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Uusimmat julkaisut

  • Zhang, Yuezhou; Xhaard, Henri; Ghemtio, Leo (Springer International Publishing, 2018)
    Abstract Betulin derivatives have been proven effective in vitro against Leishmania donovani amastigotes, which cause visceral leishmaniasis. Identifying the molecular targets and molecular mechanisms underlying their action is a currently an unmet challenge. In the present study, we tackle this problem using computational methods to establish properties essential for activity as well as to screen betulin derivatives against potential targets. Recursive partitioning classification methods were explored to develop predictive models for 58 diverse betulin derivatives inhibitors of L. donovani amastigotes. The established models were validated on a testing set, showing excellent performance. Molecular fingerprints FCFP_6 and ALogP were extracted as the physicochemical properties most extensively involved in separating inhibitors from non-inhibitors. The potential targets of betulin derivatives inhibitors were predicted by in silico target fishing using structure-based pharmacophore searching and compound-pharmacophore-target-pathway network analysis, first on PDB and then among L. donovani homologs using a PSI-BLAST search. The essential identified proteins are all related to protein kinase family. Previous research already suggested members of the cyclin-dependent kinase family and MAP kinases as Leishmania potential drug targets. The PSI-BLAST search suggests two L. donovani proteins to be especially attractive as putative betulin target, heat shock protein 83 and membrane transporter D1.
  • Trotta, Luca; Norberg, Anna; Taskinen, Mervi; Béziat, Vivien; Degerman, Sofie; Wartiovaara-Kautto, Ulla; Välimaa, Hannamari; Jahnukainen, Kirsi; Casanova, Jean-Laurent; Seppänen, Mikko; Saarela, Janna; Koskenvuo, Minna; Martelius, Timi (BioMed Central, 2018)
    Abstract Background The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs. Methods Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions. Results In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients. Conclusions Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
  • Haapanen, M. J; Perälä, M. M; Salonen, M. K; Kajantie, E.; Simonen, M.; Pohjolainen, P.; Pesonen, A. K; Räikkönen, K.; Eriksson, J. G; von Bonsdorff, M. B (BioMed Central, 2018)
    Abstract Background Evidence suggests that early life stress (ELS) may extend its effect into adulthood and predispose an individual to adverse health outcomes. We investigated whether wartime parental separation, an indicator of severe ELS, would be associated with frailty in old age. Methods Of the 972 participants belonging to the present sub-study of the Helsinki Birth Cohort Study, 117 (12.0%) had been evacuated abroad unaccompanied by their parents in childhood during World War II. Frailty was assessed at a mean age of 71 years according to Fried’s criteria. Results Thirteen frail men (4 separated and 9 non-separated) and 20 frail women (2 separated and 18 non-separated) were identified. Compared to the non-separated men, men who had been separated had an increased relative risk ratio (RRR) of frailty (age-adjusted RRR 3.93, 95% CI 1.02, 15.11) that persisted after adjusting for several confounders. No associations were observed among women (RRR 0.62; 95% CI 0.13, 2.94). Conclusions These preliminary results suggest that ELS might extend its effects not just into adulthood but also into old age, and secondly, that men may be more vulnerable to the long-term effects of ELS.
  • Mäenpää, Hanna; Mäkinen, Simo; Kilamo, Terhi; Mikkonen, Tommi; Männistö, Tomi; Ritala, Paavo (Springer London, 2018)
    Abstract This article examines organization and governance of commercially influenced Open Source Software development communities by presenting a multiple-case study of six contemporary, hybrid OSS projects. The findings provide in-depth understanding on how to design the participatory nature of the software development process, while understanding the factors that influence the delicate balance of openness, motivations, and governance. The results lay ground for further research on how to organize and manage developer communities where needs of the stakeholders are competing, yet complementary.
  • Arora, Geeti P; Almgren, Peter; Brøns, Charlotte; Thaman, Richa G; Vaag, Allan A; Groop, Leif; Prasad, Rashmi B (BioMed Central, 2018)
    Abstract Background Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Methods Five thousand one hundred pregnant women of gestational age 24–28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. Results In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. Conclusions GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.
  • Hakkarainen, Heidi; Huopio, Hanna; Cederberg, Henna; Voutilainen, Raimo; Heinonen, Seppo (BioMed Central, 2018)
    Abstract Background Whether the delivery of a large-for-gestational-age (LGA) infant predicts future maternal metabolic syndrome (MetS) is not known. To this aim, we investigated the incidence of MetS and its components in women with or without a history of gestational diabetes mellitus (GDM) with a view to the birth weight of the offspring. Methods Eight hundred seventy six women treated for their pregnancies in Kuopio University Hospital in 1989–2009 underwent a follow-up study (mean follow-up time 7.3 (SD 5.1) years), of whom 489 women with GDM and 385 normoglycemic controls. The women were stratified into two groups according to the newborn’s birth weight: 10-90th percentile (appropriate-for-gestational-age; AGA) (n = 662) and > 90th percentile (LGA) (n = 116). MetS and its components were evaluated in the follow-up study according to the International Diabetes Federation criteria. Results LGA vs. AGA delivery was associated with a higher incidence of MetS at follow-up in women with a background of GDM (54.4% vs. 43.6%), but not in women without GDM. Conclusion An LGA delivery in women with GDM is associated with a higher risk of future MetS and this group is optimal to study preventive measures for MetS. In contrast, an LGA delivery after a normoglycemic pregnancy was not associated with an increased future maternal MetS risk.
  • Salminen, Antti; Jambor, Ivan; Merisaari, Harri; Ettala, Otto; Virtanen, Johanna; Koskinen, Ilmari; Veskimae, Erik; Sairanen, Jukka; Taimen, Pekka; Kemppainen, Jukka; Minn, Heikki; Boström, Peter J (BioMed Central, 2018)
    Abstract Background To evaluate the accuracy of 11C-acetate Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in bladder cancer (BC) staging and monitoring response to neoadjuvant chemotherapy (NAC). Methods Eighteen patients were prospectively enrolled. Fifteen treatment naive patients underwent 11C-acetate PET/MRI before transurethral resection of bladder tumor (TUR-BT) for primary tumor evaluation. Five patients with muscle invasive BC were imaged after NAC and prior to radical cystectomy (RC) with extended pelvic lymph node dissection (ePLND) for NAC treatment response evaluation. Two patients were part of both cohorts. 11C-acetate PET/MRI findings were correlated with histopathology. Accuracy for lymph node detection was evaluated on patient and the ePLND template (10 regions) levels. Results The sensitivity, specificity and accuracy of 11C-acetate PET/MRI for the detection of muscle invasive BC was 1.00, 0.69 and 0.73 while the area under the receiver operating characteristic curve (95% confidence interval) was 0.85 (0.55–1.0), respectively. All five NAC patients underwent chemotherapy as planned and 11C-acetate PET/MRI correctly staged three patients, overstaged one and understaged one patient compared with RC and ePLND findings. A total of 175 lymph node were removed, median of 35 (range, 27–43) per patient in five patients who had RC and ePLND while 12 (7%) harboured metastases. Sensitivity, specificity, accuracy and AUC for N-staging were 0.20, 0.96, 0.80 and 0.58 on the ePLND template (10 regions) level. Conclusions 11C-acetate PET/MRI is feasible for staging of BC although sensitivity for the detection of nodal metastases is low. Monitoring response to NAC shows promise and warrants evaluation in larger studies. Trial registration ClinicalTrials.gov Identifier: NCT01918592 , registered August 8 2013
  • Johnson, Katherine; Bertoli, Marta; Phillips, Lauren; Töpf, Ana; Van den Bergh, Peter; Vissing, John; Witting, Nanna; Nafissi, Shahriar; Jamal-Omidi, Shirin; Łusakowska, Anna; Kostera-Pruszczyk, Anna; Potulska-Chromik, Anna; Deconinck, Nicolas; Wallgren-Pettersson, Carina; Strang-Karlsson, Sonja; Colomer, Jaume; Claeys, Kristl G; De Ridder, Willem; Baets, Jonathan; von der Hagen, Maja; Fernández-Torrón, Roberto; Zulaica Ijurco, Miren; Espinal Valencia, Juan B; Hahn, Andreas; Durmus, Hacer; Willis, Tracey; Xu, Liwen; Valkanas, Elise; Mullen, Thomas E; Lek, Monkol; MacArthur, Daniel G; Straub, Volker (BioMed Central, 2018)
    Abstract Background Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. Methods Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. Results Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. Conclusions Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.
  • Törmälehto, Soili; Mononen, Mika E; Aarnio, Emma; Arokoski, Jari P A; Korhonen, Rami K; Martikainen, Janne (BioMed Central, 2018)
    Abstract Background The purpose was to quantify the decrement in health utility (referred as disutility) associated with knee osteoarthritis (OA) and different symptomatic and radiographic uni- and bilateral definitions of knee OA in a repeated measures design of persons with knee OA or at increased risk of developing knee OA. Methods Data were obtained from the Osteoarthritis Initiative database. SF-12 health-related quality of life was converted into SF-6D utilities, and were then handled as the health utility loss by subtracting 1.000 from the utility score, yielding a negative value (disutility). Symptomatic OA was defined by radiographic findings (Kellgren-Lawrence, K-L, grade ≥ 2) and frequent knee pain in the same knee. Radiographic OA was defined by five different definitions (K-L ≥ 2 unilaterally / bilaterally, or the highest / mean / combination of K-L grades of both knees). Repeated measures generalized estimating equation (GEE) models were used to investigate disutility in relation to these different definitions. Results Utility decreased with worsening of symptomatic or radiographic status of knee OA. The participants with bilateral and unilateral symptomatic knee OA had 0.03 (p < 0.001) and 0.02 (p < 0.001) points lower utility scores, respectively, compared with the reference group. The radiographic K-L grade 4 defined as the mean or the highest grade of both knees was related to a decrease of 0.04 (p < 0.001) and 0.03 (p < 0.001) points in utility scores, respectively, compared to the reference group. Conclusions Knee OA is associated with diminished health-related quality of life. Health utility can be quantified in relation to both symptomatic and radiographic uni- and bilateral definitions of knee OA, and these definitions are associated with differing disutilities. The performance of symptomatic definition was better, indicating that pain experience is an important factor in knee OA related quality of life.
  • Medlar, Alan; Holm, Liisa (BioMed Central, 2018)
    Abstract Background Protein homology search is an important, yet time-consuming, step in everything from protein annotation to metagenomics. Its application, however, has become increasingly challenging, due to the exponential growth of protein databases. In order to perform homology search at the required scale, many methods have been proposed as alternatives to BLAST that make an explicit trade-off between sensitivity and speed. One such method, SANSparallel, uses a parallel implementation of the suffix array neighbourhood search (SANS) technique to achieve high speed and provides several modes to allow for greater sensitivity at the expense of performance. Results We present a new approach called asymmetric SANS together with scored seeds and an alternative suffix array ordering scheme called optimal substitution ordering. These techniques dramatically improve both the sensitivity and speed of the SANS approach. Our implementation, TOPAZ, is one of the top performing methods in terms of speed, sensitivity and scalability. In our benchmark, searching UniProtKB for homologous proteins to the Dickeya solani proteome, TOPAZ took less than 3 minutes to achieve a sensitivity of 0.84 compared to BLAST. Conclusions Despite the trade-off homology search methods have to make between sensitivity and speed, TOPAZ stands out as one of the most sensitive and highest performance methods currently available.
  • Urpilainen, Elina; Marttila, Mikko; Hautakoski, Ari; Arffman, Martti; Sund, Reijo; Ilanne-Parikka, Pirjo; Arima, Reetta; Kangaskokko, Jenni; Puistola, Ulla; Hinkula, Marianne; Läärä, Esa (BioMed Central, 2018)
    Abstract Background Ovarian cancer is one of the most lethal cancers and women with type 2 diabetes (T2D) have even poorer survival from it. We assessed the prognosis of ovarian cancer in women with type 2 diabetes treated with metformin, other forms of antidiabetic medication, or statins. Methods Study cohort consisted of women with T2D diagnosed with ovarian cancer in Finland 1998–2011. They were identified from a nationwide diabetes database (FinDM), being linked to several national registers. Patients were grouped according to their medication in the three years preceding ovarian cancer diagnosis. The Aalen–Johansen estimator was used to describe cumulative mortality from ovarian cancer and from other causes in different medication groups. Mortality rates were analysed by Cox models, and adjusted hazard ratios (HR) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of medication. Main outcome measures were death from ovarian cancer and death from other causes. Results During the accrual period 421 newly diagnosed ovarian cancers were identified in the FinDM database. No evidence was found for any differences in mortality from ovarian cancer or other causes between different antidiabetic medication groups. Pre-diagnostic use of statins was observed to be associated with decreased mortality from ovarian cancer compared with no such use (HR 0.72, 95% CI 0.56–0.93). Conclusions Our findings are inconclusive as regards the association between metformin and ovarian cancer survival. However, some evidence was found for improved prognosis of ovarian cancer with pre-diagnostic statin use, requiring cautious interpretation, though.
  • Lääveri, Tinja; Vlot, Jessica A; van Dam, Alje P; Häkkinen, Hanni K; Sonder, Gerard J B; Visser, Leo G; Kantele, Anu (BioMed Central, 2018)
    Abstract Background One third of travellers to low- and middle-income regions of the tropics and subtropics become colonized by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). The risk varies by destination and, for each traveller, may be substantially further increased by travellers’ diarrhoea (TD) and antibiotic use. Despite the risk of TD in Africa, ESBL-PE acquisition rates in all studies are lower there than in Asia. Africa has become increasingly popular as a destination for international travellers, yet minimal data are available from the continent’s subregions and countries. Methods We analysed subregion- and country-specific data on carriage and risk factors for ESBL-PE colonization pooled from three prospective studies conducted between 2009 and 2013 among Finnish and Dutch travellers. The data were subjected to multivariable analysis of risk factors. In addition, we compared our data to two recent large investigations reporting data by subregion and country. Results Our joint analysis comprised data on 396 travellers. The ESBL-PE colonization rate was highest in Northern Africa, followed by Middle and Eastern Africa, and lowest in Southern and Western Africa. Of individual countries with more than 15 visitors, the highest rates were seen for Egypt (12/17; 70.6%), Ghana (6/23; 26.1%), and Tanzania (14/81; 17.3%); the rates among travellers to Egypt were comparable to those reported in South and Southeast Asia. In a pooled multivariable analysis, travel destination, age, overnight hospitalisation abroad, TD, and use of fluoroquinolones were independently associated with increased ESBL-PE colonization rates. Conlusions Even in areas with relatively low risk of colonization, antimicrobials clearly predispose to colonization with ESBL-PE. Travellers to Africa should be cautioned against unnecessary use of antibiotics.
  • Suarez, Anna; Lahti, Jari; Czamara, Darina; Lahti-Pulkkinen, Marius; Girchenko, Polina; Andersson, Sture; Strandberg, Timo E; Reynolds, Rebecca M; Kajantie, Eero; Binder, Elisabeth B; Raikkonen, Katri (BioMed Central, 2018)
    Abstract Background Molecular aging biomarkers, such as epigenetic age predictors, predict risk factors of premature aging, and morbidity/mortality more accurately than chronological age in middle-aged and elderly populations. Yet, it remains elusive if such biomarkers are associated with aging-related outcomes earlier in life when individuals begin to diverge in aging trajectories. We tested if the Horvath epigenetic age predictor is associated with pubertal, neuroendocrine, psychiatric, and cognitive aging-related outcomes in a sample of 239 adolescents, 11.0–13.2 years-old. Results Each year increase in epigenetic age acceleration (AA) was associated with 0.06 SD units higher weight-for-age, 0.08 SD units taller height-for-age, -0.09 SD units less missed from the expected adult height, 13 and 16% higher odds, respectively, for each stage increase in breast/genitals development on the Tanner Staging Questionnaire and pubertal stage on the Pubertal Development Scale, 4.2% higher salivary cortisol upon awakening, and 18 to 34% higher odds for internalizing and thought problems on the Child Behavior Checklist (p values <  0.045). AA was not significantly associated with cognition. Conclusions Our findings suggest that already in adolescence, AA is associated with physiological age acceleration, which may index risk of earlier aging. AA may identify individuals for preventive interventions decades before aging-related diseases become manifest.
  • Pehkonen, Henna; Lento, Mira; von Nandelstadh, Pernilla; Filippou, Artemis; Grénman, Reidar; Lehti, Kaisa; Monni, Outi (BioMed Central, 2018)
    Abstract Background PPFIA1 is located at the 11q13 region commonly amplified in cancer. The protein liprin-α1 encoded by PPF1A1 contributes to the adhesive and invasive structures of cytoskeletal elements and is located at the invadosomes in cancer cells. However, the precise mechanism of liprin-α1 function in cancer progression has remained elusive. Methods Invasion regulating activity of liprin-α1 was examined by analyzing the functions of squamous cell carcinoma of head and neck (HNSCC) cell lines in three-dimensional collagen I after RNAi mediated gene knockdown. Transcriptome profiling and Gene Set Enrichment Analysis from HNSCC and breast cancer cells were used to identify expression changes relevant to specific cellular localizations, biological processes and signaling pathways after PPFIA1 knockdown. The significance of the results was assessed by relevant statistical methods (Wald and Benjamini-Hochberg). Localization of proteins associated to liprin-α1 was studied by immunofluorescence in 2D and 3D conditions. The association of PPFIA1 amplification to HNSCC patient survival was explored using The Cancer Genome Atlas data. Results In this study, we show that liprin-α1 regulates biological processes related to membrane microdomains in breast carcinoma, as well as protein trafficking, cell-cell and cell-substrate contacts in HNSCC cell lines cultured in three-dimensional matrix. Importantly, we show that in all these cancer cells liprin-α1 knockdown leads to the upregulation of transmembrane protein CD82, which is a suppressor of metastasis in several solid tumors. Conclusions Our results provide novel information regarding the function of liprin-α1 in biological processes essential in cancer progression. The results reveal liprin-α1 as a novel regulator of CD82, linking liprin-α1 to the cancer cell invasion and metastasis pathways.
  • Koponen, Ismo T; Nousiainen, Maija (Springer International Publishing, 2018)
    Abstract Concept maps, which are network-like visualisations of the inter-linkages between concepts, are used in teaching and learning as representations of students’ understanding of conceptual knowledge and its relational structure. In science education, research on the uses of concept maps has focused much attention on finding methods to identify key concepts that are of the most importance either in supporting or being supported by other concepts in the network. Here we propose a method based on network analysis to examine students’ representations of the relational structure of physics concepts in the form of concept maps. We suggest how the key concepts and their epistemic support can be identified through focusing on the pathways along which the information is passed from one node to another. Towards this end, concept maps are analysed as directed and weighted networks, where nodes are concepts and links represent different types of connections between concepts, and where each link is assumed to provide epistemic support to the node it is connected to. The notion of key concept can then be operationalised through the directed flow of information from one node to another in terms of communicability between the nodes, separately for out-going and in-coming weighted links. Here we analyse a collated concept network based on a sample of 12 original concept maps constructed by university students. We show that communicability is a simple and reliable way to identify the key concepts and examine their epistemic justification within the collated network. The communicabilities of the key nodes in the collated network are compared with communicabilities averaged over the set of 12 individual concept maps. The comparison shows the collated network contains an extensive set of key concepts with good epistemic support. Every individual networks contain a sub-set of these key concepts but with a limited overlap of the sub-sets with other individual networks. The epistemically well substantiated knowledge is thus sparsely distributed over the 12 individual networks.
  • Hagihara, Hideo; Fujita, Masayo; Umemori, Juzoh; Hashimoto, Makoto; Miyakawa, Tsuyoshi (BioMed Central, 2018)
    Abstract Aim Maturation abnormalities of the brain cells have been suggested in several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, and epilepsy. In this study, we examined the expression patterns of neuronal maturation markers in the brain of a mouse model of dementia with Lewy body-linked mutant β-synuclein (βS), especially in the hippocampus, to explore whether such brain abnormalities occur in neurodegenerative disorders as well. Methods Quantitative PCR (qPCR) and immunohistochemical analyses were performed using the hippocampus of 14-month-old P123H βS transgenic (Tg) mice to evaluate the expression of molecular markers for maturation of dentate granule cells. Results Based on qPCR results, expression of Tdo2 and Dsp (markers of mature granule cells) was decreased and that of Drd1a (a marker of immature granule cells) was increased in the hippocampus of P123H βS Tg mice compared to that in wild-type controls. Immunohistochemical analysis revealed decreased expression of mature granule cell markers Calb1 and Gria1, along with increased expression of the microglial marker Iba1, in the hippocampal dentate gyrus region of P123H βS Tg mice. P123H βS Tg mice exhibited immature-like neuronal molecular expression patterns and microgliosis in the hippocampus. Pseudo-immaturity of dentate granule cells, associated with neuroinflammation, may be a shared endophenotype in the brains of at least a subgroup of patients with neuropsychiatric disorders and neurodegenerative diseases.
  • Vepsäläinen, Henna; Nevalainen, Jaakko; Fogelholm, Mikael; Korkalo, Liisa; Roos, Eva; Ray, Carola; Erkkola, Maijaliisa (BioMed Central, 2018)
    Abstract Background Studies investigating dietary resemblance between parents and their children have gained mixed results, and the resemblance seems to vary across nutrients, foods, dietary-assessment tools used, and parent-child pairs. We investigated parent-child dietary resemblance using a novel approach in applying statistical analysis, which allowed the comparison of ‘whole-diet’ between parents and their children. Additionally, we sought to establish whether sociodemographic factors or family meals were associated with dietary resemblance and whether parent-child dietary resemblance was dependent on the parent providing food consumption data on behalf of the child (father or mother, “the respondent”). Methods The DAGIS study investigated health behaviors among Finnish preschoolers using a cross-sectional design. One parent filled in a food frequency questionnaire (FFQ) measuring the child’s food consumption outside preschool hours during the last week. In addition, we instructed both parents or legal guardians, should the child have two, to fill in a similar FFQ regarding their own food use. Parents also reported their educational level, the number of children living in the same household, and the number of family meals. As a measure of dietary resemblance between a parent and a child, we computed Spearman correlations ranging mostly from no resemblance (0) to complete resemblance (+ 1) between parent-child pairs over the ‘whole-diet’ (excluding preschool hours). These resemblance measures were further investigated using linear mixed models. Results We obtained 665 father-child and 798 mother-child resemblance measures. Mother-child resemblance was on average 0.57 and stronger than father-child resemblance (0.50, p < 0.0001), which was explained by a parent-respondent interaction: the diet of the child resembled more the diet of the parent who provided food consumption data for the child. In univariate models, father- and mother-reported number of family meals were positively associated with father-child and mother-child resemblances. Mother-reported number of family meals was positively associated with mother-child resemblance in a full model. Conclusions The diet of the child seems to resemble more the diet of the parent responsible for the reporting of food consumption. Studies should report who provided the food consumption data for the child and take this into account in analyses, since reporter-bias can influence the results.
  • Rimpelä, Jenni M; Pörsti, Ilkka H; Jula, Antti; Lehtimäki, Terho; Niiranen, Teemu J; Oikarinen, Lasse; Porthan, Kimmo; Tikkakoski, Antti; Virolainen, Juha; Kontula, Kimmo K; Hiltunen, Timo P (BioMed Central, 2018)
    Abstract Background Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. Methods To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10− 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. Results In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (β = − 4.8%, P = 9.6 × 10− 9 for systolic and β = − 4.3%, P = 2.2 × 10− 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10− 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (β = − 0.8%, P = 0.4 for systolic and β = − 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (β = − 7.6 g/m2, P = 0.02). Conclusions rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology.
  • Murtoniemi, Katja; Villa, Pia M; Matomäki, Jaakko; Keikkala, Elina; Vuorela, Piia; Hämäläinen, Esa; Kajantie, Eero; Pesonen, Anu-Katriina; Räikkönen, Katri; Taipale, Pekka; Stenman, Ulf-Håkan; Laivuori, Hannele (BioMed Central, 2018)
    Abstract Background The proportion of hyperglycosylated human chorionic gonadotropin (hCG-h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGβ, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort. Methods We studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models. Results We found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGβ higher in severe PE, while %hCG-h and serum PAPP-A were lower in non-severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late-onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity. Conclusions Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. Trial registration International Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered.
  • Rotejanaprasert, C.; Lawson, A.; Rossow, H.; Sane, J.; Huitu, O.; Henttonen, H.; Del Rio Vilas, V. J (BioMed Central, 2018)
    Abstract Background There are an increasing number of geo-coded information streams available which could improve public health surveillance accuracy and efficiency when properly integrated. Specifically, for zoonotic diseases, knowledge of spatial and temporal patterns of animal host distribution can be used to raise awareness of human risk and enhance early prediction accuracy of human incidence. Methods To this end, we develop a spatiotemporal joint modeling framework to integrate human case data and animal host data to offer a modeling alternative for combining multiple surveillance data streams in a novel way. A case study is provided of spatiotemporal modeling of human tularemia incidence and rodent population data from Finnish health care districts during years 1995–2012. Results Spatial and temporal information of rodent abundance was shown to be useful in predicting human cases and in improving tularemia risk estimates in 40 and 75% of health care districts, respectively. The human relative risk estimates’ standard deviation with rodent’s information incorporated are smaller than those from the model that has only human incidence. Conclusions These results support the integration of rodent population variables to reduce the uncertainty of tularemia risk estimates. However, more information on several covariates such as environmental, behavioral, and socio-economic factors can be investigated further to deeper understand the zoonotic relationship.

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