6-hourly serum sodium, and 6-hourly ICP. Results We studied 262 severe TBI patients. Of these, 39 patients (14.9%) received desmopressin. Median length of treatment with desmopressin was 1 [1–3] day and daily intravenous dose varied between centres from 0.125 to 10 mcg. The median hourly rate of decrease in serum sodium was low (− 0.1 [− 0.2 to 0.0] mmol/L/h) with a median period of decrease of 36 h. The proportion of 6-h periods in which the rate of natremia correction exceeded 0.5 mmol/L/h or 1 mmol/L/h was low, at 8% and 3%, respectively, and ICPs remained stable. After adjusting for IMPACT score and injury severity score, desmopressin administration was independently associated with increased 60-day mortality [HR of 1.83 (1.05–3.24) (p = 0.03)]. Conclusions In severe TBI, desmopressin administration, potentially representing instances of diabetes insipidus is common and is independently associated with increased mortality. Desmopressin doses vary markedly among ICUs; however, the associated decrease in natremia rarely exceeds recommended rates and median ICP values remain unchanged. These findings support the notion that desmopressin therapy is safe.
  • Satokangas, Markku; Lumme, Sonja; Arffman, Martti; Keskimäki, Ilmo (BioMed Central, 2019)
    Abstract Background Due to stagnating resources and an increase in staff workload, the quality of Finnish primary health care (PHC) is claimed to have deteriorated slowly. With a decentralised PHC organisation and lack of national stewardship, it is likely that municipalities have adopted different coping strategies, predisposing them to geographic disparities. To assess whether these disparities emerge, we analysed health centre area trajectories in hospitalisations due to ambulatory care sensitive conditions (ACSCs). Methods ACSCs, a proxy for PHC quality, comprises conditions in which hospitalisation could be avoided by timely care. We obtained ACSCs of the total Finnish population aged ≥20 for the years 1996–2013 from the Finnish Hospital Discharge Register, and divided them into subgroups of acute, chronic and vaccine-preventable causes, and calculated annual age-standardised ACSC rates by gender in health centre areas. Using these rates, we conducted trajectory analyses for identifying health centre area clusters using group-based trajectory modelling. Further, we applied area-level factors to describe the distribution of health centre areas on these trajectories. Results Three trajectories – and thus separate clusters of health centre areas – emerged with different levels and trends of ACSC rates. During the study period, chronic ACSC rates decreased (40–63%) within each of the clusters, acute ACSC rates remained stable and vaccine-preventable ACSC rates increased (1–41%). While disparities in rate differences in chronic ACSC rates between trajectories narrowed, in the two other ACSC subgroups they increased. Disparities in standardised rate ratios increased in vaccine-preventable and acute ACSC rates between northern cluster and the two other clusters. Compared to the south-western cluster, 13–16% of health centre areas, in rural northern cluster, had 47–92% higher ACSC rates – but also the highest level of morbidity, most limitations on activities of daily living and highest PHC inpatient ward usage as well as the lowest education levels and private health and dental care usage. Conclusions We identified three differing trajectories of time trends for ACSC rates, suggesting that the quality of care, particularly in northern Finland health centre areas, may have lagged behind the general improvements. This calls for further investments to strengthen rural area PHC.
  • Konki, Mikko; Malonzo, Maia; Karlsson, Ida K; Lindgren, Noora; Ghimire, Bishwa; Smolander, Johannes; Scheinin, Noora M; Ollikainen, Miina; Laiho, Asta; Elo, Laura L; Lönnberg, Tapio; Röyttä, Matias; Pedersen, Nancy L; Kaprio, Jaakko; Lähdesmäki, Harri; Rinne, Juha O.; Lund, Riikka J (BioMed Central, 2019)
    Abstract Background Alzheimer’s disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Results Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer’s disease and becomes differentially methylated after disease onset. Conclusions DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer’s disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.
  • Nauck, Michael A; McGuire, Darren K; Pieper, Karen S; Lokhnygina, Yuliya; Strandberg, Timo E; Riefflin, Axel; Delibasi, Tuncay; Peterson, Eric D; White, Harvey D; Scott, Russell; Holman, Rury R (BioMed Central, 2019)
    Abstract Background To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Methods TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. Results During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81–1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83–1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83–1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. Conclusions In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration no. NCT00790205
  • Raisamo, Susanna; Toikka, Arho; Selin, Jani; Heiskanen, Maria (BioMed Central, 2019)
    Abstract Background Electronic gambling machines (EGMs) are considered a risky form of gambling. Internationally, studies have reported that the density of EGMs tends to be higher in socioeconomically disadvantaged areas than in more advantaged ones. We examined whether this holds true in the Finnish context where a decentralised system of EGMs guarantees wide accessibility to this form of gambling. More precisely, we investigated the association between the density of EGMs and area-level socio-economic status (SES). Methods The primary measure was the EGM density, referring to the number of EGMs per 1000 adults. The area-level SES was defined on the basis of the median income of inhabitants, the proportion of unemployment in the area and educational attainment (% of those beyond primary education). Three additional area characteristics were used as control variables in the analyses; the overall population density, economic activity (the number of jobs in the area per employed inhabitant), and the mean age of the inhabitants. Analyses were based on linear regression. Results The EGM density was 3.68 per 1000 inhabitants (SD = 2.63). A lower area-level SES was correlated with a higher EGM density. In further analyses, this effect was mostly explained by the income of the inhabitants. Of the control variables, the population density had no detectable effect on the EGM density while areas with a higher mean age of the inhabitants, as well a higher density of jobs, had more EGMs. Conclusions EGMs are unequally located in Finland, with more EGMs located in socio-economically less advantaged areas. The higher machine density in areas of social disadvantage is not in line with the aim of the Finnish gambling policy, which is to prevent and reduce harm caused by gambling. Changes in policy are required, especially with regard to the decisions on the placement of EGMs. This should not be made solely by gaming operators and/or from fiscal perspectives.
  • Conenna, Irene; López-Baucells, Adrià; Rocha, Ricardo; Ripperger, Simon; Cabeza, Mar (BioMed Central, 2019)
    Abstract Background Bats are among the most successful desert mammals. Yet, our understanding of their spatio-temporal dynamics in habitat use associated with the seasonal oscillation of resources is still limited. In this study, we have employed state-of-the-art lightweight GPS loggers to track the yellow-winged bat Lavia frons in a desert in northern Kenya to investigate how seasonality in a desert affects the a) spatial and b) temporal dimensions of movements in a low-mobility bat. Methods Bats were tracked during April–May 2017 (rainy season) and January–February 2018 (dry season) using 1-g GPS loggers. Spatial and temporal dimensions of movements were quantified, respectively, as the home range and nightly activity patterns. We tested for differences between seasons to assess responses to seasonal drought. In addition, we quantified home range overlap between neighbouring individuals to investigate whether tracking data will be in accordance with previous reports on territoriality and social monogamy in L. frons. Results We obtained data for 22 bats, 13 during the rainy and 9 during the dry season. Home ranges averaged 5.46 ± 11.04 ha and bats travelled a minimum distance of 99.69 ± 123.42 m/hour. During the dry season, home ranges were larger than in the rainy season, and bats exhibited high activity during most of the night. No apparent association with free water was identified during the dry season. The observed spatial organisation of home ranges supports previous observations that L. frons partitions the space into territories throughout the year. Conclusions Our results suggest that, in low-mobility bats, a potential way to cope with seasonally harsh conditions and resource scarcity in deserts is to cover larger areas and increase time active, suggesting lower cost-efficiency of the foraging activity. Climate change may pose additional pressures on L. frons and other low-mobility species by further reducing food abundances.
  • Cooper, Rory L; Lloyd, Victoria J; Di-Poï, Nicolas; Fletcher, Alexander G; Barrett, Paul M; Fraser, Gareth J (BioMed Central, 2019)
    Abstract Background Vertebrates possess a diverse range of integumentary epithelial appendages, including scales, feathers and hair. These structures share extensive early developmental homology, as they mostly originate from a conserved anatomical placode. In the context of avian epithelial appendages, feathers and scutate scales are known to develop from an anatomical placode. However, our understanding of avian reticulate (footpad) scale development remains unclear. Results Here, we demonstrate that reticulate scales develop from restricted circular domains of thickened epithelium, with localised conserved gene expression in both the epithelium and underlying mesenchyme. These domains constitute either anatomical placodes, or circular initiatory fields (comparable to the avian feather tract). Subsequent patterning of reticulate scales is consistent with reaction–diffusion (RD) simulation, whereby this primary domain subdivides into smaller secondary units, which produce individual scales. In contrast, the footpad scales of a squamate model (the bearded dragon, Pogona vitticeps) develop synchronously across the ventral footpad surface. Conclusions Widely conserved gene signalling underlies the initial development of avian reticulate scales. However, their subsequent patterning is distinct from the footpad scale patterning of a squamate model, and the feather and scutate scale patterning of birds. Therefore, we suggest reticulate scales are a comparatively derived epithelial appendage, patterned through a modified RD system.
  • Katayama, Shintaro; Skoog, Tiina; Söderhäll, Cilla; Einarsdottir, Elisabet; Krjutškov, Kaarel; Kere, Juha (BioMed Central, 2019)
    Abstract Background Standard RNAseq methods using bulk RNA and recent single-cell RNAseq methods use DNA barcodes to identify samples and cells, and the barcoded cDNAs are pooled into a library pool before high throughput sequencing. In cases of single-cell and low-input RNAseq methods, the library is further amplified by PCR after the pooling. Preparation of hundreds or more samples for a large study often requires multiple library pools. However, sometimes correlation between expression profiles among the libraries is low and batch effect biases make integration of data between library pools difficult. Results We investigated 166 technical replicates in 14 RNAseq libraries made using the STRT method. The patterns of the library biases differed by genes, and uneven library yields were associated with library biases. The former bias was corrected using the NBGLM-LBC algorithm, which we present in the current study. The latter bias could not be corrected directly, but could be solved by omitting libraries with particularly low yields. A simulation experiment suggested that the library bias correction using NBGLM-LBC requires a consistent sample layout. The NBGLM-LBC correction method was applied to an expression profile for a cohort study of childhood acute respiratory illness, and the library biases were resolved. Conclusions The R source code for the library bias correction named NBGLM-LBC is available at and . This method is applicable to correct the library biases in various studies that use highly multiplexed sequencing-based profiling methods with a consistent sample layout with samples to be compared (e.g., “cases” and “controls”) equally distributed in each library.
  • Huhtala, Tuulia; Poutiainen, Pekka; Rytkönen, Jussi; Lehtimäki, Kimmo; Parkkari, Teija; Kasanen, Iiris; Airaksinen, Anu J; Koivula, Teija; Sweeney, Patrick; Kontkanen, Outi; Wityak, John; Dominiquez, Celia; Park, Larry C (Springer International Publishing, 2019)
    Abstract Purpose Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington’s disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD. Methods We longitudinally characterized in vivo [18F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12 month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [3H] fallypride autoradiography at 12 months of age. Results We implemented an improved synthesis method for [18F] fallypride to yield high molar activity (MA, 298–360 GBq/μmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BPND) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to WT littermates. No mass effect was observed when the MA of [18F] fallypride was > 100 GBq/μmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [3H] fallypride autoradiography. Conclusions We observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12 months of age. These results are in line with clinical findings in HD patients, suggesting [18F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.
  • Ellilä, Simo; Bromann, Paul; Nyyssönen, Mari; Itävaara, Merja; Koivula, Anu; Paulin, Lars; Kruus, Kristiina (Springer Berlin Heidelberg, 2019)
    Abstract Xylanases are in important class of industrial enzymes that are essential for the complete hydrolysis of lignocellulosic biomass into fermentable sugars. In the present study, we report the cloning of novel xylanases with interesting properties from compost metagenomics libraries. Controlled composting of lignocellulosic materials was used to enrich the microbial population in lignocellulolytic organisms. DNA extracted from the compost samples was used to construct metagenomics libraries, which were screened for xylanase activity. In total, 40 clones exhibiting xylanase activity were identified and the thermostability of the discovered xylanases was assayed directly from the library clones. Five genes, including one belonging to the more rare family GH8, were selected for subcloning and the enzymes were expressed in recombinant form in E. coli. Preliminary characterization of the metagenome-derived xylanases revealed interesting properties of the novel enzymes, such as high thermostability and specific activity, and differences in hydrolysis profiles. One enzyme was found to perform better than a standard Trichoderma reesei xylanase in the hydrolysis of lignocellulose at elevated temperatures.
  • Holm, Matilda; Joenväärä, Sakari; Saraswat, Mayank; Tohmola, Tiialotta; Ristimäki, Ari; Renkonen, Risto; Haglund, Caj (BioMed Central, 2019)
    Abstract Background Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence is expected to increase to over 2.2 million new cases in 2030. Stage II CRC is classified as localized disease, while stage III CRC has spread to regional lymph nodes. The 5-year survival rate is over 80% for patients with stage II CRC, but less than 60% for patients with stage III CRC. Proteins, especially plasma proteins that are detectable in easily obtained blood samples, that differ between stage II and III CRC could be useful for predicting and monitoring disease progression. CRC displays differences depending on primary tumor location (right colon, left colon, or rectum), and how plasma protein expression changes during CRC progression from stage II to III depending on primary tumor location is not well-characterized. Methods In this study, we have used Ultra Performance Liquid Chromatography-Ultra Definition Mass Spectrometry (UPLC-UDMSE)-based proteomics to analyze plasma samples from 83 patients with stage II or III CRC, followed by statistical and pathway analysis (data are available via ProteomeXchange). The patients were divided into groups according to tumor stage (II or III) and changes in plasma protein expression between stage II and III (localized and regional disease) samples were studied both regardless of primary tumor location and also within each primary tumor location (right colon, left colon, rectum). Results We discovered differences in plasma protein expression within all groups analyzed and identified proteins whose levels changed in one, two, or all three primary tumor locations between stage II and III CRC. Proteins were identified that could separate the groups compared and pathway analysis by IPA discovered altered pathways involved in lipid metabolism and inflammation, among others. Conclusions Plasma protein expression changes significantly as CRC progresses from stage II to III. While the levels of certain plasma proteins changed during cancer progression in only one or two primary tumor locations, the levels of 13 proteins changed in all primary tumor locations and are therefore common to CRC progression.
  • Häkkilä, Matti; Savilaakso, Sini; Johansson, Anna; Sandgren, Terhi; Uusitalo, Anne; Mönkkönen, Mikko; Puttonen, Pasi (BioMed Central, 2019)
    Abstract Background Forest harvesting is the main driver of habitat degradation and biodiversity loss in forests of the boreal zone. To mitigate harmful effects, small-scale habitats with high biodiversity values have been protected within production forests. These include woodland key habitats, and other small-scale habitat patches protected by voluntary conservation action. This article describes a protocol for a systematic review to synthesize the value of small habitat patches left within production landscapes for biodiversity. The topic for this systematic review arose from a discussion with the Finnish forestry sector and was further defined in a stakeholder workshop. Research question: Do small protected habitat patches within production forests provide value for biodiversity conservation in boreal forests? Animal, plant and fungal diversities are addressed as well as the amount of deadwood within the habitat patches as proxy indicators for biodiversity. Methods The literature, both peer-reviewed and grey, will be searched from bibliographical databases, organizational websites and internet search engines in English, Finnish, Swedish and Russian. Article screening will be done at two stages (title/abstract and full-text). The validity of the studies included will be evaluated against validity criteria and studies will be categorized based on their risk of bias. To describe the findings a narrative synthesis will be conducted. If there is enough quantitative data retrieved from the studies, a meta-analysis will be conducted.
  • Doig, Christopher J; Page, Stacey A; McKee, Jessica L; Moore, Ernest E; Abu-Zidan, Fikri M; Carroll, Rosemary; Marshall, John C; Faris, Peter D; Tolonen, Matti; Catena, Fausto; Cocolini, Federico; Sartelli, Massimo; Ansaloni, Luca; Minor, Sam F; Peirera, Bruno M; Diaz, Jose J; Kirkpatrick, Andrew W (BioMed Central, 2019)
    Abstract Background Severe complicated intra-abdominal sepsis (SCIAS) has high mortality, thought due in part to progressive bio-mediator generation, systemic inflammation, and multiple organ failure. Treatment includes early antibiotics and operative source control. At surgery, open abdomen management with negative-peritoneal-pressure therapy (NPPT) has been hypothesized to mitigate MOF and death, although clinical equipoise for this operative approach exists. The Closed or Open after Laparotomy (COOL) study ( ) will prospectively randomize eligible patients intra-operatively to formal abdominal closure or OA with NPTT. We review the ethical basis for conducting research in SCIAS. Main body Research in critically ill incapacitated patients is important to advance care. Conducting research among SCIAS is complicated due to the severity of illness including delirium, need for emergent interventions, diagnostic criteria confirmed only at laparotomy, and obtundation from anaesthesia. In other circumstances involving critically ill patients, clinical experts have worked closely with ethicists to apply principles that balance the rights of patients whilst simultaneously permitting inclusion in research. In Canada, the Tri-Council Policy Statement-2 (TCPS-2) describes six criteria that permit study enrollment and randomization in such situations: (a) serious threat to the prospective participant requires immediate intervention; (b) either no standard efficacious care exists or the research offers realistic possibility of direct benefit; (c) risks are not greater than that involved in standard care or are clearly justified by prospect for direct benefits; (d) prospective participant is unconscious or lacks capacity to understand the complexities of the research; (e) third-party authorization cannot be secured in sufficient time; and (f) no relevant prior directives are known to exist that preclude participation. TCPS-2 criteria are in principle not dissimilar to other (inter)national criteria. The COOL study will use waiver of consent to initiate enrollment and randomization, followed by surrogate or proxy consent, and finally delayed informed consent in subjects that survive and regain capacity. Conclusions A delayed consent mechanism is a practical and ethical solution to challenges in research in SCIAS. The ultimate goal of consent is to balance respect for patient participants and to permit participation in new trials with a reasonable opportunity for improved outcome and minimal risk of harm.
  • Sumasgutner, Petra; Terraube, Julien; Coulon, Aurélie; Villers, Alexandre; Chakarov, Nayden; Kruckenhauser, Luise; Korpimäki, Erkki (BioMed Central, 2019)
    Abstract Background Selecting high-quality habitat and the optimal time to reproduce can increase individual fitness and is a strong evolutionary factor shaping animal populations. However, few studies have investigated the interplay between land cover heterogeneity, limitation in food resources, individual quality and spatial variation in fitness parameters. Here, we explore how individuals of different quality respond to possible mismatches between a cue for prey availability (land cover heterogeneity) and the actual fluctuating prey abundance. Results We analyse timing of breeding and reproductive success in a migratory population of Eurasian kestrels (Falco tinnunculus) breeding in nest-boxes, over a full three-year abundance cycle of main prey (voles), and consider several components of individual quality, including body condition, blood parasite infection, and genetic diversity (n = 448 adults) that act on different time scales. Older individuals, and kestrel parents in higher body condition started egg-laying earlier than younger birds and those in lower body condition. Additionally, egg-laying was initiated earlier during the increase and decrease phases (2011 and 2012) than during the low phase of the vole cycle (2013). Nestling survival (ratio of eggs that fledged successfully) was higher in early nests and in heterogeneous landscapes (i.e., mosaic of different habitat types), which was evident during the increase and decrease phases of the vole cycle, but not during the low vole year. Conclusions We found a strong positive effect of landscape heterogeneity on nestling survival, but only when voles were relatively abundant, whereas a difference in the timing of breeding related to territory landscape heterogeneity was not evident. Therefore, landscape heterogeneity appeared as the main driver of high reproductive performance under favourable food conditions. Our results show that landscape homogenization linked to agricultural intensification disrupts the expected positive effect of vole abundance on reproductive success of kestrels.

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