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Oncoprotein Tudor-SN is a key determinant providing survival advantage under DNA damaging stress.

2018-02-22T11:23:40-00:00

Cell death and differentiation (19 February 2018)

Herein, Tudor-SN was identified as a DNA damage response (DDR)-related protein that plays important roles in the early stage of DDR. X-ray or laser irradiation could evoke the accumulation of Tudor-SN to DNA damage sites in a poly(ADP-ribosyl)ation-dependent manner via interaction with PARP-1. Additionally, we illustrated that the SN domain of Tudor-SN mediated the association of these two proteins. The accumulated Tudor-SN further recruited SMARCA5 (ATP-dependent chromatin remodeller) and GCN5 (histone acetyltransferase) to DNA damage sites, resulting in chromatin relaxation, and consequently activating the ATM kinase and downstream DNA repair signalling pathways to promote cell survival. Consistently, the loss-of-function of Tudor-SN attenuated the enrichment of SMARCA5, GCN5 and acetylation of histone H3 (acH3) at DNA break sites and abolished chromatin relaxation; as a result, the cells exhibited DNA repair and cell survival deficiency. As Tudor-SN protein is highly expressed in different tumours, it is likely to be involved in the radioresistance of cancer treatment.
Xiao Fu, Chunyan Zhang, Hao Meng, Kai Zhang, Lei Shi, Cheng Cao, Ye Wang, Chao Su, Lingbiao Xin, Yuanyuan Ren, Wei Zhang, Xiaoming Sun, Lin Ge, Olli Silvennoinen, Zhi Yao, Xi Yang, Jie Yang



Diversity of pubertal development in cartilage-hair hypoplasia - two illustrative cases.

2018-02-22T06:58:18-00:00

Journal of pediatric and adolescent gynecology (17 February 2018)

Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia, including disproportionate short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Absent pubertal growth spurt and absent pubic hair complicate monitoring of pubertal development in these patients. Two CHH patients with delayed puberty and excessive growth failure are described. One of the girls had hypogonadotropic hypogonadism while the other had hypo-normogonadotropic hypogonadism with no spontaneous pubertal development and slow response to estrogen therapy, both requiring permanent replacement therapy. Careful follow up of pubertal development in individuals with CHH and other growth restricting bone diseases is needed. In delayed pubertal development timely hormone therapy is essential to ensure maximal growth and well-developed secondary sex characteristics. Copyright © 2018. Published by Elsevier Inc.
Elina Holopainen, Svetlana Vakkilainen, Outi Mäkitie



Association of 10-year C-reactive protein trajectories with markers of healthy aging: findings from the English Longitudinal Study of Ageing.

2018-02-22T06:56:42-00:00

The journals of gerontology. Series A, Biological sciences and medical sciences (15 February 2018)

Elevated systematic inflammation is a hallmark of aging, but the association of long-term inflammation trajectories with subsequent aging phenotypes has been little examined. We assessed inflammatory marker C-reactive protein (CRP) repeatedly over time and examined whether long-term changes predicted aging outcomes. A total of 2,437 men and women aged 47-87 years at baseline (1998-2001) who were participants in the English Longitudinal Study of Ageing had CRP measured on two or three occasions between 1998 and 2009. Inflammation trajectories were computed using latent-class growth mixture modelling and were related to aging outcomes measured in 2012/2013: physical functioning, cardiometabolic, respiratory, mental health, and a composite "healthy aging" outcome. Four CRP trajectories were identified: 'stable-low' (71% of the sample) with baseline mean 1.33mg/L remaining <3mg/L; 'medium-to-high' (14%) with baseline 2.7mg/L rising to 5.3mg/L; 'high-to-medium' (10%) with baseline 6.6mg/L decreasing to 2.4mg/L; 'stable-high' (5%) with levels from 5.7 to 7.5mg/L. Relative to the stable-low trajectory, individuals in the medium-to-high had a higher risk of limitations in basic activities of daily living (ADL, Odds Ratio; 95% Confidence Interval: 2.09; 1.51,2.88), instrumental ADL (1.62; 1.15,2.30), impaired balance (1.59; 1.20,2.11) and walking speed (1.61; 1.15,2.24), arthritis (1.55; 1.16,2.06), hypertension (1.57; 1.21,2.04), obesity (1.95; 1.36,2.80), poor respiratory function (1.84; 1.36,2.50), and depression (1.55; 1.13,2.12). A lower odds of healthy aging was observed in people in the medium-to-high (0.57; 0.40,0.79) and stable-high (0.50; 0.27,0.91) trajectories. Older people who displayed an elevation in CRP levels over a decade experienced an increased risk of adverse aging outcomes.
Camille Lassale, David Batty, Andrew Steptoe, Dorina Cadar, Tasnime Akbaraly, Mika Kivimäki, Paola Zaninotto



The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

2018-02-22T06:51:20-00:00

Human mutation (20 February 2018)

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24), nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the non-pathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Mara Colombo, Irene Lòpez-Perolio, Huong Meeks, Laura Caleca, Michael Parsons, Hongyan Li, Giovanna De Vecchi, Emma Tudini, Claudia Foglia, Patrizia Mondini, Siranoush Manoukian, Raquel Behar, Encarna Gomez Garcia, Alfons Meindl, Marco Montagna, Dieter Niederacher, Ane Schmidt, Liliana Varesco, Barbara Wappenschmidt, Manjeet Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, Kristiina Aittomäki, Irene Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias Beckmann, Alicia Beeghly-Fadel, Javier Benitez, Bram Boeckx, Natalia Bogdanova, Stig Bojesen, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Jenny Chang-Claude, Don Conroy, Fergus Couch, Angela Cox, Simon Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Mikael Eriksson, Peter Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Marike Gabrielson, Montserrat García-Closas, Graham Giles, Anna González-Neira, Pascal Guénel, Christopher Haiman, Per Hall, Ute Hamann, Mikael Hartman, Jan Hauke, Antoinette Hollestelle, John Hopper, Anna Jakubowska, Audrey Jung, Veli-Matti Kosma, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubinski, Arto Mannermaa, Sara Margolin, Hui Miao, Roger Milne, Susan Neuhausen, Heli Nevanlinna, Janet Olson, Paolo Peterlongo, Julian Peto, Katri Pylkäs, Elinor Sawyer, Marjanka Schmidt, Rita Schmutzler, Andreas Schneeweiss, Minouk Schoemaker, Mee Hoong See, Melissa Southey, Anthony Swerdlow, Soo Teo, Amanda Toland, Ian Tomlinson, Thérèse Truong, Christi van Asperen, Ans van den Ouweland, Lizet van der Kolk, Robert Winqvist, Drakoulis Yannoukakos, Wei Zheng, , Alison Dunning, Douglas Easton, Alex Henderson, Frans Hogervorst, Louise Izatt, Kenneth Offitt, Lucy Side, Elizabeth van Rensburg, Study Embrace, Study Hebon, Lesley McGuffog, Antonis Antoniou, Georgia Chenevix-Trench, Amanda Spurdle, David Goldgar, Miguel de la Hoya, Paolo Radice



Heterogeneity of gestational diabetes (GDM) and long-term risk of diabetes and metabolic syndrome: findings from the RADIEL study follow-up.

2018-02-22T06:48:44-00:00

Acta diabetologica (19 February 2018)

To assess the metabolic health of obese and non-obese women at high GDM risk 5 years postpartum. This is a secondary analysis of the 5-year follow-up of the RADIEL GDM prevention study including 333 women at high GDM risk (BMI ≥ 30 kg/m2and/or previous GDM). Five years postpartum metabolic health was assessed including anthropometric measurements, oral glucose tolerance test, lipid metabolism, and body composition as well as medical history questionnaires. For the analysis, we divided the women into four groups based on parity, BMI, and previous history of GDM. Five years postpartum impaired glucose regulation (IFG, IGT, or diabetes) was diagnosed in 15% of the women; 3.6% had type 2 diabetes. The highest prevalence was observed among obese women with a history of GDM (26%), and the lowest prevalence (8%) among primiparous obese women (p = 0.021). At follow-up 25-39% of the obese women fulfilled the diagnostic criteria for the metabolic syndrome, in the non-obese group 11% (p < 0.001). This was associated with body fat percentage. The non-obese group, however, faced metabolic disturbances (IFG, IGT, diabetes, or metabolic syndrome) at a significantly lower BMI (p < 0.001). Among women who were non-obese before pregnancy, 5 years postpartum, the obesity prevalence based on BMI was 14% and based on body fat percentage 58%. The prevalence of impaired glucose regulation and metabolic syndrome is high 5 years postpartum among women at high risk of GDM. There are high-risk women also among the non-obese, who develop metabolic derangements already at a lower BMI. ClinicalTrials.gov, www.clinicaltrials.com , NCT01698385.
Emilia Huvinen, Johan Eriksson, Saila Koivusalo, Nora Grotenfelt, Aila Tiitinen, Beata Stach-Lempinen, Kristiina Rönö



Lessons learned from the 1-hour post-load glucose level during the OGTT - Current screening recommendations for dysglycemia should be revised.

2018-02-22T06:46:07-00:00

Diabetes/metabolism research and reviews (19 February 2018)

This perspective covers a novel area of research describing the inadequacies of current approaches for diagnosing dysglycemia and proposes that the 1-hour post-load glucose level during the 75 gram OGTT may serve as a novel biomarker to detect dysglycemia earlier than currently recommended screening criteria for glucose disorders. Considerable evidence suggests that a 1-hour post-load plasma glucose value >155 mg/dl (8.6 mmol/l) may identify individuals with reduced β-cell function prior to progressing to prediabetes and diabetes and is highly predictive of those likely to progress to diabetes more than the HbA1cor 2-hour post-load glucose values. An elevated 1-hour post-load glucose level was a better predictor of type 2 diabetes than isolated 2- hour post-load levels in Indian, Japanese, and Israeli and Nordic populations. Furthermore, epidemiological studies have shown that a 1-hour PG >155 mg/dl (8.6 mmol/l) predicted progression to diabetes as well as increased risk for microvascular disease and mortality when the 2-hour level was < 140 mg/dl (7.8 mmol/l). The risk of myocardial infarction or fatal ischemic heart disease was also greater among subjects with elevated 1-hour glucose levels as were risks of retinopathy and peripheral vascular complications in a Swedish cohort. The authors believe that the considerable evidence base supports redefining current screening and diagnostic recommendations with the 1-hour post-load level. Measurement of the 1-hour PG level would increase the likelihood of identifying a larger, high-risk group with the additional practical advantage of potentially replacing the conventional 2-hour OGTT making it more acceptable in a clinical setting. This article is protected by copyright. All rights reserved.
Michael Bergman, Ram Jagannathan, Martin Buysschaert, Manan Pareek, Michael Olsen, Peter Nilsson, José Luis Medina, Jesse Roth, Angela Chetrit, Leif Groop, Rachel Dankner



Secreted frizzled-related protein 2 (SFRP2) expression promotes lesion proliferation via canonical WNT signaling and indicates lesion borders in extraovarian endometriosis.

2018-02-22T06:43:40-00:00

Human reproduction (Oxford, England) (15 February 2018)

What is the role of SFRP2 in endometriosis? SFRP2 acts as a canonical WNT/CTNNB1 signaling agonist in endometriosis, regulating endometriosis lesion growth and indicating endometriosis lesion borders together with CTNNB1 (also known as beta catenin). Endometriosis is a common, chronic disease that affects women of reproductive age, causing pain and infertility, and has significant economic impact on national health systems. Despite extensive research, the pathogenesis of endometriosis is poorly understood, and targeted medical treatments are lacking. WNT signaling is dysregulated in various human diseases, but its role in extraovarian endometriosis has not been fully elucidated. We evaluated the significance of WNT signaling, and especially secreted frizzled-related protein 2 (SFRP2), in extraovarian endometriosis, including peritoneal and deep lesions. The study design was based on a cohort of clinical samples collected by laparoscopy or curettage and questionnaire data from healthy controls and endometriosis patients. Global gene expression analysis in human endometrium (n = 104) and endometriosis (n = 177) specimens from 47 healthy controls and 103 endometriosis patients was followed by bioinformatics and supportive qPCR analyses. Immunohistochemistry, Western blotting, primary cell culture and siRNA knockdown approaches were used to validate the findings. Among the 220 WNT signaling and CTNNB1 target genes analysed, 184 genes showed differential expression in extraovarian endometriosis (P < 0.05) compared with endometrium tissue, including SFRP2 and CTNNB1. Menstrual cycle-dependent regulation of WNT genes observed in the endometrium was lost in endometriosis lesions, as shown by hierarchical clustering. Immunohistochemical analysis indicated that SFRP2 and CTNNB1 are novel endometriosis lesion border markers, complementing immunostaining for the known marker CD10 (also known as MME). SFRP2 and CTNNB1 localized similarly in both the epithelium and stroma of extraovarian endometriosis tissue, and interestingly, both also indicated an additional distant lesion border, suggesting that WNT signaling is altered in the endometriosis stroma beyond the primary border indicated by the known marker CD10. SFRP2 expression was positively associated with pain symptoms experienced by patients (P < 0.05), and functional loss of SFRP2 in extraovarian endometriosis primary cell cultures resulted in decreased cell proliferation (P < 0.05) associated with reduced CTNNB1 protein expression (P = 0.05). SFRP2 and CTNNB1 improved extraovarian endometriosis lesion border detection in a relatively small cohort (n = 20), although larger studies with different endometriosis subtypes in variable cycle phases and under hormonal medication are required. The highly expressed SFRP2 and CTNNB1 improve endometriosis lesion border detection, which can have clinical implications for better visualization of endometriosis lesions over CD10. Furthermore, SFRP2 acts as a canonical WNT/CTNNB1 signaling agonist in endometriosis and positively regulates endometriosis lesion growth, suggesting that the WNT pathway may be an important therapeutic target for endometriosis. This study was funded by the Academy of Finland and by Tekes: Finnish Funding Agency for Innovation. The authors have no conflict of interest to declare.
T Heinosalo, M Gabriel, L Kallio, P Adhikari, K Huhtinen, TD Laajala, E Kaikkonen, A Mehmood, P Suvitie, H Kujari, T Aittokallio, A Perheentupa, M Poutanen



Root Canal Irrigants and Medicaments in Endodontic Malpractice Cases: A Nationwide Longitudinal Observation.

2018-02-22T06:42:07-00:00

Journal of endodontics (16 February 2018)

The aim of this study was to assess the role of root canal irrigants and medicaments in endodontic injuries verified in Finland and to estimate the rate of such events over time. The study material comprised all endodontic injuries verified by the Patient Insurance Centre in 2002 to 2006 (n = 521) and 2011 to 2013 (n = 449). The data, based on patient documents scrutinized by 2 specialists in endodontics, included patients' and dentists' sex and age and the service sector. We recorded the use of root canal irrigants and medicaments, each as a dichotomy. Furthermore, we dichotomized the injuries as those related to root canal irrigants/medicaments and any other injuries. The injuries were also dichotomized as avoidable (could have been avoided by following good clinical practice) or unavoidable (normal treatment-related risks). Statistical evaluation used chi-square tests and t tests; logistic regression produced odds ratios (ORs). The verified injuries (N = 970) comprised 635 (65%) avoidable and 335 (35%) unavoidable injuries. The number of irrigant-/medicament-related injuries was 69, accounting for 7.1% of all verified injuries; all resulted from sodium hypochlorite and calcium hydroxide, and 87% were avoidable. The overall rate of sodium hypochlorite/calcium hydroxide injuries was 4.3 cases per 100,000 endodontic patients per year. Compared with other injuries, sodium hypochlorite/calcium hydroxide injuries were more likely avoidable (OR = 3.8) and more than 5-fold likely in 2011 to 2013 than in 2002 to 2006 (OR = 5.6). Extreme care is needed when applying sodium hypochlorite and calcium hydroxide into root canals to avoid increasing harmful consequences. Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.
Outi Swanljung, Miira Vehkalahti



Higher mortality of adults with asthma: a 15 year follow-up of apopulation-based cohort.

2018-02-22T06:28:57-00:00

Allergy (20 February 2018)

Higher all-cause mortality in asthmatics has been shown previously. Polysensitization is associated with higher morbidity among asthmatic children, and allergic rhinitis and/or allergic conjunctivitis (AR/AC) is associated with higher morbidity in adult asthmatics. Little is known about the effect of AR/AC and other factors on mortality among adult asthmatics. The aim was to study mortality and its risk factors in adults with and without asthma. We randomly selected 1648 asthmatics with age over 30 years from national registers and matched the asthma sample with one or two controls. Baseline information was obtained by a questionnaire in 1997, and the study population was linked with the death certificate information of Statistics Finland from 1997 to 2013. Overall and cause-specific survival between the groups was compared in several adjusted models. During a mean follow-up period of 15.6 years, 221 deaths among 1052 asthma patients and 335 deaths among 1889 non-asthmatics were observed. Cardiovascular diseases were the main cause of death in both groups. Asthma was associated with increased all-cause mortality (adjusted HR 1.25; 95% CI 1.05-1.49, P=0.011); as well as mortality from chronic obstructive pulmonary disease (HR 12.0, 4.18-34.2, P<0.001) and malignant neoplasms of respiratory organs (HR 2.33, 1.25-4.42, P=0.008). Among asthmatics, smoking was associated with increased all-cause mortality and self-reported AR/AC was associated with decreased mortality. Among non-asthmatics, smoking and obesity were associated with increased all-cause mortality, whereas female gender showed an association with a decreased risk. Increased mortality among adult asthmatics was largely explained by the development of COPD, malignant respiratory tract neoplasms and cardiovascular diseases. Smoking cessation is important for reduction of total mortality in both asthmatic and non-asthmatic adults. AR/AC was associated with decreased mortality only in asthmatics. Thus, studies in other populations of larger size are needed to explore further the nature of this association. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Riikka Lemmetyinen, Jussi Karjalainen, Anna But, Risto Renkonen, Juha Pekkanen, Sanna Toppila-Salmi, Jari Haukka



Cut stroke in half: Polypill for primary prevention in stroke.

2018-02-22T06:26:27-00:00

International journal of stroke (01 January 2018)

This review summarizes the potential for polypill therapies for stroke prevention. While a number of studies applying different approaches regarding polypill have been performed, none of them has had a focus on stroke as the main outcome. A combination pill containing drugs such as statins, diuretics, and other antihypertensives is currently available in various formats. Estimates focusing mostly on primary prevention show that using such a combination drug a reduction in the 5-year stroke incidence by 50% can be achieved - especially in low- and middle-income countries with a high prevalence of risk factors even among people at young ages. A combination of a large supporting population-wide program with a registry-based quality control is the most likely perspective and can be achieved within a reasonable time frame and potentially have significant influence in young stroke populations.
Michael Brainin, Valery Feigin, Sheila Martins, Karl Matz, Jayanta Roy, Peter Sandercock, Yvonne Teuschl, Jaakko Tuomilehto, Anita Wiseman



A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

2018-02-21T06:52:58-00:00

American journal of human genetics (13 February 2018)Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2). Copyright © 2018 American Society of Human Genetics. All rights reserved.Yun Sung, Thomas Winkler, Lisa de Las Fuentes, Amy Bentley, Michael Brown, Aldi Kraja, Karen Schwander, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Yingchang Lu, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon Musani, Changwei Li, Mary Feitosa, Tuomas Kilpeläinen, Melissa Richard, Raymond Noordam, Stella Aslibekyan, Hugues Aschard, Traci Bartz, Rajkumar Dorajoo, Yongmei Liu, Alisa Manning, Tuomo Rankinen, Albert Vernon Smith, Salman Tajuddin, Bamidele Tayo, Helen Warren, Wei Zhao, Yanhua Zhou, Nana Matoba, Tamar Sofer, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Ilaria Gandin, Chuan Gao, Franco Giulianini, Anuj Goel, Sarah Harris, Fernando Pires Hartwig, Andrea Horimoto, Fang-Chi Hsu, Anne Jackson, Mika Kähönen, Anuradhani Kasturiratne, Brigitte Kühnel, Karin Leander, Wen-Jane Lee, Keng-Hung Lin, Jian 'an Luan, Colin McKenzie, He Meian, Christopher Nelson, Rainer Rauramaa, Nicole Schupf, Robert Scott, Wayne Sheu, Alena Stančáková, Fumihiko Takeuchi, Peter van der Most, Tibor Varga, Heming Wang, Yajuan Wang, Erin Ware, Stefan Weiss, Wanqing Wen, Lisa Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Tamuno Alfred, Najaf Amin, Dan Arking, Tin Aung, Graham Barr, Lawrence Bielak, Eric Boerwinkle, Erwin Bottinger, Peter Braund, Jennifer Brody, Ulrich Broeckel, Claudia Cabrera, Brian Cade, Yu Caizheng, Archie Campbell, Mickaël Canouil, Aravinda Chakravarti, , Ganesh Chauhan, Kaare Christensen, Massimiliano Cocca, , Francis Collins, John Connell, Renée de Mutsert, Janaka de Silva, Stephanie Debette, Marcus Dörr, Qing Duan, Charles Eaton, Georg Ehret, Evangelos Evangelou, Jessica Faul, Virginia Fisher, Nita Forouhi, Oscar Franco, Yechiel Friedlander, He Gao, , Bruna Gigante, Misa Graff, Charles Gu, Dongfeng Gu, Preeti Gupta, Saskia Hagenaars, Tamara Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Albert Hofman, Barbara Howar[...]



Hypothalamic ER-associated degradation regulates POMC maturation, feeding, and age-associated obesity.

2018-02-21T06:51:41-00:00

The Journal of clinical investigation (19 February 2018)

Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron-specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding.
Geun Hyang Kim, Guojun Shi, Diane Rm Somlo, Leena Haataja, Soobin Song, Qiaoming Long, Eduardo Nillni, Malcolm Low, Peter Arvan, Martin Myers, Ling Qi



Perioperative Complications of Transanal Pull-through Surgery for Hirschsprung's Disease.

2018-02-21T06:48:56-00:00

European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie (19 February 2018)

Transanal pull-through is currently one of the most commonly used operation to treat Hirschsprung's disease (HD) worldwide. It has undergone some technical modifications during the last decades and still contains variable surgical practices. As high quality comparative studies between different surgical approaches are missing, debate over the optimal operation for HD still continues. Transanal pull-through is associated with multiple potential complications, which may result in permanently impaired functional outcome, life-long morbidity, and significant social restrictions. Although some of the surgical complications can be successfully managed by repeated surgery, the best changes for optimal bowel function and fecal continence are lost. Surgical complications are best treated by efficient prevention with careful adherence to established surgical techniques and principles during the primary operation. Georg Thieme Verlag KG Stuttgart · New York.
Mikko Pakarinen



Work-loss years among people diagnosed with diabetes: a reappraisal from a life course perspective.

2018-02-21T06:47:16-00:00

Acta diabetologica (17 February 2018)

Early exit from the workforce has been proposed to be one of the unfavorable consequences of diabetes. We examined whether early exit from the workforce differed between persons who were and were not diagnosed with diabetes during their work career. The cohort included 12,726 individuals of the Helsinki Birth Cohort Study, born between 1934 and 1944. Using data from nationwide registers, the cohort was followed up from early adulthood until they transitioned into retirement or died. Work-loss years were estimated using the restricted mean work years method. During a follow-up of 382,328 person-years for men and 349 894 for women, 36.8% transitioned into old age pension and 63.2% exited workforce early. Among men, 40.5% of those with and 32.8% of those without diabetes transitioned into old age pension (p=0.003). The corresponding numbers for women were 48.6% and 40.4% (p = 0.013), respectively. Mean age at exit from the workforce was 60.1 (95% confidence interval [CI], 59.6 to 60.7) years among men with diabetes and 57.6 (95% CI, 57.2 to 58.0) years among men without diabetes (p = 0.016). Among women, corresponding ages were 61.4 (95% CI, 60.8 to 61.9) years for those with diabetes and 59.5 (95% CI, 59.3 to 59.7) years for those without diabetes (p < 0.001). The difference in mean restricted work-loss years according to diabetes was 2.5 (95% CI 0.5 to 4.6) for men and 1.9 (95% CI 1.0 to 2.8) for women. Among individuals followed up throughout their work career, those with a diabetes diagnosis exited the workforce approximately two years later compared to those without diabetes.
Mikaela von Bonsdorff, Monika von Bonsdorff, Maija Haanpää, Minna Salonen, Tuija Mikkola, Hannu Kautiainen, Johan Eriksson



Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients with Crohn's Disease.

2018-02-20T12:39:02-00:00

Gastroenterology (15 February 2018)

Individuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's Disease (CD). We tested for associations between mutations in genes encoding NADPH oxidases, neutrophil function, and phenotypes of CD in pediatric patients. We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production. We identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P=.0008) and stricturing complications (P=.002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P=.0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P=.002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P=.009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and anti-microbial responses. We identified missense mutations in genes that encode NADPH oxidases in children with CD; these associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
Lee Denson, Ingrid Jurickova, Rebekah Karns, Kelly Shaw, David Cutler, David Okou, Anne Dodd, Kathryn Quinn, Kajari Mondal, Bruce Aronow, Yael Haberman, Aaron Linn, Adam Price, Ramona Bezold, Kathleen Lake, Kimberly Jackson, Thomas Walters, Anne Griffiths, Robert Baldassano, Joshua Noe, Jeffrey Hyams, Wallace Crandall, Barbara Kirschner, Melvin Heyman, Scott Snapper, Stephen Guthery, Marla Dubinsky, Neal Leleiko, Anthony Otley, Ramnik Xavier, Christine Stevens, Mark Daly, Michael Zwick, Subra Kugathasan



The outcome and timing of death of 17,767 nosocomial bloodstream infections in acute care hospitals in Finland during 1999-2014.

2018-02-20T12:27:57-00:00

European journal of clinical microbiology & infectious diseases (17 February 2018)

Few studies covering all patient groups and specialties are available regarding the outcome of nosocomial bloodstream infections (BSI). We analyzed the role of patient characteristics and causative pathogens of nosocomial BSIs reported by the hospitals participating in national surveillance in Finland during 1999-2014, in terms of outcome, with particular interest in those leading to death within 2 days (i.e. early death). National nosocomial BSI surveillance was laboratory-based and hospital-wide. Data on nosocomial BSIs was collected by infection control nurses, and dates of death were obtained from the national population registry with linkage to national identity codes. A total of 17,767 nosocomial BSIs were identified; 557 BSIs (3%) were fatal within 2 days and 1150 (6%) within 1 week. The 1-month case fatality was 14% (2460 BSIs), and 23% of the deaths occurred within 2 days and 47% within 1 week. The patients who died early were older than those who survived > 28 days, and their BSIs were more often related to intensive care. Gram-positive bacteria caused over half of the BSIs of patients who survived, whereas gram-negative bacteria, especially Pseudomonas aeruginosa, caused more often BSIs of patients who died early, and fungi BSIs of patients who died within 1 week. A significant portion of patients with nosocomial BSIs died early, which underlines the importance of rapid recognition of BSI. Hospital-wide surveillance data of causative pathogens can be utilized when composing recommendations for empiric antimicrobial treatment in collaboration with clinicians, as well as when promoting infection prevention.
Keiju Kontula, Kirsi Skogberg, Jukka Ollgren, Asko Järvinen, Outi Lyytikäinen



An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans.

2018-02-20T12:26:10-00:00

Cell metabolism (07 February 2018)

A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum β-hydroxybutyrate concentrations, reflecting increased mitochondrial β-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD. Copyright © 2018 Elsevier Inc. All rights reserved.
Adil Mardinoglu, Hao Wu, Elias Bjornson, Cheng Zhang, Antti Hakkarainen, Sari Räsänen, Sunjae Lee, Rosellina Mancina, Mattias Bergentall, Kirsi Pietiläinen, Sanni Söderlund, Niina Matikainen, Marcus Ståhlman, Per-Olof Bergh, Martin Adiels, Brian Piening, Marit Granér, Nina Lundbom, Kevin Williams, Stefano Romeo, Jens Nielsen, Michael Snyder, Mathias Uhlén, Göran Bergström, Rosie Perkins, Hanns-Ulrich Marschall, Fredrik Bäckhed, Marja-Riitta Taskinen, Jan Borén



Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study.

2018-02-19T11:07:18-00:00

The Lancet. Infectious diseases (13 February 2018)

Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p<0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05-2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p<0·001). Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication. DFID-MRC-Wellcome Trust Joint Global Health Trial Development Grant, National Institute of Health Research Global Health Research Unit Grant. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.



Late gadolinium enhancement (LGE) progresses with right ventricle volume in children after repair of tetralogy of fallot.

2018-02-19T11:00:07-00:00

International journal of cardiology. Heart & vessels, Vol. 3 (June 2014), pp. 15-20

Fibrosis after myocardial damage can be determined by cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE). We studied whether ventricular LGE is visible in the ventricles of pediatric and adolescent TOF (tetralogy of Fallot) patients by measuring LGE and investigating whether fibrosis correlated with right ventricular volume, pulmonary regurgitation, N-terminal pro-brain natriuretic peptide (NT-proBNP) or the aminoterminal propeptide of type III procollagen (PIIINP). We also studied if the patient's age, post-operative follow-up time or surgical history would affect LGE. A total of 40 pediatric patients who had undergone TOF repair and 43 healthy age and gender matched controls underwent a CMR study, whereby LGE was scored in the right (RV) and the left ventricle. To exclude the possible iatrogenic scarring we calculated the LGE score by excluding the right ventricular outflow tract and VSD patch region. All patients had RV LGE and in 39 of 40 it was seen also outside the surgically affected areas. The amount of LGE correlated positively with the RV end-diastolic volume (r = 0.44, P = 0.0045), pulmonary regurgitation (r = 0.40, P = 0.013), and with NT-proBNP. The presence of LGE also depended on post-operative follow-up time (r = 0.53, P = 0.006). PIIINP levels of TOF patients were significantly higher than in the control subjects but it did not correlate with LGE or with any of the studied clinical markers. LGE is present globally in the right ventricular muscle in children and adolescents with TOF. The longer the follow-up time the more common was the LGE in the right ventricle.
Pekka Ylitalo, Olli Pitkänen, Kirsi Lauerma, Miia Holmström, Otto Rahkonen, Markku Heikinheimo, Heikki Sairanen, Eero Jokinen



Voiding school as a treatment for daytime incontinence or enuresis: Assessing the effectiveness of intervention by measuring changes in wetting episodes.

2018-02-19T10:57:20-00:00

Journal of pediatric urology (05 February 2018)

Most urotherapy interventions are planned for children with daytime incontinence or symptoms, and are based on individual education. This study conducted a voiding school (VS) program with groups of 4-6 children with daytime incontinence or enuresis with or without daytime symptoms. The aim of this quasi-experimental study with a one-group pretest-posttest design was to assess the effectiveness of the VS intervention for treating children's daytime incontinence or enuresis. Sixty-nine 6-12-year-old children with incontinence classified as treatment resistant participated in the VS at an outpatient clinic. Based on a power analysis, a sample of 52 participants was required. The VS involved two whole-day group visits 2 months apart. The educational content of the intervention was based on the International Children's Continence Society's standards for urotherapy, and was delivered with child-oriented teaching methods, including group discussions with peers. The primary outcome measure was the number of dry days and nights. The amount of wetting was also estimated, and the frequency of voiding measured. Data were collected with 1-week voiding diaries before and after each visit. Changes in dependent variables between four measurement points was measured by using repeated measures variance analysis. The long-term effectiveness was evaluated from patient records concerning 3-month follow-up phone calls or other contacts 8-18 months after the VS. Fifty-eight children, 34 girls and 24 boys, completed the study. Twelve children had daytime incontinence, 18 had enuresis, and 28 had both. The number of dry days increased from a mean of 3.5-5.3 (P < 0.001), and the number of dry nights increased from a mean of 2.4-3.9 (P < 0.001) (Summary table). Thirteen (22%) children became completely dry. Three of them had daytime incontinence, five enuresis, and five both. Twenty-four out of 40 (60%) children with daytime incontinence, and 23 out of 46 (50%) children with enuresis showed ≥50% decrease in wetting episodes. The amount of wetting reduced, but the voiding frequency remained unchanged based on the voiding diaries. Twenty-two (45%) of the children were completely dry (six had daytime incontinence, nine enuresis, and seven both), and 16 (39%) showed further improvement, but eight (16%) children remained unchanged 8-18 months after the VS. Voiding school (VS) was an effective intervention for treating both daytime incontinence and nocturnal enuresis in children who had not benefited from standard treatment and were classified as treatment resistant. Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
A Saarikoski, R Koppeli, S Taskinen, A Axelin



European families reveal MHC class I and II associations with autoimmune-mediated congenital heart block.

2018-02-19T10:54:48-00:00

Annals of the rheumatic diseases (16 February 2018)
Nikolaos Kyriakidis, Ingrid Kockum, Heikki Julkunen, Ariela Hoxha, Stina Salomonsson, Lauro Meneghel, Cathrine Ebbing, , Alexander Dilthey, Marianne Eronen, Sara De Carolis, Torvid Kiserud, Amelia Ruffatti, Juha Kere, Sabrina Meisgen, Marie Wahren-Herlenius



Humoral response to John Cunningham virus during pregnancy in multiple sclerosis.

2018-02-19T10:52:48-00:00

Multiple sclerosis and related disorders, Vol. 21 (09 February 2018), pp. 11-18

Pregnancy induces an immunosuppressive state in the mother to ensure immunological acceptance of the foetus. Impairment of cell-mediated immune responses may render the mother susceptible to intracellular pathogens. It is not presently known whether pregnancy alters the immunosurveillance for John Cunningham virus (JCV), an opportunistic pathogen associated with natalizumab treatment for multiple sclerosis (MS). To evaluate whether the humoral immune response to JCV is altered during pregnancy among MS patients and healthy controls to get insight to potential pregnancy-induced alterations related to immune response to JCV during pregnancy. Serum anti-JCV-antibody-indices (JCV-Ab-index) were determined by a two-step second-generation enzyme-linked immunosorbent assay in 49 MS patients during and after pregnancy and in 49 healthy controls during pregnancy. For comparison, total IgG levels and antibodies against Epstein-Barr, cytomegalo and measles viruses were similarly measured. The JCV-Ab-indices of MS patients were not altered during the pregnancy (1st vs. 3rd trimester, 0.62 vs. 0.77, p = 0.99). Contrary to this, in the healthy controls JCV-Ab-indices (p = 0.005), antibody levels to the other viruses, and total IgG levels (p < 0.0001) decreased significantly during pregnancy. JCV-Ab levels remain unaltered during MS pregnancy, while the total IgG concentration is reduced/diluted due to increasing plasma volumes during the course of pregnancy. This may imply a biologically significant alteration in the immune response to JCV during MS pregnancy. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
M Saraste, S Atula, K Hedman, S Hurme, A Jalkanen, M Sneck, H-M Surcel, AH Maghzi, L Airas



Risk of Cardiovascular Disease and Death in Individuals With Prediabetes Defined by Different Criteria: The Whitehall II Study.

2018-02-19T10:50:20-00:00

Diabetes care (16 February 2018)

We compared the risk of cardiovascular disease (CVD) and all-cause mortality in subgroups of prediabetes defined by fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), or HbA1c. In the Whitehall II cohort, 5,427 participants aged 50-79 years, without diabetes, were followed for a median of 11.5 years. A total of 628 (11.6%) had prediabetes by the World Health Organization (WHO)/International Expert Committee (IEC) criteria (FPG 6.1-6.9 mmol/L and/or HbA1c6.0-6.4%), and 1,996 (36.8%) by the American Diabetes Association (ADA) criteria (FPG 5.6-6.9 mmol/L and/or HbA1c5.7-6.4%). In a subset of 4,730 individuals with additional measures of 2hPG, 663 (14.0%) had prediabetes by 2hPG. Incidence rates of a major event (nonfatal/fatal CVD or all-cause mortality) were compared for different definitions of prediabetes, with adjustment for relevant confounders. Compared with that for normoglycemia, incidence rate in the context of prediabetes was 54% higher with the WHO/IEC definition and 37% higher with the ADA definition (P< 0.001) but declining to 17% and 12% after confounder adjustment (P≥ 0.111). Prediabetes by HbA1cwas associated with a doubling in incidence rate for both the IEC and ADA criteria. However, upon adjustment, excess risk was reduced to 13% and 17% (P≥ 0.055), respectively. Prediabetes by FPG or 2hPG was not associated with an excess risk in the adjusted analysis. Prediabetes defined by HbA1cwas associated with a worse prognosis than prediabetes defined by FPG or 2hPG. However, the excess risk among individuals with prediabetes is mainly explained by the clustering of other cardiometabolic risk factors associated with hyperglycemia. © 2018 by the American Diabetes Association.
Dorte Vistisen, Daniel Witte, Eric Brunner, Mika Kivimäki, Adam Tabák, Marit Jørgensen, Kristine Færch



Serum matrix metalloproteinase-8, tissue inhibitor of metalloproteinase and myeloperoxidase in ischemic stroke.

2018-02-19T10:32:30-00:00

Atherosclerosis, Vol. 271 (08 February 2018), pp. 9-14

Matrix metalloproteinase (MMP)-8 and myeloperoxidase (MPO) may contribute to cerebral damage in acute ischemic stroke. We tested the hypothesis that levels of MPO, MMP-8 and the ratio between MMP-8 and its regulator, tissue inhibitor of metalloproteinase (TIMP-1), are increased in acute ischemic stroke and its etiologic subgroups and they correlate with stroke severity. In a cross-sectional case-control study, serum concentrations of MMP-8, MPO and TIMP-1 were assessed within 24 h after admission in 470 first-ever ischemic stroke patients and 809 age- and sex-matched controls, randomly selected from the population. Odds ratios (OR) per decade of log transformed dependent variables were calculated and adjusted for age, sex and vascular risk factors. Levels of MMP-8 (OR 4.9; 95% CI 3.4-7.2), MMP-8/TIMP-1 ratio (3.0; 2.2-4.1) and MPO (6.6; 4.0-11.0) were independently associated with ischemic stroke. MMP-8 levels differed between etiologic stroke subgroups (p = 0.019, ANOVA), with higher levels in cardioembolic stroke and stroke due to large vessel disease, and lower levels in microangiopathic stroke. MMP-8, MMP-8/TIMP-1 ratio and MPO (p < 0.001) concentrations showed positive associations with stroke severity independent of stroke etiology. Concentrations of serum neutrophil markers are increased after ischemic stroke and associate with stroke severity and etiology. The value of these biomarkers in diagnostics and prognostics is worth being evaluated. Copyright © 2018 Elsevier B.V. All rights reserved.
Frederick Palm, Pirkko Pussinen, Anton Safer, Taina Tervahartiala, Timo Sorsa, Christian Urbanek, Heiko Becher, Armin Grau



Genetic basis of diabetic kidney disease and other diabetic complications.

2018-02-19T08:31:55-00:00

Current opinion in genetics & development, Vol. 50 (13 February 2018), pp. 17-24

Diabetic kidney disease and other long-term complications are common in diabetes, and comprise the main cause of co-morbidity and premature mortality in individuals with diabetes. While familial clustering and heritability have been reported for all diabetic complications, the genetic background and the molecular mechanisms remain poorly understood. In recent years, genome-wide association studies have identified a few susceptibility loci for the renal complications as well as for diabetic retinopathy, diabetic cardiovascular disease and mortality. As for many complex diseases, the genetic factors increase the risk of complications in concert with the environment, and certain associations seem specific for particular conditions, for example, SP3-CDCA7 associated with end-stage renal disease only in women, or MGMT and variants on chromosome 5q13 associated with cardiovascular mortality only under tight glycaemic control. The characterization of the phenotypes is one of the main challenges for genetic research on diabetic complications, in addition to an urgent need to increase the number of individuals with diabetes with high quality phenotypic data to be included in future genetic studies. Copyright © 2018 Elsevier Ltd. All rights reserved.
Niina Sandholm, Per-Henrik Groop



Differential Regulation of PAI-1 in Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever With Renal Syndrome.

2018-02-19T08:27:36-00:00

Open forum infectious diseases, Vol. 5, No. 2. (February 2018)

We analyzed the levels of circulating tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-1 in acute hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). The levels of tPA commonly increased in both diseases, whereas PAI-1 correlated with disease severity in HCPS but not in HFRS.
Carla Bellomo, Miša Korva, Anna Papa, Satu Mäkelä, Jukka Mustonen, Tatjana Avšič-Županc, Antti Vaheri, Valeria Martinez, Tomas Strandin



Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

2018-02-19T08:19:53-00:00

Nature communications, Vol. 9, No. 1. (15 February 2018)

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
A Schrader, G Crispatzu, S Oberbeck, P Mayer, S Pützer, J von Jan, E Vasyutina, K Warner, N Weit, N Pflug, T Braun, EI Andersson, B Yadav, A Riabinska, B Maurer, MS Ventura Ferreira, F Beier, J Altmüller, M Lanasa, CD Herling, T Haferlach, S Stilgenbauer, G Hopfinger, M Peifer, TH Brümmendorf, P Nürnberg, KSJ Elenitoba-Johnson, S Zha, M Hallek, R Moriggl, HC Reinhardt, M-H Stern, S Mustjoki, S Newrzela, P Frommolt, M Herling



Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment.

2018-02-19T08:17:58-00:00

PloS one, Vol. 13, No. 2. (2018)

Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.
Michaela Angelika Ihle, Sebastian Huss, Wiebke Jeske, Wolfgang Hartmann, Sabine Merkelbach-Bruse, Hans-Ulrich Schildhaus, Reinhard Büttner, Harri Sihto, Kirsten Sundby Hall, Mikael Eriksson, Peter Reichardt, Heikki Joensuu, Eva Wardelmann



Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling.

2018-02-19T08:16:11-00:00

EBioMedicine (02 February 2018)

Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies. Copyright © 2018. Published by Elsevier B.V.
Helle Sadam, Arno Pihlak, Anri Kivil, Susan Pihelgas, Mariliis Jaago, Priit Adler, Jaak Vilo, Olli Vapalahti, Toomas Neuman, Dan Lindholm, Markku Partinen, Antti Vaheri, Kaia Palm



Early age exposure to moisture damage and systemic inflammation at the age of 6 years.

2018-02-19T08:00:54-00:00

Indoor air (16 February 2018)

Cross-sectional studies have shown that exposure to indoor moisture damage and mold may be associated with subclinical inflammation. Our aim was to determine whether early age exposure to moisture damage or mold is prospectively associated with subclinical systemic inflammation or with immune responsiveness in later childhood. Home inspections were performed in children's homes in the first year of life. At age 6 years, subclinical systemic inflammation was measured by serum C-reactive protein(CRP) and blood leucocytes and immune responsiveness by ex vivo production of interleukin 1-beta(IL-1β), IL-6 and tumor necrosis factor-alpha(TNF-α) in whole blood cultures without stimulation or after 24h stimulation with phorbol 12-myristate 13-acetate and ionomycin(PI), lipopolysaccharide(LPS) or peptidoglycan(PPG) in 251 to 270 children. Moisture damage in child's main living areas in infancy was not significantly associated with elevated levels of CRP or leucocytes at 6 years. In contrast, there was some suggestion for an effect on immune responsiveness, as moisture damage with visible mold was positively associated with LPS-stimulated production of TNF-α and minor moisture damage was inversely associated with PI-stimulated IL-1β. While early life exposure to mold damage may have some influence on later immune responsiveness, it does not seem to increase subclinical systemic inflammation in later life. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
AM Karvonen, C Tischer, PV Kirjavainen, M Roponen, A Hyvärinen, S Illi, K Mustonen, PI Pfefferle, H Renz, S Remes, B Schaub, E von Mutius, J Pekkanen



Immunoglobulin E-an Innocent Bystander in Host Defense?

2018-02-19T07:59:16-00:00

Journal of clinical immunology (15 February 2018)
Qian Zhang, Mikko Seppänen



Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis".

2018-02-19T07:57:17-00:00

British journal of cancer (15 February 2018)
Alhadi Almangush, Ilkka Heikkinen, Antti Mäkitie, Ricardo Coletta, Esa Läärä, Ilmo Leivo, Tuula Salo



Cancer costs and outcomes for common cancer sites in the Finnish population between 2009-2014.

2018-02-19T07:53:56-00:00

Acta oncologica (Stockholm, Sweden) (16 February 2018), pp. 1-6

The cost of cancer and outcomes of cancer care have been discussed a lot since cancer represents 3-6% of total healthcare costs and cost estimations have indicated growing costs. There are studies considering the cost of all cancers, but studies focusing on the cost of disease and outcomes in most common cancer sites are limited. The objective of this study was to analyze the development of the costs and outcomes in Finland between 2009 and 2014 per cancer site. The National cost, episode and outcomes data were obtained from the National register databases based on International Statistical Classification of Diseases (ICD)-10 diagnosis codes. Cost data included both the direct and indirect costs. Two hospitals were used to validate the costs of care. The outcome measures included relative survival rate, mortality, sick leave days per patient and number of new disability pensions. The outcomes of cancer care in most common cancer sites have improved in Finland between 2009-2014. The real costs per new cancer patient decreased in seven out of ten most common cancer sites. The significance of different cost components differ significantly between the different cancer sites. The share of medication costs of the total cost of all cancers increased, but decreased for the five most common cancer sites. The changes in the cost components indicate that the length of stay has shortened in special care and treatment methods have developed towards outpatient care. This partially explains the decrease of costs. Also, at the same time outcomes improved, which indicates that decrease in costs did not come at the expense of treatment quality. As the survival rates increase, the relevance of mortality measures decreases and the relevance of other, patient-relevant outcome measures increases. In the future, the outcomes and costs of health care systems should be assessed routinely for the most common patient groups.
Paulus Torkki, Riikka-Leena Leskelä, Miika Linna, Suvi Mäklin, Jukka-Pekka Mecklin, Petri Bono, Vesa Kataja, Sakari Karjalainen



What's New in Epidemiology?

2018-02-19T07:52:28-00:00

European urology focus (12 February 2018)

There have been a number of recent advances in the epidemiological study of male lower urinary tract symptoms (LUTS). Here, we have reviewed the most novel and important literature. Studies assessing the risk factors, natural history as well as impact of male LUTS are included, focussing on recent progress in the field. Copyright © 2018. Published by Elsevier B.V.
Sachin Malde, Rufus Cartwright, Kari Tikkinen



Strong conservation of inbred mouse strain microRNA loci but broad variation in brain microRNAs due to RNA editing and isomiR expression.

2018-02-19T07:50:27-00:00

RNA (New York, N.Y.) (14 February 2018)

Diversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by 1) identifying miRNA SNPs in whole genome sequence data from 36 strains, and 2) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of 6 strains, to facilitate the study of miRNAs in neurobehavioral phenotypes. miRNA loci were strongly conserved among the 36 strains, but even the highly conserved seed region contained 16 SNPs. In contrast, we identified RNA editing in 58.9% of miRNAs, including 11 consistent editing events in the seed region. We confirmed the functional significance of three conserved edits in the miR-379/410 cluster, demonstrating that edited miRNAs gained novel target mRNAs not recognized by the unedited miRNAs. We found significant interstrain differences in miRNA and isomiR expression: of 779 miRNAs expressed in Hpc and 719 in FCx, 262 were differentially expressed (190 in Hpc, 126 in FCx, 54 in both). We also identified 32 novel miRNA candidates using miRNA prediction tools. Our studies provide the first comprehensive analysis of SNP, isomiR, and RNA editing variation in miRNA loci across inbred mouse strains, and a detailed catalogue of expressed miRNAs in Hpc and FCx in 6 commonly used strains. These findings will facilitate the molecular analysis of neurological and behavioral phenotypes in this model organism. Published by Cold Spring Harbor Laboratory Press for the RNA Society.
Kalevi Trontti, Juho Väänänen, Tessa Sipilä, Dario Greco, Iiris Hovatta



Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency.

2018-02-19T07:45:44-00:00

Thrombosis and haemostasis (15 February 2018)

Recombinant factor XIII-A2(rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A2(exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A2dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A2efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A2; their median age was 26.0 years (range: 7.0-77.0). rFXIII-A2was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A2prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A2dose, and four were performed 10 to 21 days after the last dose. Schattauer GmbH Stuttgart.
Manuel Carcao, Carmen Altisent, Giancarlo Castaman, Katsuyuki Fukutake, Bryce Kerlin, Craig Kessler, Riitta Lassila, Diane Nugent, Johannes Oldenburg, May-Lill Garly, Anders Rosholm, Aida Inbal



Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations.

2018-02-19T07:42:21-00:00

Human mutation (15 February 2018)The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on 6 continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Timothy Rebbeck, Tara Friebel, Eitan Friedman, Ute Hamann, Dezheng Huo, Ava Kwong, Edith Olah, Olufunmilayo Olopade, Angela Solano, Soo-Hwang Teo, Mads Thomassen, Jeffrey Weitzel, TL Chan, Fergus Couch, David Goldgar, Torben Kruse, Edenir Inêz Palmero, Sue Kyung Park, Diana Torres, Elizabeth van Rensburg, Lesley McGuffog, Michael Parsons, Goska Leslie, Cora Aalfs, Julio Abugattas, Julian Adlard, Simona Agata, Kristiina Aittomäki, Lesley Andrews, Irene Andrulis, Adalgeir Arason, Norbert Arnold, Banu Arun, Ella Asseryanis, Leo Auerbach, Jacopo Azzollini, Judith Balmaña, Monica Barile, Rosa Barkardottir, Daniel Barrowdale, Javier Benitez, Andreas Berger, Raanan Berger, Amie Blanco, Kathleen Blazer, Marinus Blok, Valérie Bonadona, Bernardo Bonanni, Angela Bradbury, Carole Brewer, Bruno Buecher, Saundra Buys, Trinidad Caldes, Almuth Caliebe, Maria Caligo, Ian Campbell, Sandrine Caputo, Jocelyne Chiquette, Wendy Chung, Kathleen Claes, Margriet Collée, Jackie Cook, Rosemarie Davidson, Miguel de la Hoya, Kim De Leeneer, Antoine de Pauw, Capucine Delnatte, Orland Diez, Yuan Chun Ding, Nina Ditsch, Susan Domchek, Cecilia Dorfling, Carolina Velazquez, Bernd Dworniczak, Jacqueline Eason, Douglas Easton, Ros Eeles, Hans Ehrencrona, Bent Ejlertsen, , Christoph Engel, Stefanie Engert, Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Sandra Fert Ferrer, Lenka Foretova, Jeffrey Fowler, Debra Frost, Henrique Galvão, Patricia Ganz, Judy Garber, Marion Gauthier-Villars, Andrea Gehrig, , Anne-Marie Gerdes, Paul Gesta, Giuseppe Giannini, Sophie Giraud, Gord Glendon, Andrew Godwin, Mark Greene, Jacek Gronwald, Angelica Gutierrez-Barrera, Eric Hahnen, Jan Hauke, , Alex Henderson, Julia Hentschel, Frans Hogervorst, Ellen Honisch, Evgeny Imyanitov, Claudine Isaacs[...]



New prostate cancer grade grouping system predicts survival after radical prostatectomy.

2018-02-16T12:49:21-00:00

Human pathology (12 February 2018)
Andrew Erickson, Kevin Sandeman, Kanerva Lahdensuo, Stig Nordling, Markku Kallajoki, Heikki Seikkula, Anna Bützow, Hanna Vasarainen, Peter Boström, Pekka Taimen, Antti Rannikko, Tuomas Mirtti



-methylnicotinamide is a signalling molecule produced in skeletal muscle coordinating energy metabolism.

2018-02-16T12:20:16-00:00

Scientific reports, Vol. 8, No. 1. (14 February 2018)

Obesity is a major health problem, and although caloric restriction and exercise are successful strategies to lose adipose tissue in obese individuals, a simultaneous decrease in skeletal muscle mass, negatively effects metabolism and muscle function. To deeper understand molecular events occurring in muscle during weight-loss, we measured the expressional change in human skeletal muscle following a combination of severe caloric restriction and exercise over 4 days in 15 Swedish men. Key metabolic genes were regulated after the intervention, indicating a shift from carbohydrate to fat metabolism. Nicotinamide N-methyltransferase (NNMT) was the most consistently upregulated gene following the energy-deficit exercise. Circulating levels of N1-methylnicotinamide (MNA), the product of NNMT activity, were doubled after the intervention. The fasting-fed state was an important determinant of plasma MNA levels, peaking at ~18 h of fasting and being lowest ~3 h after a meal. In culture, MNA was secreted by isolated human myotubes and stimulated lipolysis directly, with no effect on glucagon or insulin secretion. We propose that MNA is a novel myokine that enhances the utilization of energy stores in response to low muscle energy availability. Future research should focus on applying MNA as a biomarker to identify individuals with metabolic disturbances at an early stage.
Kristoffer Ström, David Morales-Alamo, Filip Ottosson, Anna Edlund, Line Hjort, Sine Jörgensen, Peter Almgren, Yuedan Zhou, Marcos Martin-Rincon, Carl Ekman, Alberto Pérez-López, Ola Ekström, Ismael Perez-Suarez, Markus Mattiasson, Pedro de Pablos-Velasco, Nikolay Oskolkov, Emma Ahlqvist, Nils Wierup, Lena Eliasson, Allan Vaag, Leif Groop, Karin Stenkula, Céline Fernandez, Jose Calbet, Hans-Christer Holmberg, Ola Hansson



Sex bias in MHC I-associated shaping of the adaptive immune system.

2018-02-16T12:18:35-00:00

Proceedings of the National Academy of Sciences of the United States of America (12 February 2018)

HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.
Tilman Schneider-Hohendorf, Dennis Görlich, Paula Savola, Tiina Kelkka, Satu Mustjoki, Catharina Gross, Geoffrey Owens, Luisa Klotz, Klaus Dornmair, Heinz Wiendl, Nicholas Schwab



Repolarization Heterogeneity Measured With T-Wave Area Dispersion in Standard 12-Lead ECG Predicts Sudden Cardiac Death in General Population.

2018-02-16T12:16:44-00:00

Circulation. Arrhythmia and electrophysiology, Vol. 11, No. 2. (February 2018)

We developed a novel electrocardiographic marker, T-wave area dispersion (TW-Ad), which measures repolarization heterogeneity by assessing interlead T-wave areas during a single cardiac cycle and tested whether it can identify patients at risk for sudden cardiac death (SCD) in the general population. TW-Ad was measured from standard digital 12-lead ECG in 5618 adults (46% men; age, 50.9±12.5 years) participating in the Health 2000 Study-an epidemiological survey representative of the Finnish adult population. Independent replication was performed in 3831 participants of the KORA S4 Study (Cooperative Health Research in the Region of Augsburg; 49% men; age, 48.7±13.7 years; mean follow-up, 8.8±1.1 years). During follow-up (7.7±1.4 years), 72 SCDs occurred in the Health 2000 Survey. Lower TW-Ad was univariately associated with SCD (0.32±0.36 versus 0.60±0.19;P<0.001); it had an area under the receiver operating characteristic curve of 0.809. TW-Ad (≤0.46) conferred a hazard ratio of 10.8 (95% confidence interval, 6.8-17.4;P<0.001) for SCD; it remained independently predictive of SCD after multivariable adjustment for clinical risk markers (hazard ratio, 4.6; 95% confidence interval, 2.7-7.4;P<0.001). Replication analyses performed in the KORA S4 Study confirmed an increased risk for cardiac death (unadjusted hazard ratio, 5.5; 95% confidence interval, 3.2-9.5;P<0.001; multivariable adjusted hazard ratio, 1.9; 95% confidence interval, 1.1-3.5;P<0.05). Low TW-Ad, reflecting increased heterogeneity of repolarization, in standard 12-lead resting ECGs is a powerful and independent predictor of SCD in the adult general population. © 2018 American Heart Association, Inc.
Tuomas Kenttä, Moritz Sinner, Bruce Nearing, Rebecca Freudling, Kimmo Porthan, Jani Tikkanen, Martina Müller-Nurasyid, Katharina Schramm, Matti Viitasalo, Antti Jula, Markku Nieminen, Annette Peters, Veikko Salomaa, Lasse Oikarinen, Richard Verrier, Stefan Kääb, Juhani Junttila, Heikki Huikuri



Exploring variability in basal ganglia connectivity with functional MRI in healthy aging.

2018-02-16T12:14:56-00:00

Brain imaging and behavior (13 February 2018)

Changes in functional connectivity (FC) measured using resting state fMRI within the basal ganglia network (BGN) have been observed in pathologies with altered neurotransmitter systems and conditions involving motor control and dopaminergic processes. However, less is known about non-disease factors affecting FC in the BGN. The aim of this study was to examine associations of FC within the BGN with dopaminergic processes in healthy older adults. We explored the relationship between FC in the BGN and variables related to demographics, impulsive behavior, self-paced tasks, mood, and motor correlates in 486 participants in the Whitehall-II imaging sub-study using both region-of-interest- and voxel-based approaches. Age was the only correlate of FC in the BGN that was consistently significant with both analyses. The observed adverse effect of aging on FC may relate to alterations of the dopaminergic system, but no unique dopamine-related function seemed to have a link with FC beyond those detectable in and linearly correlated with healthy aging.
Ludovica Griffanti, Philipp Stratmann, Michal Rolinski, Nicola Filippini, Enikő Zsoldos, Abda Mahmood, Giovanna Zamboni, Gwenaëlle Douaud, Johannes Klein, Mika Kivimäki, Archana Singh-Manoux, Michele Hu, Klaus Ebmeier, Clare Mackay



Biodegradable Spheres Protect Traumatically Injured Spinal Cord by Alleviating the Glutamate-Induced Excitotoxicity.

2018-02-15T13:04:45-00:00

Advanced materials (Deerfield Beach, Fla.) (14 February 2018)

New treatment strategies for spinal cord injury with good therapeutic efficacy are actively pursued. Here, acetalated dextran (AcDX), a biodegradable polymer obtained by modifying vicinal diols of dextran, is demonstrated to protect the traumatically injured spinal cord. To facilitate its administration, AcDX is formulated into microspheres (≈7.2 µm in diameter) by the droplet microfluidic technique. Intrathecally injected AcDX microspheres effectively reduce the traumatic lesion volume and inflammatory response in the injured spinal cord, protect the spinal cord neurons from apoptosis, and ultimately, recover the locomotor function of injured rats. The neuroprotective feature of AcDX microspheres is achieved by sequestering glutamate and calcium ions in cerebrospinal fluid. The scavenging of glutamate and calcium ion reduces the influx of calcium ions into neurons and inhibits the formation of reactive oxygen species. Consequently, AcDX microspheres attenuate the expression of proapoptotic proteins, Calpain, and Bax, and enhance the expression of antiapoptotic protein Bcl-2. Overall, AcDX microspheres protect traumatically injured spinal cord by alleviating the glutamate-induced excitotoxicity. This study opens an exciting perspective toward the application of neuroprotective AcDX for the treatment of severe neurological diseases. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Dongfei Liu, Jian Chen, Tao Jiang, Wei Li, Yao Huang, Xiyi Lu, Zehua Liu, Weixia Zhang, Zheng Zhou, Qirui Ding, Hélder Santos, Guoyong Yin, Jin Fan



Spatial Aspects of Oncogenic Signaling Determine Response to Combination Therapy in Slice Explants from Kras-driven Lung Tumors.

2018-02-15T12:39:36-00:00

The Journal of pathology (14 February 2018)

A key question in precision medicine is how functional heterogeneity in solid tumors informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signaling and therapy response can be modeled in precision-cut slices from Kras-driven non-small cell lung cancer (NSCLC) of varying histopathologies. Unexpectedly, profiling of in situ tumors demonstrates that signaling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma (ASC), and MAPK activity in adenocarcinoma (AC). In addition, high inter- and intra-tumor variability is detected, particularly of MAPK and mTORC1 activity. Using short-term treatment of slice explants, we show that cytotoxic responses to combination MAPK and PI3K/mTOR inhibition correlate with the spatially-defined activities of both pathways. Thus, while genetic drivers determine histopathology spectra, histopathology-associated and spatially-variable signaling activities determine drug sensitivity. Our study endorses that spatial aspects of signaling heterogeneity are considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. This article is protected by copyright. All rights reserved.
Katja Närhi, Ashwini Nagaraj, Elina Parri, Riku Turkki, Petra van Duijn, Annabrita Hemmes, Jenni Lahtela, Virva Uotinen, Mikko Mäyränpää, Kaisa Salmenkivi, Jari Räsänen, Nina Linder, Jan Trapman, Antti Rannikko, Olli Kallioniemi, Taija Af Hällström, Johan Lundin, Wolfgang Sommergruber, Simon Anders, Emmy Verschuren



Diabetes and intracerebral hemorrhage: Baseline characteristics and mortality.

2018-02-15T12:37:34-00:00

European journal of neurology (14 February 2018)

Acknowledging the conflicting evidence of diabetes as a predictor of short- and long-term mortality following an intracerebral hemorrhage (ICH), we compared baseline characteristics and 30-day and long-term mortality between patients with and without diabetes after an ICH-paying special attention to differences between type 1 (T1D) and type 2 (T2D) diabetes. Patients with a first-ever ICH were followed for a median of 2.3 years. Adjusting for demographics, comorbidities and documented ICH characteristics increasing mortality after ICH, logistic regression analysis assessed factors associated with case-fatality and 1-year survival among the 30-day survivors. Diabetes was compared to patients without diabetes in separate models as (1) any diabetes and (2) T1D or T2D. Of our 969 patients, 813 (83.9%) had no diabetes, 41 (4.2%) had T1D, and 115 (11.9%) T2D. Compared to patients without diabetes, those with diabetes were younger, more often men, and had more frequently hypertension, coronary heart disease, and chronic kidney disease (CKD)-with similar ICH characteristics. T1D-patients were younger, had more often CKD and brain-stem ICH, and less often atrial fibrillation and lobar ICH, than did patients with T2D. Diabetes had no impact on case-fatality. Any diabetes (OR 2.42, 1.19-4.93), T1D (5.27, 0.95-29.28), and T2D (OR 2.20, 1.04-4.67) were independently associated with 1-year mortality. ICH patients with diabetes exhibit a distinct pattern of comorbidities and disease characteristics with specific differences between T1D and T2D. Despite their younger age, T1D seems to carry a substantially higher likelihood for long-term mortality after an ICH than do T2D. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Ron Liebkind, Daniel Gordin, Daniel Strbian, Atte Meretoja, Lena Thorn, Stephanie Hägg-Holmberg, Carol Forsblom, Turgut Tatlisumak, Per-Henrik Groop, Jukka Putaala



Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of Cyclin C-CDK8/19.

2018-02-15T12:24:07-00:00

The Journal of biological chemistry (13 February 2018)

Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate CycC-dependent kinase 8 (CDK8), implicating impaired Mediator-associated CDK8 activity in the pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of MED12 mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, within the Mediator kinase module, we find that MED13 directly binds to the MED12 C-terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation, and reveal an additional step in the activation process - one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that tumorigenic mutations in MED12 disrupt composite Mediator kinase activity, and identify CDK8/19 as prospective therapeutic targets in UFs. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
Min Ju Park, Hailian Shen, Jason Spaeth, Jaana Tolvanen, Courtney Failor, Jennifer Knudtson, Jessica McLaughlin, Sunil Halder, Qiwei Yang, Serdar Bulun, Ayman Al-Hendy, Robert Schenken, Lauri Aaltonen, Thomas Boyer



Endocannabinoid signaling in embryonic neuronal motility and cell-cell contact - Role of mGluR5 and TRPC3 channels.

2018-02-15T11:22:39-00:00

Neuroscience (10 February 2018)

Cell-cell communication plays a central role in the guidance of migrating neuronal precursor cells during the development of the cerebral cortex. Endocannabinoids (eCBs) have previously been shown to be one of the central factors regulating neuronal migration. In this study the effects of eCBs on different parameters, expected to affect embryonic cortical neuronal motility have been analyzed in neurosphere derived neuroblasts using time-lapse microscopy. Increased endogenous production of the endocannabinoid 2-arachidonyl glycerol (2-AG) causes bursts of neuroblast motility. The neuroblasts move longer distances, show a low frequency of turning and number of neuron-neuron contacts are reduced. Similar changes occur interference with the function of the metabotropic glutamate receptor 5 (mGluR5) or its transducer canonical transient receptor potential channel 3 (TRPC3) or the neuregulin receptor ErbB4. Blocking of 2-AG production reverses these effects. The data suggest that eCB regulated neuronal motility is controlled by mGluR5/TRPC3 activity possibly via NRG/ErbB4 signaling. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
Pauli Turunen, Lauri Louhivuori, Verna Louhivuori, Jyrki Kukkonen, Karl Åkerman



Analysis of the Histologic Features Associated With Interobserver Variation in Idiopathic Pulmonary Fibrosis.

2018-02-15T11:20:51-00:00

The American journal of surgical pathology (12 February 2018)

The histologic manifestation of idiopathic pulmonary fibrosis (IPF) is usual interstitial pneumonia (UIP), which is a good prognostic determinant of survival compared with other histologic interstitial lung disease patterns. According to the current international guidelines, the histologic features of suspected IPF/UIP are divided into 4 categories: UIP, probable UIP, possible UIP, and not UIP pattern. Four pulmonary pathologists who were blinded to clinicoradiologic information reevaluated 50 surgical lung biopsies (83.3%), 6 lung explant (10.0%), and 4 autopsy samples (6.7%) from the FinnishIPF registry (N=60) using the current diagnostic guidelines. Additional histologic features atypical for UIP were also evaluated and compared with clinicora-diologic information. The interobserver agreement of pathologists was examined by Cohen kappa (κ) coefficient; the survival of the patients was estimated with Kaplan-Meier curves. The histologic reevaluation indicated that 38 of 60 patients (63.3%) had definite UIP. Inflammation was the most common additional histologic finding (15/60, 25.0%). The interobserver agreement on histologic diagnosis ranged from slight (κ=0.044) to substantial (κ=0.779). The interobserver agreement varied extensively with regard to the presence of giant cells. The observed histologic features displayed no association with radiologic patterns or survival. Definite UIP and honeycombing findings in high-resolution computed tomography correlated with poor prognosis. A high level of interobserver variability was observed between pathologists, even in this well-defined cohort of IPF patients, which highlights the importance of multidisciplinary decision making in IPF diagnostics and stresses the need for a reassessment of the histologic criteria.
Kati Mäkelä, Ulla Hodgson, Anneli Piilonen, Katariina Kelloniemi, Risto Bloigu, Eva Sutinen, Kaisa Salmenkivi, Mikko Rönty, Elisa Lappi-Blanco, Marjukka Myllärniemi, Riitta Kaarteenaho



Socioeconomic inequality in recovery from poor physical and mental health in mid-life and early old age: prospective Whitehall II cohort study.

2018-02-15T11:19:04-00:00

Journal of epidemiology and community health (08 February 2018)

Few studies have examined the influence of socioeconomic status on recovery from poor physical and mental health. Prospective study with four consecutive periods of follow-up (1991-2011) of 7564 civil servants (2228 women) recruited while working in London. Health was measured by the Short-Form 36 questionnaire physical and mental component scores assessed at beginning and end of each of four rounds. Poor health was defined by a score in the lowest 20% of the age-sex-specific distribution. Recovery was defined as changing from a low score at the beginning to a normal score at the end of the round. The analysis took account of retirement status, health behaviours, body mass index and prevalent chronic disease. Of 24 001 person-observations in the age range 39-83, a total of 8105 identified poor physical or mental health. Lower grade of employment was strongly associated with slower recovery from poor physical health (OR 0.73 (95% CI 0.59 to 0.91); trend P=0.002) in age, sex and ethnicity-adjusted analyses. The association was halved after further adjustment for health behaviours, adiposity, systolic blood pressure (SBP) and serum cholesterol (OR 0.85 (0.68 to 1.07)). In contrast, slower recovery from poor mental health was associated robustly with low employment grade even after multiple adjustment (OR 0.74 (0.59 to 0.93); trend P=0.02). Socioeconomic inequalities in recovery from poor physical health were explained to a considerable extent by health behaviours, adiposity, SBP and serum cholesterol. These risk factors explained only part of the gradient in recovery for poor mental health. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Akihiro Tanaka, Martin Shipley, Catherine Welch, Nora Groce, Michael Marmot, Mika Kivimaki, Archana Singh-Manoux, Eric Brunner



Cardiometabolic dysregulation and cognitive decline: potential role of depressive symptoms.

2018-02-15T11:17:11-00:00

The British journal of psychiatry : the journal of mental science, Vol. 212, No. 2. (February 2018), pp. 96-102

Previous studies have examined associations of cardiometabolic factors with depression and cognition separately. Aims To determine if depressive symptoms mediate the association between cardiometabolic factors and cognitive decline in two community studies. Data for the analyses were drawn from the Rotterdam Study, the Netherlands (n = 2940) and the Whitehall II study, UK (n = 4469). Mediation analyses suggested a direct association between cardiometabolic factors and cognitive decline and an indirect association through depression: poorer cardiometabolic status at time 1 was associated with a higher level of depressive symptoms at time 2 (standardised regression coefficient 0.07 and 0.06, respectively), which, in turn, was associated with greater cognitive decline between time 2 and time 3 (standardised regression coefficient of -0.15 and -0.41, respectively). Evidence from two independent cohort studies suggest an association between cardiometabolic dysregulation and cognitive decline and that depressive symptoms tend to precede this decline. Declaration of interest None.
Norbert Schmitz, Sonya Deschênes, Rachel Burns, Sofia Danna, Oscar Franco, Arfan Ikram, Mika Kivimäki, Archana Singh-Manoux, Henning Tiemeier