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CiteULike: Terkko's library

CiteULike: Terkko's library


Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties.


The American journal of pathology (14 November 2017)

Lipid accumulation is a key characteristic of advancing atherosclerotic lesions. Here we analyzed the ultrastructure of the accumulated lipids in endarterectomized human carotid atherosclerotic plaques using three-dimensional (3D) electron microscopy, a method never used in this context before. 3D-electron microscopy revealed intracellular lipid droplets and extracellular lipoprotein particles. The majority of the particles were aggregated and some connected to needle-shaped or sheet-like cholesterol crystals. Proteomic analysis of isolated extracellular lipoprotein particles revealed that apolipoprotein B is their main protein component indicating their origin from low density lipoprotein, intermediate density lipoprotein, very low density lipoprotein, lipoprotein (a), or chylomicron remnants. The particles also contained small exchangeable apolipoproteins, complement components, and immunoglobulins. Lipidomic analysis revealed differences between plasma lipoproteins and the particles thereby indicating involvement of lipolytic enzymes in their generation. Incubation of human monocyte-derived macrophages with the isolated extracellular lipoprotein particles or with plasma lipoproteins that had been lipolytically modified in vitro induced intracellular lipid accumulation and triggered inflammasome activation in them. Taken together, extracellular lipids accumulate in human carotid plaques as distinct 3D-structures that include aggregated and fused lipoprotein particles and cholesterol crystals. The particles originate from plasma lipoproteins, show signs of lipolytic modifications and associate with cholesterol crystals. By inducing intracellular cholesterol accumulation (ie, foam cell formation) and inflammasome activation, the extracellular lipoprotein particles may actively enhance atherogenesis. Copyright © 2017. Published by Elsevier Inc.
Satu Lehti, Su Nguyen, Ilya Belevich, Helena Vihinen, Hanna Heikkilä, Rabah Soliymani, Reijo Käkelä, Jani Saksi, Matti Jauhiainen, Gregory Grabowski, Outi Kummu, Sohvi Hörkkö, Marc Baumann, Perttu Lindsberg, Eija Jokitalo, Petri Kovanen, Katariina Öörni

Population-based Borrelia burgdorferi sensu lato seroprevalence and associated risk factors in Finland.


Ticks and tick-borne diseases (11 November 2017)

Lyme borreliosis (LB) is caused by Borrelia burgdorferi sensu lato (Bb-sl) and is the most common vector-borne disease in Europe. The objectives of this study were to determine the Bb-sl seroprevalence among the general Finnish adult population and to identify risk factors associated with Bb-sl-seropositive status. Two thousand sera from a nationwide health survey from 2011 were tested by whole-cell sonicate IgG ELISA, C6 peptide ELISA, and recomBead IgG 2.0 and test results were linked to a general health questionnaire. A multivariable logistic regression model was used to identify risk factors. The median age of the study population was 56 years (range 29-97) and the Bb-sl weighted seroprevalence was 3.9% (95% confidence interval (CI) 3.03-5.08). The weighted seroprevalence was significantly higher among males than females (adjusted odds ratio 1.91, 95%CI 1.21-3.04). The seroprevalence was highest in Southern, Central, and Eastern regions. The first Bb-sl seroprevalence study in Finland showed a seroprevalence of 3.9% (regional range 0.87%-6.12%). The results of this study can be used, together with previous data on LB incidence and spatial tick distribution, to target public health communication about preventive measures. Copyright © 2017 Elsevier GmbH. All rights reserved.
Janko van Beek, Eeva Sajanti, Otto Helve, Jukka Ollgren, Mikko Virtanen, Harri Rissanen, Outi Lyytikäinen, Jukka Hytönen, Jussi Sane

Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation.


Kidney international (14 November 2017)

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Benjamin Storey, Natalie Staplin, Richard Haynes, Christina Reith, Jonathan Emberson, William Herrington, David Wheeler, Robert Walker, Bengt Fellström, Christoph Wanner, Martin Landray, Colin Baigent,

Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin B in murine Escherichia coli pyelonephritis.


The Journal of antimicrobial chemotherapy (14 November 2017)

Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree. Here we have compared the efficacy of these NAB compounds and polymyxin B in the therapy of murine pyelonephritis caused by E. coli. The challenge organism was a uropathogenic E. coli clinical isolate. Mice were inoculated via urethral catheterization with 5 × 108 cfu. All treatment groups consisted of 12 animals. On day 1 and day 2 post-infection, the mice were treated subcutaneously with NAB739, NAB815, polymyxin B or vehicle twice a day and on day 3 post-infection the animals were sacrificed. cfu in the kidney and bladder tissues and in the urine were determined. NAB739 reduced the bacterial burden in the kidney, urine and bladder at doses approximately 10-fold lower than those of polymyxin B. In the kidneys, the half-maximal effective dose (ED50) was 9-fold lower for NAB739 than for polymyxin B (0.24 mg/kg versus 2.1 mg/kg, respectively). NAB815 was as effective as NAB739. NAB739 and NAB815 were unequivocally more effective than polymyxin B in the murine pyelonephritis model.
Martti Vaara, Timo Vaara, Carina Vingsbo Lundberg

Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation.


British journal of cancer (16 November 2017)

Periodontal pathogens have been linked to oral and gastrointestinal (orodigestive) carcinogenesis. However, the exact mechanisms remain unknown. Treponema denticola (Td) is associated with severe periodontitis, a chronic inflammatory disease leading to tooth loss. The anaerobic spirochete Td is an invasive bacteria due to its major virulence factor chymotrypsin-like proteinase. Here we aimed to investigate the presence of Td chymotrypsin-like proteinase (Td-CTLP) in major orodigestive tumours and to elucidate potential mechanisms for Td to contribute to carcinogenesis. The presence of Td-CTLP within orodigestive tumour tissues was examined using immunohistochemistry. Oral, tonsillar, and oesophageal squamous cell carcinomas, alongside gastric, pancreatic, and colon adenocarcinomas were stained with a Td-CTLP-specific antibody. Gingival tissue from periodontitis patients served as positive controls. SDS-PAGE and immunoblot were used to analyse the immumodulatory activity of Td-CTLP in vitro. Td-CTLP was present in majority of orodigestive tumour samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and α-1-antichymotrypsin, as well as complement C1q. Because of its presence within tumours and regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation, the Td-CTLP may contribute to orodigestive carcinogenesis.British Journal of Cancer advance online publication, 16 November 2017; doi:10.1038/bjc.2017.409
Mikko Nieminen, Dyah Listyarifah, Jaana Hagström, Caj Haglund, Daniel Grenier, Dan Nordström, Veli-Jukka Uitto, Marcela Hernandez, Tülay Yucel-Lindberg, Taina Tervahartiala, Mari Ainola, Timo Sorsa

Anti-adalimumab antibodies in juvenile idiopathic arthritis-related uveitis.


Clinical and experimental rheumatology (14 November 2017)

To evaluate the association of adalimumab trough levels and anti-adalimumab antibodies with activity of uveitis in juvenile idiopathic arthritis-related uveitis. This was a retrospective observational case series in a clinical setting at the Department of Ophthalmology, Helsinki University Hospital, Finland in 2014-2016. Thirty-one paediatric patients with chronic anterior juvenile idiopathic arthritis-related uveitis in 58 eyes and who had been on adalimumab ≥6 months were eligible for the study. Uveitis activity during adalimumab treatment, adalimumab trough levels and anti-adalimumab antibody levels were recorded. Anti-adalimumab antibody levels ≥12 AU /ml were detected in nine patients (29%). This level of anti-adalimumab antibodies was associated with a higher grade of uveitis (p<0.001), uveitis that was not in remission (p=0.001) and with lack of concomitant methotrexate therapy (p=0.043). In patients with anti-adalimumab antibody levels <12 AU/ml, higher serum trough levels did not associate with better control of uveitis (p=0.86). Adalimumab treatment might be better guided by monitoring anti-adalimumab antibody formation in treating JIA-related uveitis.
Sanna Leinonen, Kristiina Aalto, Kaisu Kotaniemi, Tero Kivelä

Epidemiological and treatment-related factors contribute to improved outcome of oropharyngeal squamous cell carcinoma in Finland.


Acta oncologica (Stockholm, Sweden) (17 November 2017), pp. 1-11

Treatment for oropharyngeal squamous cell carcinoma (OPSCC) has changed, as the proportion of human papilloma virus (HPV)-related disease has increased. We evaluated nationwide information on its management and outcome during the treatment paradigm change period. We included all patients diagnosed and treated for OPSCC at the five Finnish university hospitals from 2000 to 2009. Patient records and pathology registries provided the clinicopathological data. p16 staining was performed on primary tumor samples of patients who had received treatment with curative intent. A total of 674 patients were diagnosed and treated for OPSCC and the incidence increased along the study period. Of the evaluable tumors 58.5% were p16-positive and the number of p16-positive tumors increased along the years. The treatment was given with curative intent for 600 patients and it was completed in 564. Of them, 47.9% underwent primary surgery and 52.1% received definitive oncological treatment. Also, the treatment protocol changed towards a more oncological approach. Among patients treated with curative intent the five-year overall, disease-specific and disease-free survival rates were 60.1, 71.5 and 57.0%. In multivariate analysis, p16-positivity seemed to relate to reduced disease mortality in lateral and anterior-wall disease. Depending on primary tumor localization, also sex, classes T3-4, presence of regional metastasis and radiotherapy modality had an association with disease mortality. The incidence of p16-positive OPSCC and delivery of definitive oncological treatment increased in Finland during the study period. An improved survival outcome compared with the previous nationwide investigation was observed in this subset of patients.
Lauri Jouhi, Elina Halme, Heikki Irjala, Kauko Saarilahti, Petri Koivunen, Matti Pukkila, Jaana Hagström, Caj Haglund, Paula Lindholm, Pasi Hirvikoski, Samuli Vaittinen, Anna Ellonen, Jukka Tikanto, Henry Blomster, Jussi Laranne, Reidar Grénman, Antti Mäkitie, Timo Atula

Defective WNT signaling associates with bone marrow fibrosis-a cross-sectional cohort study in a family with WNT1 osteoporosis.


Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA (16 November 2017)

This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis. WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation. We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density. Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early-phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype. Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis.
RE Mäkitie, R Niinimäki, S Kakko, T Honkanen, PE Kovanen, O Mäkitie

Hypomethylation of HOXA4 promoter is common in Silver-Russell syndrome and growth restriction and associates with stature in healthy children.


Scientific reports, Vol. 7, No. 1. (16 November 2017)

Silver-Russell syndrome (SRS) is a growth retardation syndrome in which loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy for chromosome 7 [UPD(7)mat] explain 20-60% and 10% of the syndrome, respectively. To search for a molecular cause for the remaining SRS cases, and to find a possible common epigenetic change, we studied DNA methylation pattern of more than 450 000 CpG sites in 44 SRS patients. Common to all three SRS subgroups, we found a hypomethylated region at the promoter region of HOXA4 in 55% of the patients. We then tested 39 patients with severe growth restriction of unknown etiology, and found hypomethylation of HOXA4 in 44% of the patients. Finally, we found that methylation at multiple CpG sites in the HOXA4 promoter region was associated with height in a cohort of 227 healthy children, suggesting that HOXA4 may play a role in regulating human growth by epigenetic mechanisms.
Mari Muurinen, Katariina Hannula-Jouppi, Lovisa Reinius, Cilla Söderhäll, Simon Kebede Merid, Anna Bergström, Erik Melén, Göran Pershagen, Marita Lipsanen-Nyman, Dario Greco, Juha Kere

Pre-pregnancy overweight or obesity and gestational diabetes as predictors of body composition in offspring twenty years later-evidence from two birth cohort studies.


International journal of obesity (2005) (17 November 2017)

Global prevalence of overweight/obesity and gestational diabetes (GDM) is increasing. In pregnant women both conditions affect offspring's later health. Overweight/obesity is a risk factor of GDM; to what extent maternal overweight/obesity explains long-term effects of GDM in offspring is unknown. To evaluate effects of maternal pre-pregnancy overweight/obesity (BMI ⩾25 kg/m(2)) and GDM, occurring together or separately, on body composition among adult offspring. Participants include 891 individuals aged 24.1 years (s.d. 1.4) from two longitudinal cohort studies (ESTER and AYLS). Adult offspring of normoglycemic mothers with overweight/obesity (ONOO, n=153), offspring of mothers with GDM (OGDM; n=191) and controls (n=547) underwent anthropometric measurements and bioimpedance analysis. GDM was diagnosed by oral glucose tolerance test. Data were analyzed by linear regression models adjusted for confounders. Compared with controls, ONOO-participants showed higher BMI [men 1.64 kg/m(2) (95% confidence interval 0.57, 2.72); women 1.41 kg/m(2) (0.20, 2.63)] and fat percentage [men 2.70% (0.99, 4.41); women 2.98% (0.87, 5.09)] with larger waist circumferences [men 3.34 cm (0.68, 5.99); women 3.09 cm (0.35, 5.83)]. Likewise, OGDM-participants showed higher fat percentage [men 1.97% (0.32, 3.61); women 2.32% (0.24, 4.41)]. BMI was non-significantly different between OGDM-participants and controls [men 0.88kg/m(2) (-0.17, 1.92); women 0.82 kg/m(2) (-0.39, 2.04)]. Also waist circumferences were larger [men 2.63 cm (-0.01, 5.28); women 3.39 cm (0.60, 6.18)], this difference was statistically significant in OGDM-women only. Differences in body composition measures were stronger among offspring of women with both GDM and overweight/obesity. For instance, fat mass was higher among OGDM-participants of overweight mothers [men 4.24 kg (1.36, 7.11) vs controls; women 5.22 kg (1.33, 9.11)] than OGDM participants of normal weight mothers [men 1.50 kg (-2.11, 5.11) higher vs controls; women 1.57 kg (-3.27, 6.42)]. Maternal pre-pregnancy overweight and GDM are associated with unhealthy body size and composition in offspring over 20 years later. Effects of maternal pre-pregnancy overweight appear more pronounced.International Journal of Obesity accepted article preview online, 17 November 2017. doi:10.1038/ijo.2017.277.
N Kaseva, M Vääräsmäki, H-M Matinolli, M Sipola-Leppänen, M Tikanmäki, K Heinonen, A Lano, D Wolke, S Andersson, M-R Järvelin, K Räikkönen, G Eriksson Johan, E Kajantie

A Partial Loss-of-Function Variant in AKT2 is Associated with Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin Sensitive Tissues: a Genotype-Based Callback Positron Emission Tomography Study.


Diabetes (15 November 2017)

Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of p.Pro50Thr on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N=20) and matched non-carriers (N=25) for this allele in the population-based METSIM study and invited these individuals back for positron emission tomography study with [(18)F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to non-carriers, we found a 39.4% reduction in whole body GU (P=0.006) and a 55.6% increase in the rate of endogenous glucose production (P=0.038). We found significant reductions in GU in multiple tissues: skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%), and increases of 16.8-19.1% in 7 tested brain regions. These data demonstrate that the P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin sensitive tissues, and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers. © 2017 by the American Diabetes Association.
Aino Latva-Rasku, Miikka-Juhani Honka, Alena Stančáková, Heikki Koistinen, Johanna Kuusisto, Li Guan, Alisa Manning, Heather Stringham, Anna Gloyn, Cecilia Lindgren, , Francis Collins, Karen Mohlke, Laura Scott, Tomi Karjalainen, Lauri Nummenmaa, Michael Boehnke, Pirjo Nuutila, Markku Laakso

Development and plasticity of meningeal lymphatic vessels.


The Journal of experimental medicine (15 November 2017)

The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF-C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS. © 2017 Antila et al.
Salli Antila, Sinem Karaman, Harri Nurmi, Mikko Airavaara, Merja Voutilainen, Thomas Mathivet, Dmitri Chilov, Zhilin Li, Tapani Koppinen, Jun-Hee Park, Shentong Fang, Aleksanteri Aspelund, Mart Saarma, Anne Eichmann, Jean-Léon Thomas, Kari Alitalo

Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease.


Scientific reports, Vol. 7, No. 1. (15 November 2017)

Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1β, IFNγ, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.
Kati Hyvärinen, Jarmo Ritari, Satu Koskela, Riitta Niittyvuopio, Anne Nihtinen, Liisa Volin, David Gallardo, Jukka Partanen

The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484.


Open biology, Vol. 7, No. 11. (November 2017)

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the 'DISC1 network'. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 × 10(-8)), located on a non-coding exon of NDE1 Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment. © 2017 The Authors.
Nicholas Bradshaw, Liisa Ukkola-Vuoti, Maiju Pankakoski, Amanda Zheutlin, Alfredo Ortega-Alonso, Minna Torniainen-Holm, Vishal Sinha, Sebastian Therman, Tiina Paunio, Jaana Suvisaari, Jouko Lönnqvist, Tyrone Cannon, Jari Haukka, William Hennah

Systems pathology by multiplexed immunohistochemistry and whole-slide digital image analysis.


Scientific reports, Vol. 7, No. 1. (14 November 2017)

The paradigm of molecular histopathology is shifting from a single-marker immunohistochemistry towards multiplexed detection of markers to better understand the complex pathological processes. However, there are no systems allowing multiplexed IHC (mIHC) with high-resolution whole-slide tissue imaging and analysis, yet providing feasible throughput for routine use. We present an mIHC platform combining fluorescent and chromogenic staining with automated whole-slide imaging and integrated whole-slide image analysis, enabling simultaneous detection of six protein markers and nuclei, and automatic quantification and classification of hundreds of thousands of cells in situ in formalin-fixed paraffin-embedded tissues. In the first proof-of-concept, we detected immune cells at cell-level resolution (n = 128,894 cells) in human prostate cancer, and analysed T cell subpopulations in different tumour compartments (epithelium vs. stroma). In the second proof-of-concept, we demonstrated an automatic classification of epithelial cell populations (n = 83,558) and glands (benign vs. cancer) in prostate cancer with simultaneous analysis of androgen receptor (AR) and alpha-methylacyl-CoA (AMACR) expression at cell-level resolution. We conclude that the open-source combination of 8-plex mIHC detection, whole-slide image acquisition and analysis provides a robust tool allowing quantitative, spatially resolved whole-slide tissue cytometry directly in formalin-fixed human tumour tissues for improved characterization of histology and the tumour microenvironment.
Sami Blom, Lassi Paavolainen, Dmitrii Bychkov, Riku Turkki, Petra Mäki-Teeri, Annabrita Hemmes, Katja Välimäki, Johan Lundin, Olli Kallioniemi, Teijo Pellinen

Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management.


The Pediatric infectious disease journal, Vol. 36, No. 12. (December 2017), pp. 1205-1213
Suzanne Luck, Jantien Wieringa, Daniel Blázquez-Gamero, Philipp Henneke, Katharina Schuster, Karina Butler, Maria Grazia Capretti, Maria José Cilleruelo, Nigel Curtis, Francesca Garofoli, Paul Heath, Elias Iosifidis, Nigel Klein, Giuseppina Lombardi, Hermione Lyall, Tea Nieminen, Dasja Pajkrt, Vassiliki Papaevangelou, Klara Posfay-Barbe, Laura Puhakka, Emmanuel Roilides, Pablo Rojo, Jesús Saavedra-Lozano, Teshri Shah, Mike Sharland, Harri Saxen, Ann Vossen,

A Four-kallikrein Panel and β-Microseminoprotein in Predicting High-grade Prostate Cancer on Biopsy: An Independent Replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer.


European urology focus (11 November 2017)

A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™. To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether β-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. The predictive accuracy of prespecified prediction models was compared with biopsy outcomes. Among men with PSA of 4.0-25ng/ml, 1111 had prostate cancer, 318 of whom had high-grade disease. Total PSA and age predicted high-grade cancer with an area under the curve of 0.648 (95% confidence interval [CI] 0.614-0.681) and the four-kallikrein panel increased discrimination to 0.746 (95% CI 0.717-0.774). Adding MSP to the four-kallikrein panel led to a significant (Wald test; p=0.015) but small increase (0.003) in discrimination. Limitations include a risk of verification bias among men with PSA of 3.0-3.99ng/ml and the absence of digital rectal examination results. These findings provide additional evidence that kallikrein markers can be used to inform biopsy decision-making. Further studies are needed to define the role of MSP. Four kallikrein markers and β-microseminoprotein in blood improve discrimination of high-grade prostate cancer at biopsy in men with elevated prostate-specific antigen. Copyright © 2017. Published by Elsevier B.V.
Melissa Assel, Liisa Sjöblom, Teemu Murtola, Kirsi Talala, Paula Kujala, Ulf-Håkan Stenman, Kimmo Taari, Anssi Auvinen, Andrew Vickers, Tapio Visakorpi, Teuvo Tammela, Hans Lilja

Health-related quality of life in different states of breast cancer - comparing different instruments.


Acta oncologica (Stockholm, Sweden) (15 November 2017), pp. 1-7

The prognosis of breast cancer has improved significantly during the last few decades increasing the interest in health-related quality of life (HRQoL). The aim of this study was to compare the HRQoL scores produced by different instruments and to shed light on their validity in various states of breast cancer by studying the association of cancer-related symptoms with HRQoL. An observational, cross-sectional study of breast cancer patients treated in the Helsinki and Uusimaa Hospital District from September 2009 to April 2011. A total of 840 patients completed three HRQoL questionnaires: the EQ-5D-3L (including VAS), 15D and EORTC QLQ-30 and a questionnaire concerning sociodemographic factors. Patients were divided into five mutually exclusive groups: primary treatment (n = 118), recovery (6-18 months from diagnosis) (n = 150), remission (>18 months) (n = 382), metastatic disease (n = 176) and palliative care (n = 14). The association of HRQoL with sociodemographic and clinical factors and cancer-related symptoms, screened by the EORTC QLQ-30, was studied by multivariate modeling using stepwise linear regression analysis. HRQoL scores were the best at the time closest to diagnosis and deteriorated with disease progression. The EQ-5D had a pronounced ceiling effect with 40.8% of the respondents scoring 1 (perfect health) compared to 6% for the 15D and 5.6% for VAS. In regression analyses, pain, fatigue and financial difficulties were the most important predictors of lower HRQoL. The 15D showed better discriminatory power and content validity. The EORTC QLQ-C30 functioning deteriorated in advanced states of the disease with physical, social and role functioning being the most affected. Insomnia, fatigue and pain were the most commonly reported symptoms in all groups. Different HRQoL instruments produce notably different HRQoL scores. The EQ-5D has a pronounced ceiling effect. Pain and fatigue are the most common symptoms associated with poor HRQoL in all disease states.
Mervi Rautalin, Niilo Färkkilä, Harri Sintonen, Tiina Saarto, Kimmo Taari, Tiina Jahkola, Risto Roine

Clopidogrel carboxylic acid glucuronidation is mediated mainly by UGT2B7, UGT2B4 and UGT2B17: Implications for pharmacogenetics and drug-drug interactions.


Drug metabolism and disposition: the biological fate of chemicals (14 November 2017)

The antiplatelet drug clopidogrel is metabolized to an acyl-β-D-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-D-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLM and HIM, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers. UGT2B7 and UGT2B17 exhibited the highest clopidogrel carboxylic acid glucuronidation activities, with a CLint,u of 2.42 and 2.82 µL∙min(-1)·mg(-1), respectively. Of other enzymes displaying activity (UGT1A3, UGT1A9, UGT1A10-H and UGT2B4), UGT2B4 (CLint,u 0.51 µL∙min(-1)·mg(-1)) was estimated to contribute significantly to the hepatic clearance. Nonselective UGT2B inhibitors strongly inhibited clopidogrel acyl-β-D-glucuronide formation in HLM and HIM. The UGT2B17 inhibitor imatinib and the UGT2B7 and UGT1A9 inhibitor mefenamic acid inhibited clopidogrel carboxylic acid glucuronidation in HIM and HLM, respectively. Incubation of clopidogrel carboxylic acid in HLM with UDPGA and NADPH resulted in strong inhibition of CYP2C8 activity. In healthy volunteers, UGT2B17*2 deletion allele was associated with a 10% decrease per copy in the plasma clopidogrel acyl-β-D-glucuronide to clopidogrel carboxylic acid AUC0-4 ratio (P<0.05). To conclude, clopidogrel carboxylic acid is mainly metabolized by UGT2B7 and UGT2B4 in the liver, and by UGT2B17 in the small intestinal wall. The formation of clopidogrel acyl-β-D-glucuronide is impaired in carriers of the UGT2B17 deletion. The findings may have implications regarding intracellular mechanisms leading to CYP2C8 inactivation by clopidogrel. The American Society for Pharmacology and Experimental Therapeutics.
Helina Kahma, Anne Filppula, Mikko Neuvonen, Katriina Tarkiainen, Aleksi Tornio, Mikko Holmberg, Matti Itkonen, Moshe Finel, Pertti Neuvonen, Mikko Niemi, Janne Backman

Evolution and postglacial colonization of Seewis hantavirus with Sorex araneus in Finland.


Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases (10 November 2017)

Hantaviruses have co-existed with their hosts for millions of years. Seewis virus (SWSV), a soricomorph-borne hantavirus, is widespread in Eurasia, ranging from Central Siberia to Western Europe. To gain insight into the phylogeography and evolutionary history of SWSV in Finland, lung tissue samples of 225 common shrews (Sorex araneus) trapped from different parts of Finland were screened for the presence of SWSV RNA. Forty-two of the samples were positive. Partial small (S), medium (M) and large (L) segments of the virus were sequenced, and analyzed together with all SWSV sequences available in Genbank. The phylogenetic analysis of the partial S-segment sequences suggested that all Finnish SWSV strains shared their most recent common ancestor with the Eastern European strains, while the L-segment suggested multiple introductions. The difference between the L- and S-segment phylogenies implied that reassortment events play a role in the evolution of SWSV. Of the Finnish strains, variants from Eastern Finland occupied the root position in the phylogeny, and had the highest genetic diversity, supporting the hypothesis that SWSV reached Finland first form the east. During the spread in Finland, the virus has formed three separate lineages, identified here by correlation analysis of genetic versus geographic distance combined with median-joining network analysis. These results support the hypothesis that Finnish SWSV recolonized Finland with its host, the common shrew, from east after the last ice age 12,000-8000years ago, and then subsequently spread along emerging land bridges towards west or north with the migration and population expansion of its host. Copyright © 2017. Published by Elsevier B.V.
Jiaxin Ling, Teemu Smura, Daniel Tamarit, Otso Huitu, Liina Voutilainen, Heikki Henttonen, Antti Vaheri, Olli Vapalahti, Tarja Sironen

Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial.


Trials, Vol. 18, No. 1. (13 November 2017)

Acute respiratory distress syndrome (ARDS) results in vascular leakage, inflammation and respiratory failure. There are currently no approved pharmacological treatments for ARDS and standard of care involves treatment of the underlying cause, and supportive care. The vascular leakage may be related to reduced concentrations of local adenosine, which is involved in maintaining endothelial barrier function. Interferon (IFN) beta-1a up-regulates the cell surface ecto-5'-nucleotidase cluster of differentiation 73 (CD73), which increases adenosine levels, and IFN beta-1 may, therefore, be a potential treatment for ARDS. In a phase I/II, open-label study in 37 patients with acute lung injury (ALI)/ARDS, recombinant human IFN beta-1a was well tolerated and mortality rates were significantly lower in treated than in control patients. In this phase III, double-blind, randomized, parallel-group trial, the efficacy and safety of recombinant human IFN beta-1a (FP-1201-lyo) will be compared with placebo in adult patients with ARDS. Patients will be randomly assigned to receive 10 μg FP-1201-lyo or placebo administered intravenously once daily for 6 days and will be monitored for 28 days or until discharged from the intensive care unit. Follow-up visits will then take place at days 90, 180 and 360. The primary endpoint is a composite endpoint including any cause of death at 28 days and days free of mechanical ventilation within 28 days among survivors. Secondary endpoints include: all-cause mortality at 28, 90, 180 and 360 days; organ failure-free days; length of hospital stay; pharmacodynamic assessment including measurement of myxovirus resistance protein A concentrations; and measures of quality of life, respiratory and neurological function at 180 and 360 days. The estimated sample size to demonstrate a reduction in the primary outcome between groups from 30% to 15% is 300 patients, and the study will be conducted in 70-80 centers in nine countries across Europe. There are no effective specific treatments for patients with ARDS and mortality rates remain high. The results from this study will provide evidence regarding the efficacy of a potential new therapeutic agent, FP-1201-lyo, in improving the clinical course and outcome for patients with moderate/severe ARDS. European Union Clinical Trials Register, no: 2014-005260-15 . Registered on 15 July 2017.
Geoff Bellingan, David Brealey, Jordi Mancebo, Alain Mercat, Nicolò Patroniti, Ville Pettilä, Michael Quintel, Jean-Louis Vincent, Mikael Maksimow, Markku Jalkanen, Ilse Piippo, Marco Ranieri

A prospective study of travellers' diarrhoea - analysis of pathogen findings by destination in various (sub)tropical regions.


Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases (10 November 2017)

Eighty million travellers visiting (sub)tropical regions contract travellers' diarrhoea (TD) each year, yet prospective data comparing the prevalence of TD pathogens in various geographical regions are scarce. Our recent study employing modern molecular methods found enteropathogenic (EPEC) and enteroaggregative (EAEC) Escherichia coli to be the most frequent pathogens, followed by enterotoxigenic E. coli (ETEC) and Campylobacter. We revisited our data to compare the findings by geographical region. A total of 459 prospectively recruited travellers provided stool samples and completed questionnaires before and after visiting destinations in various geographical regions. A multiplex qPCR assay was used to analyse Salmonella, Yersinia, Campylobacter jejuni /Campylobacter coli, Shigella, Vibrio cholerae, EPEC, EAEC, ETEC, EHEC (enterohaemorrhagic E. coli) and EIEC (enteroinvasive E. coli). TD was contracted by 69% (316/459) of the subjects; EPEC and EAEC outnumbered ETEC and Campylobacter in all regions. Multiple pathogens were detected in 42% (133/316) of the samples. The proportions of all pathogens varied by region. The greatest differences were seen for Campylobacter: while relatively frequent in South Asia (n=11; 20% of those 55 with TD during travel) and Southeast Asia (15/84; 15%), it was less common in East and West Africa (5/71; 7% and 1/57; 2%), and absent in South America and the Caribbean (0/40; 0%). EPEC and EAEC outnumbered ETEC and Campylobacter everywhere, yet the proportions of pathogen findings varied by region, ETEC and Campylobacter rates showing the greatest differences. The high frequency of multibacterial findings in many regions indicates a need for further investigating the clinical role of each pathogen. Copyright © 2017. Published by Elsevier Ltd.
Tinja Lääveri, Katri Vilkman, Sari Pakkanen, Juha Kirveskari, Anu Kantele

Inhibition of Skin Wound Contraction by Nanofibrillar Cellulose Hydrogel.


Plastic and reconstructive surgery (08 November 2017)

Although wound contraction is an essential part of healing, excessive contraction can compromise healing through induction of scarring and fibrosis. This in turn leads to development of wound contractures that limit elasticity and function. Major research efforts have focused on development of novel therapeutic approaches to gain inhibitory control over wound contraction. Despite these efforts, the need for cost-effective, clinically feasible and effective agents to inhibit wound contraction remains. In this study, we investigated the effect of nanofibrillar cellulose (NFC) hydrogel on wound contraction both in vitro and in vivo. Two different porcine full thickness wounds (8mm punch-biopsy wounds and 4 x 4cm wounds covered with a 1:3-meshed split thickness skin graft) were treated with or without nanofibrillar cellulose or carboxymethylcellulose (Purilon hydrogel), which was used as a reference treatment. Wound contraction was observed macroscopically, and histological sections were taken at 14 days' follow-up. Nanofibrillar cellulose hydrogel inhibited 70% of punch-biopsy wound contraction whereas the carboxymethylcellulose hydrogel was ineffective. Importantly, application of nanocellulose on split thickness skin grafts did not inhibit epithelialization of the interstices or cell migration from the graft. Our results, although preliminary, indicate a potential for nanofibrillar cellulose hydrogel as a novel material for controlling excessive wound contraction.
Kristo Nuutila, Antti Laukkanen, Andrew Lindford, Susanna Juteau, Markus Nuopponen, Jyrki Vuola, Esko Kankuri

Workplace bullying and violence as risk factors for type 2 diabetes: a multicohort study and meta-analysis.


Diabetologia (13 November 2017)

The aim of this multicohort study was to examine whether employees exposed to social stressors at work, such as workplace bullying and violence, have an increased risk of type 2 diabetes. The study included 45,905 men and women (40-65 years of age and free of diabetes at baseline) from four studies in Sweden, Denmark and Finland. Workplace bullying and violence were self-reported at baseline. Incident diabetes was ascertained through national health and medication records and death registers. Marginal structural Cox models adjusted for age, sex, country of birth, marital status and educational level were used for the analyses. Nine per cent of the population reported being bullied at work and 12% were exposed to workplace violence or threats of violence. Bullied participants had a 1.46 (95% CI 1.23, 1.74) times higher risk of developing diabetes compared with non-bullied participants. Exposure to violence or threats of violence was also associated with a higher risk of diabetes (HR 1.26 [95% CI 1.02, 1.56]). The risk estimates attenuated slightly when taking BMI into account, especially for bullying. The results were similar for men and women, and were consistent across cohorts. We found a higher risk of incident type 2 diabetes among employees exposed to bullying or violence in the workplace. Further research is needed to determine whether policies to reduce bullying and violence at work may reduce the incidence of type 2 diabetes in working populations. Research on the mechanisms is also highly warranted.
Tianwei Xu, Linda Magnusson Hanson, Theis Lange, Liis Starkopf, Hugo Westerlund, Ida Madsen, Reiner Rugulies, Jaana Pentti, Sari Stenholm, Jussi Vahtera, Åse Hansen, Mika Kivimäki, Naja Rod

Intestinal failure as a significant risk factor for renal impairment in children.


Nutrition (Burbank, Los Angeles County, Calif.), Vol. 45 (January 2018), pp. 90-93

Although impaired renal function has been a frequent finding among adults with intestinal failure (IF), the data on children is scarce. The aim of this study was to assess renal function in pediatric-onset IF. Medical records of 70 patients (38 boys) with pediatric-onset IF due to either short bowel syndrome (n = 59) or primary motility disorder (n = 11) and a history of parenteral nutrition (PN) dependency for ≥1 mo were evaluated. Renal function at the most recent follow-up was studied using plasma creatinine, cystatin C, and urea concentrations and estimated glomerular filtration rate (eGFR). At a median age of 5.7 y and after PN duration of 3.2 y, 20 patients (29%) had decreased eGFR and higher cystatin C and urea concentrations. Patients with decreased renal function had significantly longer duration of PN (3.2 versus 0.9 y; P = 0.030) and shorter percentage of age-adjusted small bowel length remaining (22 versus 32%; P = 0.041) compared with patients with preserved renal function. No other predisposing factors for decreased eGFR were identified. Patients with pediatric-onset IF are at significant risk for impaired renal function, which is associated with the duration of PN and the length of the remaining small bowel. In the present study, no other predisposing factors for decreased eGFR were found. Further studies using measured GFR are needed. Copyright © 2017 Elsevier Inc. All rights reserved.
Elisa Ylinen, Laura Merras-Salmio, Riikka Gunnar, Timo Jahnukainen, Mikko Pakarinen

Treatment of Paget-Schroetter syndrome with a three-stage approach including thoracoscopic rib resection at the second stage.


Journal of vascular surgery. Venous and lymphatic disorders (09 November 2017)

Young, active persons may suffer lifelong consequences of subclavian vein thrombosis, but the best treatment options remain unclear. On introduction of more active pharmacomechanical thrombus removal and thoracoscopic rib resection in our institution, we planned a diagnostic and treatment protocol and aimed to analyze the early, midterm, and intermediate-term results. The study included 72 patients who were diagnosed with an upper limb deep venous thrombosis and underwent phlebography between 2006 and 2013. After the initial treatment, control phlebography was performed and a thoracoscopic first rib resection was considered. Postoperative balloon angioplasty was performed when appropriate, and 1-year follow-up phlebography was carried out. After the initial thrombus removal, 60 patients were treated with thoracoscopic first rib resection and subsequent phlebography with or without balloon angioplasty. The median time from symptom to surgery was 124 days, and six (10%) patients had a reocclusion before surgery. Ten (16.7%) patients experienced complications, which were treated mainly with a chest tube (n = 3) or thoracoscopic re-exploration (n = 4). Three months after surgery, 98.3% (59/60) experienced an overall relief of symptoms. No recurrence of clinical thrombosis or residual compression due to incomplete rib resection was seen, and 96.6% (56/58) of the patients reported an overall improvement of symptoms at 13 months. Two patients (3.4%) were treated for chronic pain and had electroneuromyography-verified nerve plexus damage. In both cases, the pain was relieved in the long run. A combination of early thrombus removal, thoracoscopic first rib resection, and postoperative venous balloon angioplasty seems to yield acceptable intermediate-term results after Paget-Schroetter thrombosis. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Osman Mahmoud, Eero Sihvo, Jari Räsänen, Leena Vikatmaa, Pirkka Vikatmaa, Maarit Venermo

Dirofilaria repens transmission in southeastern Finland.


Parasites & vectors, Vol. 10, No. 1. (10 November 2017)

The spread of vector-borne diseases to new regions has become a global threat due to climate change, increasing traffic, and movement of people and animals. Dirofilaria repens, the canine subcutaneous filarioid nematode, has expanded its distribution range northward during the last decades. The northernmost European locations, where the parasite life-cycle has been confirmed, are Estonia and the Novgorod Region in Russia. Herein, we describe an autochthonous D. repens infection in a Finnish woman. We also present two cases of D. repens infection in imported dogs indicating the life-cycle in the Russian Vyborg and St Petersburg areas, close to the Finnish border. The most obvious limiting factor of the northern distribution of D. repens is the summer temperature, due to the temperature-dependent development of larvae in vectors. With continuing climate change, further spread of D. repens in Fennoscandia can be expected.
Risto Pietikäinen, Stig Nordling, Sakari Jokiranta, Seppo Saari, Petra Heikkinen, Chris Gardiner, Anne-Marie Kerttula, Tiina Kantanen, Anna Nikanorova, Sauli Laaksonen, Antti Lavikainen, Antti Oksanen

Exploring sociodemographic and economic factors that promote adverse drug reactions reporting by patients.


Health policy (Amsterdam, Netherlands) (08 November 2017)

Adverse drug reactions (ADRs) are recognized as a leading cause of morbidity and mortality, and an important cost factor to health systems. Patient reporting of ADRs has emerged as an important topic in recent years but reporting rates are still low in many countries. To explore different countries' sociodemographic and economic features as explanatory factors for population ADRs reporting, including the propensity of patients' reporting to pharmacovigilance authorities. Cross-sectional observational design. A data set of 42 global sociodemographic and economic factors for 44 countries were retrieved, as to analyse statistical associations between these factors and the patient reporting rate of ADRs. Multivariate logistic regression models were designed to identify the predictive covariables. Health investment indicators, such as per capita public health expenditure, hospital bed density and under five mortality rate were the relevant factors responsible to discriminate between countries that have higher patient reporting rates. This study shows that healthcare investment-related factors help explain the propensity of patients to report suspected ADRs, while pharmacovigilance features were not directly associated with higher patient participation in drug safety mechanisms. Although general, these results point a direction in further policy making to improve resources allocation concerning the promotion of patients' participation. Copyright © 2017 Elsevier B.V. All rights reserved.
Pedro Inácio, João José Gomes, Marja Airaksinen, Afonso Cavaco

Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes.


Scientific reports, Vol. 7, No. 1. (10 November 2017)

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
Liz Rietschel, Fabian Streit, Gu Zhu, Kerrie McAloney, Josef Frank, Baptiste Couvy-Duchesne, Stephanie Witt, Tina Binz, , , John McGrath, Ian Hickie, Narelle Hansell, Margaret Wright, Nathan Gillespie, Andreas Forstner, Thomas Schulze, Stefan Wüst, Markus Nöthen, Markus Baumgartner, Brian Walker, Andrew Crawford, Lucía Colodro-Conde, Sarah Medland, Nicholas Martin, Marcella Rietschel

Fighting vessel dysmorphia to improve glioma chemotherapy.


EMBO molecular medicine (10 November 2017)
Marja Lohela, Kari Alitalo

Mortality and health-related habits in 900 Finnish former elite athletes and their brothers.


British journal of sports medicine (10 November 2017)

There is conflicting evidence on the associations between participation in vigorous sports, health habits, familial factors and subsequent mortality. We investigated all-cause mortality and health-related behaviour among former elite athletes and their brothers. The mortality of Finnish male former elite athletes, who had represented Finland between 1920 and 1965 (n=900) and their age-matched brothers (n=900), was followed from the time when athlete started an elite athlete career until 31 December 2015. The age-adjusted HRs were calculated by a paired Cox proportional hazards model. In 2001, surviving participants (n=199 athletes and n=199 age-matched brothers) reported their self-rated health (SRH), physical activity, alcohol consumption and smoking habits in the questionnaire. During the total follow-up period, 1296 deaths (72% of the cohort) occurred. The age-adjusted HRs for all-cause mortality in former athletes was 0.75 (95% CI 0.65 to 0.87, P<0.001) compared with their age-matched brothers. Median age at death was 79.9 years for endurance, 75.9 years for mixed sports and 72.2 years for power sports athletes, and 77.5, 73.7 and 72.2 years for their age-matched brothers, respectively. In 2001, compared with their brothers, former athletes smoked less (P<0.001), were more physically active (P<0.05) and rated their health more often as very good (P<0.05). Former elite athletes are more physically active, smoke less, have better self-rated health and live longer than their brothers. Genetic differences between athletes and brothers, aerobic training for endurance elite sports and a healthier lifestyle may all contribute to reduced mortality. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Titta Katariina Kontro, Seppo Sarna, Jaakko Kaprio, Urho Kujala

Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis.


The Lancet. Oncology (07 November 2017)Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure. We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models. 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4-25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9-23·2] for laser conisation to 25·9% [22·3-29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9-8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2-7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8-65·5) and 84·4% (79·5-88·4), respectively, for the margin status, and 91·0% (82·3-95·5) and 83·8% (77·7-88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free. The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than mar[...]

Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer Xenografts.


The American journal of pathology (07 November 2017)

The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Here, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (2-fold, P < 0.05) and the AR splice variants AR-V1 (3-fold, P < 0.05) and AR-V7 (3-fold, P < 0.01) were further increased in the antiandrogen-treated tumors. Non-significant effects were observed in the expression of certain classical androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels. Copyright © 2017. Published by Elsevier Inc.
Matias Knuuttila, Arfa Mehmood, Riikka Huhtaniemi, Emrah Yatkin, Merja Häkkinen, Riikka Oksala, Teemu Laajala, Henrik Ryberg, David Handelsman, Tero Aittokallio, Seppo Auriola, Claes Ohlsson, Asta Laiho, Laura Elo, Petra Sipilä, Sari Mäkelä, Matti Poutanen

Impact of the automated dose dispensing with medication review on geriatric primary care patients drug use in Finland: a nationwide cohort study with matched controls.


Scandinavian journal of primary health care (10 November 2017), pp. 1-8

In an automated dose dispensing (ADD) service, medicines are dispensed in unit-dose bags according to administration times. When the service is initiated, the patient's medication list is reconciled and a prescription review is conducted. The service is expected to reduce drug use. The aim of this national controlled study was to investigate whether the ADD service with medication review reduces drug use among geriatric primary care patients. This is a nationwide cohort study with matched controls. The study group consisted of all primary care patients ≥65 years enrolled in the ADD service in Finland during 2007 (n = 2073). Control patients (n = 2073) were matched by gender, age, area of patient's residence and number of the prescription drugs reimbursed. The data on all prescription drugs reimbursed during the 1 year periods before and after the ADD service enrollment were extracted from the Finnish National Prescription Register. Drug use was calculated as defined daily doses (DDD) per day. The studied 20 most used drugs covered 86% of all reimbursed drug use (in DDD) of the study group. The use of 11 out of these 20 active substances studied was reduced significantly (p < .001-.041) when the drug use was adjusted by the number of chronic diseases. Two of these drugs were hypnotics and six were cardiovascular system drugs. Drug use was decreased after initiation of the ADD service in primary care patients ≥65 years compared to matched controls in this 1 year cohort study. Further studies should be conducted in order to explore the causality, assess the ADD service's impact on drug use quality and costs, as well as impact of accompanied prescription review on positive outcomes.
Juha Sinnemäki, Marja Airaksinen, Maria Valaste, Leena Saastamoinen

Head Injuries in Urban Environment Skiing and Snowboarding: A Retrospective Study on Injury Severity and Injury Mechanisms.


Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society (01 November 2017)

During the last decade urban skiing and snowboarding has gained a lot of popularity. In urban skiing/snowboarding riders try to balance on handrails and jump off buildings. Previous studies in skiing and snowboarding accidents have mostly been conducted at hospitals located close to alpine terrain with big ski resort areas. The aim of this study is to evaluate the types and severity of traumatic brain injuries occurring in small, suburban hills and in urban environment, and to characterize injury patterns to find out the specific mechanisms of injuries behind. This study included all patients admitted to the Helsinki University Hospital Trauma Unit from 2006 to 2015 with a head injury (ICD 10 S06-S07) from skiing or snowboarding accidents in Helsinki capital area. Head injuries that did not require a CT-scan, and injuries older than 24 hours were excluded from this study. There were a total of 72 patients that met the inclusion criteria Mean length of stay in hospital was 2.95 days. According to the AIS classification, 30% had moderate, 14% had severe, and 10% had critical head injuries. Patients who got injured in terrain parks or on streets where more likely to be admitted to ICU than those injured on slopes. Based on GOS score at discharge, 78% were classified as having a good recovery from the injury, 13% had a moderate disability, 5% had a severe disability and 3% of the injuries were fatal. There were no statistically significant differences in decreased GOS between the accident sites. Head injuries occurring in small suburban hills and in urban environments can be serious and potentially fatal. The profile and severity of skiing injuries in urban environments and small, suburban hills is comparable to those on alpine terrain.
A Stenroos, L Handolin

Cancer and risk of cerebral venous thrombosis: a case-control study.


Journal of thrombosis and haemostasis : JTH (10 November 2017)

Cancer is an established risk factor for leg vein thrombosis and pulmonary embolism. Controlled studies assessing the risk of cerebral venous thrombosis (CVT) in patients with cancer have not been performed. To assess whether cancer is a risk factor for CVT. Case-control study. We assessed consecutive adult patients with CVT from three academic hospitals from 1987-2015, and control subjects from the Dutch MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis). We adjusted for age, sex and oral contraceptive use, and stratified for type of cancer and time since diagnosis of cancer. We included 594 cases and 6278 controls. In total, 53 cases (8.9%) and 160 controls (2.5%) had a history of cancer. Cases were younger (median 42 vs. 48 years), more often female (68% vs. 54%) and more often used oral contraceptives (55% vs. 23%) than controls. The risk of CVT was increased in patients with cancer compared to those without cancer (adjusted odds ratio [aOR] 4.86, 95% confidence interval [CI] 3.46-6.81). Patients with a hematological type of cancer had a higher risk of CVT (aOR 25.14, 95% CI 11.64-54.30) than those with a solid type of cancer (aOR 3.07, 95% CI 2.03-4.65). The association was strongest in the first year after diagnosis of cancer (hematological aOR 85.57, 95% CI 19.70-371.69; solid aOR 10.50, 95% CI 5.40-20.42). Our study indicates that cancer is a strong risk factor for CVT, particularly within the first year of diagnosis and in patients with a hematological type of cancer. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
SM Silvis, S Hiltunen, E Lindgren, K Jood, SM Zuurbier, S Middeldorp, J Putaala, SC Cannegieter, T Tatlisumak, JM Coutinho

Vitamin D research and public health nutrition: a current perspective.


Public health nutrition, Vol. 20, No. 10. (July 2017), pp. 1713-1717
Mona Calvo, Christel Lamberg-Allardt

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research.


The Lancet. Neurology (06 November 2017)
Andrew Maas, David Menon, David Adelson, Nada Andelic, Michael Bell, Antonio Belli, Peter Bragge, Alexandra Brazinova, András Büki, Randall Chesnut, Giuseppe Citerio, Mark Coburn, Jamie Cooper, Tamara Crowder, Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas van Essen, Valery Feigin, Guoyi Gao, Joseph Giacino, Laura Gonzalez-Lara, Russell Gruen, Deepak Gupta, Jed Hartings, Sean Hill, Ji-Yao Jiang, Naomi Ketharanathan, Erwin Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Söderberg, Simon Stanworth, Murray Stein, Nicole von Steinbüchel, William Stewart, Ewout Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin Wang, Huw Williams, Lindsay Wilson, Kristine Yaffe,

Firesetting and general criminal recidivism among a consecutive sample of Finnish pretrial male firesetters: A register-based follow-up study.


Psychiatry research, Vol. 259 (05 November 2017), pp. 377-384

The rate of criminal reoffending among firesetters varies greatly. Our aim was to investigate firesetting and general criminal recidivism in a consecutive sample of Finnish males who were sent for a forensic psychiatric examination (FPE)(1) after committing firesetting offenses. We also wanted to evaluate the relationships between psychopathy and criminal recidivism, and between schizophrenia-spectrum disorders and criminal recidivism. The sample comprised 113 firesetters with a mean age of 32.8 years, and the average follow-up time was 16.9 years. The FPE statements of the firesetters were reviewed and psychiatric diagnoses were collected. The psychopathy assessments were based on the 20-item Hare Psychopathy Checklist-Revised (PCL-R). Information on reoffending was gathered from the Finnish National Police Register. During the follow-up 20 (18%) persons were registered for a new firesetting and 84 (74%) for any new offense. Firesetters with high traits (PCL-R ≥ 25) of psychopathy were more likely than those with low traits (PCL-R < 25) to reoffend with any crime during the follow-up. The risk of general criminal recidivism was lower among firesetters with a schizophrenia-spectrum disorder than among those with non-psychotic disorders. Conclusively, both firesetting and general criminal-recidivism rates were high in this sample of offenders. Copyright © 2017 Elsevier B.V. All rights reserved.
Annika Thomson, Jari Tiihonen, Jouko Miettunen, Matti Virkkunen, Nina Lindberg

Brain activation induced by chronic psychosocial stress in mice.


Scientific reports, Vol. 7, No. 1. (08 November 2017)

Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of ∆FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of ∆FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.
Mikaela Laine, Ewa Sokolowska, Mateusz Dudek, Saija-Anita Callan, Petri Hyytiä, Iiris Hovatta

Symptom relief and health-related quality of life in globus patients: a prospective study.


Logopedics, phoniatrics, vocology (09 November 2017), pp. 1-6

Globus may be a persistent symptom impairing patients' quality of life. Diagnostics and treatment are controversial but some globus patients may benefit from reassurance and attention. We investigated how globus symptoms change during a short-term follow-up without any treatment after an examination by an ear, nose and throat (ENT) physician and further diagnostic procedures. We also surveyed whether patients with persistent globus suffer from simultaneous voice problems. The study comprised 30 consecutive globus patients referred to Helsinki University Hospital, Department of Otorhinolaryngology - Head and Neck Surgery. We performed an ENT examination and scored patients' videolaryngostroboscopies using the Reflux Finding Score (RFS). Patients filled in three questionnaires: the Reflux Symptom Index (RSI), the Deglutition Handicap Index (DHI) and the 15-Dimensional Measure of Health-Related Quality of Life (15-D HRQoL). Patients underwent transnasal esophagoscopy, high-resolution manometry, and 24-hour multichannel intraluminal impedance and pH monitoring. After a four-month follow-up, patients re-answered the same questionnaires and a speech and language pathologist (SLP) examined the patients. Baseline and follow-up questionnaires were available from 27 (90%) patients. According to the RSI (p = .001) and the DHI (p = .003), patients' symptoms diminished after four months. The 15-D showed improvement in one subscale measuring discomfort and symptoms (p = .023). The SLP examined 23 (77%) patients, finding functional voice problems in six (26%). The study showed that most globus patients felt their symptoms diminished without any treatment during four months. In some patients, coexisting voice problems may be associated with persistent globus.
Pia Järvenpää, Assi Laatikainen, Risto Roine, Harri Sintonen, Perttu Arkkila, Leena-Maija Aaltonen

Total or subtotal glossectomy with laryngeal preservation: a national study of 29 patients.


European archives of oto-rhino-laryngology (08 November 2017)

Total glossectomy remains a controversial procedure as it often leads to notorious sequalae in swallowing and speaking functions. Disease entities indicating total glossectomy tend to have poor prognosis. We evaluated whether this type of surgery can be concidered justified based on our national series. We reviewed all total and subtotal glossectomies with laryngeal preservation performed in Finland between 2005 and 2014 in terms of overall survival (OS), disease-specific survival (DSS), locoregional control (LRC), and functional outcome as assessed by gastric tube or tracheostomy dependence and ability to produce intelligible speech. Of the 29 eligible patients, 15 had undergone total and 14 subtotal glossectomy with curative intent. In eight patients, total/subtotal glossectomy was performed as salvage procedure after the previous treatment. One-year estimates for OS, DSS, and LRC were 48, 59, and 66%, and corresponding 3-year estimates were 31, 46, and 46%, respectively. The gastrostomy and tracheostomy dependence rates at 1 year after operation were 77 and 15%, respectively. Fifty-nine percent of the patients were assessed to be able to communicate verbally. As in most other published studies, we found unsatisfactory survival figures after subtotal or total glossectomy and most patients remained dependent on gastrostomy tube. This surgery is, however, presumably the best and often only chance for cure in a selective patient population, and according to our opinion, it is indicated as a primary or salvage treatment provided that the reconstruction is planned optimally to guarantee a reasonable quality of life after surgery.
Harri Keski-Säntti, Leif Bäck, Patrik Lassus, Petri Koivunen, Ilpo Kinnunen, Henry Blomster, Antti Mäkitie, Katri Aro

Structural social relations and cognitive ageing trajectories: evidence from the Whitehall II cohort study.


International journal of epidemiology (07 November 2017)

Social relations are important for health, particularly at older ages. We examined the salience of frequency of social contacts and marital status for cognitive ageing trajectories over 21 years, from midlife to early old age. Data are from the Whitehall II cohort study, including 4290 men and 1776 women aged 35-55 years at baseline (1985-88). Frequency of social contacts and marital status were measured in 1985-88 and 1989-90. Assessment of cognitive function on five occasions (1991-94, 1997-99, 2003-04, 2007-09 and 2012-13) included the following tests: short-term memory, inductive reasoning, verbal fluency (phonemic and semantic) and a combined global score. Cognitive trajectories over the study period were analysed using longitudinal latent growth class analyses, and the associations of these latent classes (trajectory memberships) with social relations were analysed using multinominal logistic regression. More frequent social contacts [relative risk (RRR) 0.96, 95% confidence interval (CI) 0.94 - 0.98] and being married (RRR 0.70, 95% CI 0.58 - 0.84) were associated with lower probability of being on a low rather than high cognitive performance trajectory over the subsequent 21 years. These associations persisted after adjustment for covariates. Of the sub-tests, social relations variables had the strongest association with phonemic fluency (RRR 0.95, 95% CI 0.94 - 0.97 for frequent contact; RRR 0.59, 95% CI 0.48 - 0.71 for being married). More frequent social contacts and having a spouse were associated with more favourable cognitive ageing trajectories. Further studies are needed to examine whether interventions designed to improve social connections affect cognitive ageing.
Marko Elovainio, Andrew Sommerlad, Christian Hakulinen, Laura Pulkki-Råback, Marianna Virtanen, Mika Kivimäki, Archana Singh-Manoux

Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes.


Diabetologia (08 November 2017)

Enterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus-induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Longitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA. Seven of these samples were detected as enterovirus-positive, each of them collected from a different child, and transcriptomics data from these children were analysed to understand the individual-level responses associated with enterovirus infections. Transcript clusters with peaking or dropping expression at the time of enterovirus positivity were selected as the enterovirus-associated signals. Strong signs of activation of an interferon response were detected in four children at enterovirus positivity, while transcriptomic changes in the other three children indicated activation of adaptive immune responses. Additionally, a large proportion of the enterovirus-associated changes were specific to individuals. An enterovirus-induced signature was built using 339 genes peaking at enterovirus positivity in four of the children, and 77 of these genes were also upregulated in human peripheral blood mononuclear cells infected in vitro with different enteroviruses. These genes separated the four enterovirus-positive samples clearly from the remaining 352 blood samples analysed. We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes. The datasets analysed during the current study are included in this published article and its supplementary information files ( ) or are available from the Gene Expression Omnibus (GEO) repository (accession GSE30211).
Niina Lietzen, Le An, Maria Jaakkola, Henna Kallionpää, Sami Oikarinen, Juha Mykkänen, Mikael Knip, Riitta Veijola, Jorma Ilonen, Jorma Toppari, Heikki Hyöty, Riitta Lahesmaa, Laura Elo

Talking about paranoid experiences: Interactional dynamics of accomplishing disclosure of psychotic symptoms in triadic conversation.


Communication & medicine, Vol. 12, No. 1., pp. 25-40

The present study is the first to investigate, using conversation analysis, the effects of a family member’s participation in conversation regarding the assessment of need for treatment. We aim at describing the course of a treatment negotiation, focusing on interactional dynamics and on disclosure of paranoid symptoms in a clinically challenging situation characterized by an acutely psychotic patient with (1) disorganized discourse, (2) poor insight, (3) aspiration to avoid hospital treatment, and (4) a relative who was supporting in-patient care. In the triadic conversation, in which the patient, his relative, and the psychiatrist participated, different consecutive phases were distinguished. The Relative Prominent Information Phase (RIP) was characterized by the relative’s statements on the patient’s problematic behavior, and conflicting views between the patient and his relative led to denial of symptoms by the patient. When the patient was prominent in the latter Patient Prominent Information Phase (PIP), the display of several different social actions and corresponding linguistic devices were linked with more overt talk about paranoid experiences by the patient, albeit in a disorganized manner. RIP and PIP were followed by an Evaluation and Decision Phase (EDP).
Pertti Olavi Hella, Jussi Niemi, Jani-Matti Tirkkonen, Jukka Hintikka, Hannu Koponen, Heli Koivumaa-Honkanen

Incorporating functional genomic information to enhance polygenic signal and identify variants involved in gene-by-environment interaction for young adult alcohol problems.


Alcoholism, clinical and experimental research (09 November 2017)

Characterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene-by-environment interaction (G×E) effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse, and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit G×E effects. We examined these questions in the young adult FinnTwin12 sample (n=1170). We used genome-wide association estimates from an independent sample to derive two types of polygenic scores for alcohol problems in FinnTwin12. Genome-wide polygenic scores included all SNPs surpassing a designated p-value threshold. DNase polygenic scores were a subset of the genome-wide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a non-psychiatric model phenotype in order to evaluate the consistency of effects. For the G×E analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant G × E effects in an interaction between romantic relationship status and intoxication frequency. Contrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per-SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In G×E models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. These findings highlight the potential utility of integrating functional genomic annotation information in order to increase the signal-to-noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Jessica Salvatore, Jeanne Savage, Peter Barr, Aaron Wolen, Fazil Aliev, Eero Vuoksimaa, Antti Latvala, Lea Pulkkinen, Richard Rose, Jaakko Kaprio, Danielle Dick

Adults who were born preterm with a very low birth weight reported a similar health-related quality of life to their term-born peers.


Acta paediatrica (Oslo, Norway : 1992) (08 November 2017)

Approximately 1% of European infants are born preterm with a very low birth weight (VLBW) of less than 1,500g and the first babies born at the threshold of viability who received modern neonatal intensive care are now adults. While most live healthy lives, average VLBW adults tend to have more neurodevelopmental disabilities, lower educational achievement and higher rates of chronic conditions (1). Health-related quality of life (HRQoL) is defined as a construct of physical, mental and social wellbeing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Johan Björkqvist, Petteri Hovi, Anu-Katriina Pesonen, Katri Räikkönen, Kati Heinonen, Anna-Liisa Järvenpää, Johan Eriksson, Sture Andersson, Eero Kajantie

Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis.


British journal of anaesthesia, Vol. 119, No. 4. (01 October 2017), pp. 821-829

To prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients' performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain. We analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2-4 °C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain. Whether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the "persistent pain" group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate. Results provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent.
J Lötsch, A Ultsch, E Kalso

Effects of four different antihypertensive drugs on plasma metabolomic profiles in patients with essential hypertension.


PloS one, Vol. 12, No. 11. (2017)

In order to search for metabolic biomarkers of antihypertensive drug responsiveness, we measured >600 biochemicals in plasma samples of subjects participating in the GENRES Study. Hypertensive men received in a double-blind rotational fashion amlodipine, bisoprolol, hydrochlorothiazide and losartan, each as a monotherapy for one month, with intervening one-month placebo cycles. Metabolomic analysis was carried out using ultra high performance liquid chromatography-tandem mass spectrometry. Full metabolomic signatures (the drug cycles and the mean of the 3 placebo cycles) became available in 38 to 42 patients for each drug. Blood pressure was monitored by 24-h recordings. Amlodipine (P values down to 0.002), bisoprolol (P values down to 2 x 10-5) and losartan (P values down to 2 x 10-4) consistently decreased the circulating levels of long-chain acylcarnitines. Bisoprolol tended to decrease (P values down to 0.002) the levels of several medium- and long-chain fatty acids. Hydrochlorothiazide administration was associated with an increase of plasma uric acid level (P = 5 x 10-4) and urea cycle metabolites. Decreases of both systolic (P = 0.06) and diastolic (P = 0.04) blood pressure after amlodipine administration tended to associate with a decrease of plasma hexadecanedioate, a dicarboxylic fatty acid recently linked to blood pressure regulation. Although this systematic metabolomics study failed to identify circulating metabolites convincingly predicting favorable antihypertensive response to four different drug classes, it provided accumulating evidence linking fatty acid metabolism to human hypertension.
Timo Hiltunen, Jenni Rimpelä, Robert Mohney, Steven Stirdivant, Kimmo Kontula

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years.


The New England journal of medicine, Vol. 377, No. 19. (09 November 2017), pp. 1836-1846The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years. Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.).Hongchao Pan, Richard Gray, Jeremy Braybro[...]