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Mitochondrial diseases: the contribution of organelle stress responses to pathology.

2017-08-11T05:57:42-00:00

Nature reviews. Molecular cell biology (09 August 2017)

Mitochondrial diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in mitochondrial protein synthesis and mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human mitochondrial diseases.
Anu Suomalainen, Brendan Battersby



European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes.

2017-08-11T05:54:54-00:00

Journal of the European Academy of Dermatology and Venereology : JEADV (09 August 2017)

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum. © 2017 European Academy of Dermatology and Venereology.
R Knobler, P Moinzadeh, N Hunzelmann, A Kreuter, A Cozzio, L Mouthon, M Cutolo, F Rongioletti, CP Denton, L Rudnicka, LA Frasin, V Smith, A Gabrielli, E Aberer, M Bagot, G Bali, J Bouaziz, A Braae Olesen, I Foeldvari, C Frances, A Jalili, U Just, V Kähäri, S Kárpáti, K Kofoed, D Krasowska, M Olszewska, C Orteu, J Panelius, A Parodi, A Petit, P Quaglino, A Ranki, JM Sanchez Schmidt, J Seneschal, A Skrok, M Sticherling, C Sunderkötter, A Taieb, A Tanew, P Wolf, M Worm, NJ Wutte, T Krieg



Frontal Cortex Myo-Inositol Is Associated with Sleep and Depression in Adolescents: A Proton Magnetic Resonance Spectroscopy Study.

2017-08-11T05:53:19-00:00

Neuropsychobiology, Vol. 75, No. 1. (10 August 2017), pp. 21-31

This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the neurochemistry of the frontal cortex in adolescents with symptoms of sleep and depression. Nineteen non-medicated adolescent boys (mean age 16.0 years; 9 clinical cases with depression/sleep symptoms and 10 healthy controls) underwent 1H MRS at 3 T. MR spectra were acquired from the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex, and frontal white matter. Concentrations of N-acetyl aspartate, total creatine, choline-containing compounds, total glutamine plus glutamate, and myo-inositol (mI) were compared in the 2 subgroups, and correlated with sleep and clinical measures in the total sample. Sleep was assessed with self-report questionnaires and ambulatory polysomnography recordings. Concentrations of mI were lower in both frontal cortical regions among the depressed adolescents than in controls. No statistically significant differences in other metabolite concentrations were observed between the subgroups. Frontal cortex mI concentrations correlated negatively with depression severity, subjective daytime sleepiness, insomnia symptoms, and the level of anxiety, and correlated positively with total sleep time and overall psychosocial functioning. The correlations between mI in the ACC and total sleep time as well as daytime sleepiness remained statistically significant when depression severity was controlled in the analyses. Lower frontal cortex mI may indicate a disturbed second messenger system. Frontal cortical mI may thus be linked to the pathophysiology of depression and concomitant sleep symptoms among maturing adolescents. Short sleep and daytime sleepiness may be associated with frontal cortex mI independently from depression. © 2017 S. Karger AG, Basel.
Anna Urrila, Antti Hakkarainen, Anu Castaneda, Tiina Paunio, Mauri Marttunen, Nina Lundbom



Variants in calcium voltage-gated channel subunit Alpha1 C-gene (CACNA1C) are associated with sleep latency in infants.

2017-08-11T05:50:49-00:00

PloS one, Vol. 12, No. 8. (2017)

Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C) are associated with bipolar disorder and schizophrenia where sleep disturbances are common. In an experimental model, Cacna1c has been found to modulate the electrophysiological architecture of sleep. There are strong genetic influences for consolidation of sleep in infancy, but only a few studies have thus far researched the genetic factors underlying the process. We hypothesized that genetic variants in CACNA1C affect the regulation of sleep in early development. Seven variants that were earlier associated (genome-wide significantly) with psychiatric disorders at CACNA1C were selected for analyses. The study sample consists of 1086 infants (520 girls and 566 boys) from the Finnish CHILD-SLEEP birth cohort (genotyped by Illumina Infinium PsychArray BeadChip). Sleep length, latency, and nightly awakenings were reported by the parents of the infants with a home-delivered questionnaire at 8 months of age. The genetic influence of CACNA1C variants on sleep in infants was examined by using PLINK software. Three of the examined CACNA1C variants, rs4765913, rs4765914, and rs2239063, were associated with sleep latency (permuted P<0.05). There was no significant association between studied variants and night awakenings or sleep duration. CACNA1C variants for psychiatric disorders were found to be associated with long sleep latency among 8-month-old infants. It remains to be clarified whether the findings refer to defective regulation of sleep, or to distractibility of sleep under external influences.
Katri Kantojärvi, Johanna Liuhanen, Outi Saarenpää-Heikkilä, Anna-Liisa Satomaa, Anneli Kylliäinen, Pirjo Pölkki, Julia Jaatela, Auli Toivola, Lili Milani, Sari-Leena Himanen, Tarja Porkka-Heiskanen, Juulia Paavonen, Tiina Paunio



Cardiovascular pre-participation screening in young athletes: Recommendations of the Association of European Paediatric Cardiology.

2017-08-11T05:48:49-00:00

Cardiology in the young (09 August 2017), pp. 1-6

Sudden death in young competitive athletes can be avoided by implementation of pre-participation screening programmes. A screening programme should be performed only by trained physicians and should include the athlete's personal and family history, physical examination results, and the readings from a 12-lead-electrocardiogram. The athlete should undergo this screening programme every second year to detect progressive diseases. In addition, the programme should include detailed instructions to the athletes to pause training during infections in order to prevent sudden death due to myocarditis.
Peter Fritsch, Robert Dalla Pozza, Doris Ehringer-Schetitska, Eero Jokinen, Vesna Herceg, Erzsebet Hidvegi, Renate Oberhoffer, Andreas Petropoulos



Change in β2-agonist use after severe life events in adults with asthma: A population-based cohort study: Life events and bronchodilator usage among adults with asthma.

2017-08-11T05:39:55-00:00

Journal of psychosomatic research, Vol. 100 (September 2017), pp. 46-52

This prospective, population-based cohort study of 1102 Finnish adults with asthma, examined whether exposure to stressful life events is associated with the intensity of usage of inhaled short-acting β2-agonists. Survey data was collected by two postal questionnaires. Baseline characteristics were obtained in 1998 and data on 19 specific stressful events (e.g. death of a child or spouse or divorce) within the six preceding months in 2003. Exposure to life events was indicated by a sum score weighted by mean severity of the events. Participants were linked to records of filled prescriptions for inhaled short-acting β2-agonists from national registers from 2000 through 2006. The rates of purchases of short-acting β2-agonists before (2000-2001), during (2002-2003) and after (2004-2006) the event exposure were estimated using repeated-measures Poisson regression analyses with the generalized estimating equation. Of the 1102 participants, 162 (15%) were exposed to highly stressful events, 205 (19%) to less stressful events. During the 7-year observation period, 5955 purchases of filled prescription for inhaled short-acting β2-agonists were recorded. After exposure to highly stressful events, the rate of purchases of β2-agonists was 1.50 times higher (95% confidence interval (CI): 1.05, 2.13) than before the stressful event occurred. Among those with low or no exposure to life events, the corresponding rate ratios were not elevated (rate ratio 0.81, 95% CI: 0.66, 0.99 and 0.95, 95% CI: 0.83, 1.09 respectively). An increase in β2-agonist usage after severe life events suggests that stressful experiences may worsen asthma symptoms. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Raija Lietzén, Pekka Virtanen, Mika Kivimäki, Jyrki Korkeila, Sakari Suominen, Lauri Sillanmäki, Markku Koskenvuo, Jussi Vahtera



Molecular alterations in pediatric brainstem gliomas.

2017-08-10T11:36:49-00:00

Pediatric blood & cancer (09 August 2017)

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas. © 2017 Wiley Periodicals, Inc.
Mikaela Porkholm, Anna Raunio, Reetta Vainionpää, Tarja Salonen, Juha Hernesniemi, Leena Valanne, Jarno Satopää, Atte Karppinen, Minna Oinas, Olli Tynninen, Virve Pentikäinen, Sanna-Maria Kivivuori



Quality Items Required for Running a Paediatric Inflammatory Bowel Disease Centre: An ECCO Paper.

2017-08-10T11:32:37-00:00

Journal of Crohn's & colitis, Vol. 11, No. 8. (01 August 2017), pp. 981-987

The importance of a holistic approach with a comprehensive multidisciplinary team, including nutritional and psychosocial support, is becoming well recognised as a key contributor to optimal care in paediatric inflammatory bowel disease [IBD]. The Paediatric committee of ECCO [P-ECCO] aimed to determine important components that would contribute to quality of care in a paediatric IBD centre [henceforth 'quality items']. First, a list of items has been generated by a Delphi group of 111 international paediatric IBD experts. Through an iterative process, the group graded and ranked the items according to their perceived relative contribution to quality care. We then surveyed 101 paediatric IBD centres affiliated with the Porto and Interest groups of ESPGHAN in Europe and with the ImproveCareNow registry in North America, exploring the availability of the retained items in their centres. A total of 68 items were generated and reduced to a list of 60 ranked order items, grouped in six domains: Facility, Personnel, Management, Supportive Services, Patient Support and Accessibility, and Academia and Communications. Of the retained items, 52 [88%] were present in most of the 101 high-performing paediatric IBD centres, and there was a trend for increased availability with increased patient volume at the centres. In this P-ECCO study, we attempted to tabulate, for the first time in paediatrics, 60 quality items that paediatric IBD referral centres may wish to include.
Dan Turner, Adam Carle, Steven Steiner, Peter Margolis, Richard Colletti, Richard Russell, Arie Levine, Kaija-Leena Kolho, Frank Ruemmele,



Meeting American Diabetes Association diabetes management targets: trends in Mauritius.

2017-08-10T11:19:32-00:00

Diabetic medicine : a journal of the British Diabetic Association (09 August 2017)

To examine the proportion of people with diabetes in the multi-ethnic country of Mauritius meeting American Diabetes Association targets in 2009 and 2015. Data from independent population-based samples of 858 and 656 adults with diagnosed diabetes in 2009 and 2015, respectively, were analysed with regard to recommended American Diabetes Association targets for HbA1c , blood pressure and LDL cholesterol. In 2015 compared with 2009, the proportion of people achieving American Diabetes Association targets for glycaemic control in Mauritius was higher in women (P≤0.01) and in those with only a primary education level (P=0.07), but not in men or people with a higher level of education. Achievement of blood pressure <140/90 mmHg was higher in 2015 compared with 2009 (60% vs 42%) in people of South Asian ethnicity (P<0.001), but not in those of African ethnicity (P=0.16). The percentages of people with LDL cholesterol <2.59 mmol/l were 42.1% and 50.4%, in 2009 and 2015, respectively (P=0.27). Better control of HbA1c and blood pressure was observed in groups in which that control was poorest in 2009. The use of glucose-, blood pressure- and LDL cholesterol-lowering medication was higher in 2015 than in 2009. In certain subgroups, namely women, those with poorer education and those of South Asian ethnicity, whose target achievement was the poorest in 2009, control of glycaemia and blood pressure was better in 2015 as compared with 2009. While these findings are encouraging, further work is required to improve outcomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
M Tabesh, JE Shaw, PZ Zimmet, S Soderberg, S Kowlessur, M Timol, N Joonas, GMM Alberti, J Tuomilehto, BJ Shaw, DJ Magliano



Incidence of inflammatory joint diseases in Finland: results from a population-based epidemiological study.

2017-08-10T11:13:27-00:00

Rheumatology international (08 August 2017)

The objective of the study was to assess the incidence of inflammatory joint diseases and possible environmental factors contributing to their occurrence in a defined population in Finland. All rheumatologists practising in the Northern Savo rheumatological outpatient departments collected data on their newly diagnosed patients with an inflammatory joint disease in 2010. Antibodies to Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) were determined from patients with various arthritides. The incidence of all arthritis cases was 141.8/100,000 (95% CI 126.1-159.1). Eighty-six patients, 43 men and 43 women, satisfied the ACR/Eular 2010 classification criteria for rheumatoid arthritis (RA) yielding an annual incidence of 41.6/100,000 (33.3-51.4), 42.5 (30.8-57.3) for men and 40.8 (29.9-56.1) for women. The incidence of chronic spondyloarthritides was 36.3 (28.6-45.5), reactive arthritis 7.8 (4.4-12.6), undifferentiated arthritis 38.7 (30.7-48.2), and crystalline arthritis 15.0 (10.2-21.3). Immunoglobulin A (IgA) antibody levels to Pg were higher among men, patients with anti-cyclic citrullinated peptide antibodies (ACPA) or missing teeth and AaIgA antibody levels in patients with missing teeth. In RA, 67 % of men and 35% of women had a smoking history, p = 0.012. There was no difference between the genders in the incidence of RA, which might be explained by a higher carriage of periodontal bacteria and a higher smoking rate among men. In other disease categories, the incidences were comparable to those earlier reported. By influencing behavioral and environmental factors, it might be possible to reduce the burden of ACPA-positive RA.
A Kononoff, L Arstila, P Pussinen, H Kautiainen, P Elfving, E Savolainen, H Niinisalo, J Rutanen, O Marjoniemi, O Kaipiainen-Seppänen



Domain-Specific Cognitive Recovery after First-Ever Stroke: A 2-Year Follow-Up.

2017-08-10T11:09:16-00:00

Journal of the International Neuropsychological Society : JINS (09 August 2017), pp. 1-11

The aim of this work was to study the change in different cognitive domains after stroke during a 2-year follow-up. We evaluated both neuropsychologically and neurologically a consecutive cohort of working-age patients with a first-ever stroke at baseline (within the first weeks), 6 months, and 2 years after stroke-onset. A total of 153 patients participated in all examinations and were compared to 50 healthy controls. Forty-nine percent of the patients were cognitively impaired at baseline, 41% at 6 months, and 39% at 2-year follow-up. We analyzed seven cognitive domains (impairment rates at baseline and 2-year follow-up): psychomotor speed (34%; 23%), executive functions (27%; 17%), visual memory (21%; 4%), visuospatial function (20%; 14%), verbal memory (18%; 12%), basic language processing (baseline 11%; 6 months 5%), and reasoning (2 years 14%). The patients who were cognitively impaired at baseline improved more within 6 months, than either the controls or cognitively intact patients in all cognitive domains (all p<.05). Later on, between 6 months and 2 years, the domain-specific change scores did not differ between patients who were cognitively intact and impaired at 6 months. Also, the cognitive status (intact or impaired) remained the same in 90% of patients between 6-month and 2-year follow-ups. At 2 years, half of the patients, who were categorized cognitively impaired, were rated as well-recovered according to neurological evaluation. Most of the cognitive improvement took place within 6 months. Long-lasting cognitive impairment was common even after good neurological recovery. An early neuropsychological examination is essential in evaluating cognitive dysfunction and need for rehabilitation. (JINS, 2017, 23, 1-11).
Katri Turunen, Siiri Laari, Tatu Kauranen, Jenni Uimonen, Satu Mustanoja, Turgut Tatlisumak, Erja Poutiainen



Incidence and risk factors of exercise-related knee disorders in young adult men.

2017-08-10T07:14:58-00:00

BMC musculoskeletal disorders, Vol. 18, No. 1. (07 August 2017)

Musculoskeletal disorders and injuries are common causes of morbidity and loss of active, physically demanding training days in military populations. We evaluated the incidence, diagnosis, and risk factors of knee disorders and injuries in male Finnish military conscripts. The study population comprised 5 cohorts of 1000 men performing their military service, classified according to birth year (1969, 1974, 1979, 1984, and 1989). Follow-up time for each conscript was the individual conscript's full, completed military service period. Data for each man were collected from a standard pre-information questionnaire used by defense force healthcare officials and from all original medical reports of the garrison healthcare centers. Background variables for risk factor analysis included the conscripts' service data, i.e., service class (A, B), length of military service, age, height, weight, body mass index (BMI), underweight, overweight, obesity, smoking habit, education, diseases, injuries, and subjective symptoms. Of the 4029 conscripts, 853 visited healthcare professionals for knee symptoms during their military service, and 103 of these had suffered a knee injury. Independent risk factors for the incidence of knee symptoms were: older age; service class A; overweight (BMI 25.0-29.9 kg/m(2)); smoking habit; comprehensive school education only; and self-reported previous symptoms of the musculoskeletal, respiratory, and gastrointestinal system. The majority of visits to garrison healthcare services due to knee symptoms occurred during the first few months of military service. Knee symptoms were negatively correlated with self-reported mental and behavioral disorders. The present study highlights the frequency of knee disorders and injuries in young men during physically demanding military training. One-fifth of the male conscripts visited defense force healthcare professionals due to knee symptoms during their service period. Independent risk factors for the incidence of knee symptoms during military service were age at military service; military service class A; overweight; smoking habit; comprehensive school education only; and self-reported previous symptoms of the musculoskeletal system, respiratory system, or gastrointestinal system. These risk factors should be considered when planning and implementing procedures to reduce knee disorders and injuries during compulsory military service.
Harri Pihlajamäki, Mickael Parviainen, Hannu Kautiainen, Ilkka Kiviranta



Analysis of lifestyle factors in patients with concomitant chronic pancreatitis and liver cirrhosis.

2017-08-10T07:13:17-00:00

Pancreatology (31 July 2017)

Chronic pancreatitis (CP) and liver cirrhosis (LC) are common gastroenterological disorders but their co-incidence is considered to be rare. This study was designed to identify lifestyle factors that are associated with the development of concomitant LC in patients with CP. In a retrospective case-control study between 2000 and 2005 122 patients with both CP and LC and 223 matched control patients with CP and no known liver disease were identified in 11 European university medical centers. Another 24 patients and 48 CP controls were identified in the period between 2006 and 2012. Alcoholism was most commonly regarded as aetiology for both CP (82.2%; 95% confidence interval (CI): 75.0-88.0%) and LC (79.5%; 95% CI: 72.0-85.7%) as compared to controls with CP only (68.6%; 95% CI: 62.7-74.1%). The preferred type of alcoholic beverage and pattern of alcohol intake were the only significant lifestyle factors in multivariate analysis. Frequency of alcohol intake (p = 0.105) and smoking status (p = 0.099) were not significant in bivariate analysis and dropped out of the multivariate model. Recurrent and chronic pancreatic pain was observed more often in patients with only CP, whereas gallstones were more common in individuals with both chronic disorders. These findings indicate that certain lifestyle factors might be important for the development of concomitant CP and LC. More studies will be needed to identify additional genetic and environmental factors underlying this association. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Ali Aghdassi, Alexander Schneider, Matthias Kahl, Kerstin Schütte, Irma Kuliaviene, Paola Salacone, Jon Lutz, Eija Tukiainen, Peter Simon, Birgit Schauer, Generoso Uomo, Truls Hauge, Güralp Ceyhan



European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis.

2017-08-10T07:10:17-00:00

Journal of the European Academy of Dermatology and Venereology : JEADV (08 August 2017)

The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy). © 2017 European Academy of Dermatology and Venereology.
R Knobler, P Moinzadeh, N Hunzelmann, A Kreuter, A Cozzio, L Mouthon, M Cutolo, F Rongioletti, CP Denton, L Rudnicka, LA Frasin, V Smith, A Gabrielli, E Aberer, M Bagot, G Bali, J Bouaziz, A Braae Olesen, I Foeldvari, C Frances, A Jalili, U Just, V Kähäri, S Kárpáti, K Kofoed, D Krasowska, M Olszewska, C Orteu, J Panelius, A Parodi, A Petit, P Quaglino, A Ranki, JM Sanchez Schmidt, J Seneschal, A Skrok, M Sticherling, C Sunderkötter, A Taieb, A Tanew, P Wolf, M Worm, NJ Wutte, T Krieg



Midkine and Melanoma Metastasis: A Malevolent Mix.

2017-08-10T07:08:23-00:00

Developmental cell, Vol. 42, No. 3. (07 August 2017), pp. 205-207

Using an in vivo reporter for lymphangiogenesis, a recent study in Nature from Olmeda et al. (2017) describes a new subset of melanomas that induce systemic pre-conditioning of distant organs for formation of tumor metastatic niches, and identifies the responsible factor as the pleiotropic cytokine midkine. Copyright © 2017 Elsevier Inc. All rights reserved.
Sinem Karaman, Kari Alitalo



Sport disciplines, types of sports, and waist circumference in young adulthood - a population-based twin study.

2017-08-10T07:06:22-00:00

European journal of sport science (08 August 2017), pp. 1-10

The benefits of physical activity (PA) in preventing abdominal obesity are well recognized, but the role of different sport disciplines remains open. We aimed, therefore, to investigate how participation in different sport disciplines, and the number and types of sports engaged in are associated with waist circumference (WC) in young adulthood. This population-based cohort study comprised 4027 Finnish twin individuals (1874 men), with a mean age of 34 y (32-37), who answered a survey, including self-measured WC. We extracted the number and identified the types (aerobic, power, and mixed) of the different sport disciplines respondents reported participating in. The number of sport disciplines participated in was inversely associated with WC, the linear decrease averaging 1.38 cm (95% CI 1.10-1.65) per each additional sport discipline. The result persisted after adjustment for the main covariates, such as volume of PA and diet quality. Among dizygotic twin pairs discordant for sports participation (0-2 vs. 5 or more disciplines), the mean within-pair difference in WC was 4.8 cm (95% CI 0.4-9.1) for men and 11.2 cm (95% CI 4.4-18.0) for women; among discordant monozygotic pairs, no differences were observed. In men, all three types of sports were individually associated with smaller WC, while in women, only mixed and power sports showed this association. Participation in several sport disciplines and sport types was associated with smaller WC among young adults in their mid-30s. Shared genetic background may explain some of the associations.
Mirva Rottensteiner, Sara Mäkelä, Leonie Bogl, Timo Törmäkangas, Jaakko Kaprio, Urho Kujala



Physical Activity, Sedentary Behavior, and Long-Term Changes in Aortic Stiffness: The Whitehall II Study.

2017-08-10T07:04:10-00:00

Journal of the American Heart Association, Vol. 6, No. 8. (07 August 2017)

Physical activity is associated with reduced cardiovascular disease risk, mainly through effects on atherosclerosis. Aortic stiffness may be an alternative mechanism. We examined whether patterns of physical activity and sedentary behavior are associated with rate of aortic stiffening. Carotid-femoral pulse wave velocity (PWV) was measured twice using applanation tonometry at mean ages 65 (in 2008/2009) and 70 (in 2012/2013) years in the Whitehall-II study (N=5196). Physical activity was self-reported at PWV baseline (2008/2009) and twice before (in 1997/1999 and 2002/2003). Sedentary time was defined as sitting time watching television or at work/commute. Linear mixed models adjusted for metabolic and lifestyle risk factors were used to analyze PWV change. Mean (SD) PWV (m/s) was 8.4 (2.4) at baseline and 9.2 (2.7) at follow-up, representing a 5-year increase of 0.76 m/s (95% CI 0.69, 0.83). A smaller 5-year increase in PWV was observed for each additional hour/week spent in sports activity (-0.02 m/s [95% CI -0.03, -0.001]) or cycling (-0.02 m/s [-0.03, -0.008]). Walking, housework, gardening, or do-it-yourself activities were not significantly associated with aortic stiffening. Each additional hour/week spent sitting was associated with faster PWV progression in models adjusted for physical activity (0.007 m/s [95% CI 0.001, 0.013]). Increasing physical activity over time was associated with a smaller subsequent increase in PWV (-0.16 m/s [-0.32, -0.002]) compared with not changing activity levels. Higher levels of moderate-to-vigorous physical activity and avoidance of sedentary behavior were each associated with a slower age-related progression of aortic stiffness independent of conventional vascular risk factors. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
Sara Ahmadi-Abhari, Severine Sabia, Martin Shipley, Mika Kivimäki, Archana Singh-Manoux, Adam Tabak, Carmel McEniery, Ian Wilkinson, Eric Brunner



Computational-experimental approach to drug-target interaction mapping: A case study on kinase inhibitors.

2017-08-10T06:57:48-00:00

PLoS computational biology, Vol. 13, No. 8. (07 August 2017)

Due to relatively high costs and labor required for experimental profiling of the full target space of chemical compounds, various machine learning models have been proposed as cost-effective means to advance this process in terms of predicting the most potent compound-target interactions for subsequent verification. However, most of the model predictions lack direct experimental validation in the laboratory, making their practical benefits for drug discovery or repurposing applications largely unknown. Here, we therefore introduce and carefully test a systematic computational-experimental framework for the prediction and pre-clinical verification of drug-target interactions using a well-established kernel-based regression algorithm as the prediction model. To evaluate its performance, we first predicted unmeasured binding affinities in a large-scale kinase inhibitor profiling study, and then experimentally tested 100 compound-kinase pairs. The relatively high correlation of 0.77 (p < 0.0001) between the predicted and measured bioactivities supports the potential of the model for filling the experimental gaps in existing compound-target interaction maps. Further, we subjected the model to a more challenging task of predicting target interactions for such a new candidate drug compound that lacks prior binding profile information. As a specific case study, we used tivozanib, an investigational VEGF receptor inhibitor with currently unknown off-target profile. Among 7 kinases with high predicted affinity, we experimentally validated 4 new off-targets of tivozanib, namely the Src-family kinases FRK and FYN A, the non-receptor tyrosine kinase ABL1, and the serine/threonine kinase SLK. Our sub-sequent experimental validation protocol effectively avoids any possible information leakage between the training and validation data, and therefore enables rigorous model validation for practical applications. These results demonstrate that the kernel-based modeling approach offers practical benefits for probing novel insights into the mode of action of investigational compounds, and for the identification of new target selectivities for drug repurposing applications.
Anna Cichonska, Balaguru Ravikumar, Elina Parri, Sanna Timonen, Tapio Pahikkala, Antti Airola, Krister Wennerberg, Juho Rousu, Tero Aittokallio



Changes in disability, self-rated health, comorbidities and psychological wellbeing in community-dwelling 75-95-year-old cohorts over two decades in Helsinki.

2017-08-10T06:52:46-00:00

Scandinavian journal of primary health care (07 August 2017), pp. 1-7

To explore changes in self-reported disabilities, health, comorbidities and psychological wellbeing (PWB) in aged cohorts over two decades. Cross-sectional cohort studies with postal surveys were conducted among community-dwelling people aged 75, 80, 85, 90 and 95 years in 1989 (n = 660), 1999 (n = 2598) and 2009 (n = 1637) in Helsinki, Finland. Self-reported items on disability, self-rated health (SRH), diagnoses and PWB were compared between cohorts of the same age. Standardized mortality ratios (SMRs) were calculated for each study year to explore the representativeness of the samples compared to general population of same age. A significantly lower proportion of the 75-85-year-olds of the later study years reported going outdoors daily, although this group had improvements in both SRH and PWB scores. The number of comorbidities increased over time among 75-85-year-olds. The only significant change that could be verified among 90- and 95-year-olds between 1999 and 2009, was the lower proportion of participants going outdoors daily. The trend of leveling-off in disabilities was not explained by the SMRs (0.90, 0.71 and 0.60 for 1989, 1999 and 2009). The latest older people's cohorts showed an end to previously reported improvements in disabilities, despite having favorable trends in SRH and PWB. Primary care may be faced with increasing need of appropriate services for their senior members.
Helena Karppinen, Kaisu Pitkälä, Hannu Kautiainen, Reijo Tilvis, Jaakko Valvanne, Käthe Yoder, Timo Strandberg



Childhood adversity, adult socioeconomic status and risk of work disability: a prospective cohort study.

2017-08-10T06:50:50-00:00

Occupational and environmental medicine (07 August 2017)

To examine the combined effects of childhood adversities and low adult socioeconomic status (SES) on the risk of future work disability. Included were 34 384 employed Finnish Public Sector study participants who responded to questions about childhood adversities (none vs any adversity, eg, parental divorce or financial difficulties) in 2008, and whose adult SES in 2008 was available. We categorised exposure into four groups: neither (reference), childhood adversity only, low SES only or both. Participants were followed from 2009 until the first period of register-based work disability (sickness absence >9 days or disability pension) due to any cause, musculoskeletal or mental disorders; retirement; death or end of follow-up (December 2011). We ran Cox proportional hazard models adjusted for behavioural, health-related and work-related covariates, and calculated synergy indices for the combined effects. When compared with those with neither exposure, HR for work disability from any cause was increased among participants with childhood adversity, with low SES, and those with both exposures. The highest hazard was observed in those with both exposures: HR 2.53, 95% CI 2.29 to 2.79 for musculoskeletal disability, 1.55, 95% CI 1.36 to 1.78 for disability due to mental disorders and 1.29, 95% CI 1.20 to 1.39 for disability due to other reasons. The synergy indices did not indicate synergistic effects. These findings indicate that childhood psychosocial adversity and low adult SES are additive risk factors for work disability. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Jaana Halonen, Mika Kivimäki, Jussi Vahtera, Jaana Pentti, Marianna Virtanen, Jenni Ervasti, Tuula Oksanen, Tea Lallukka



Alcohol use and smoking in burn patients at the Helsinki Burn Center.

2017-08-10T06:49:27-00:00

Burns : journal of the International Society for Burn Injuries (04 August 2017)

We investigated alcohol use and smoking at time of burn and their relationships with severity of burn and presence of mental disorders. Consecutive acute burn patients (N=107) admitted to the Helsinki Burn Center were assessed with the structured clinical interview for mental disorders (SCID) at baseline and after 6 months. Information regarding being under the influence of alcohol and having smoking-related activity at burn as well as about hazardous drinking (Alcohol Use Disorders Identification Test) and heavy smoking before the burn was recorded. Around half (52%) of the acute burn patients were under the influence of alcohol and 19% had been both drinking and smoking at the time of the burn. Patients under the influence at the time of burn had significantly higher prevalence of lifetime mental disorders compared to those patients who were not under the influence of alcohol (73.2% vs. 45.1%, p=0.003), especially alcohol dependence (55.4% vs. 13.7%, p<0.001) and anxiety disorders (28.6% vs. 9.8%, p=0.015). Patients who had both alcohol use and smoking at burn had even more often at least one mental disorder (95.0% vs. 51.7%, p<0.001), in specific alcohol dependence (90.0% vs. 23.0%, p<0.001), or psychotic disorder (25.0% vs. 6.9%, p=0.016). The main characteristics of the burns themselves did not differ significantly between these groups. Half of the burn patients were under the influence of alcohol at the time of the burn in this study. In almost all patients where alcohol and smoking contributed to the burn a diagnosable alcohol use disorder was present. Interventions for those with alcohol use disorders and the associated risk behaviors are important for the prevention of burns. Copyright © 2017. Published by Elsevier Ltd.
Raimo Palmu, Timo Partonen, Kirsi Suominen, Jyrki Vuola, Erkki Isometsä



Haematopoietic stem cell transplantation induces severe dysbiosis in intestinal microbiota of paediatric ALL patients.

2017-08-09T05:26:03-00:00

Bone marrow transplantation (07 August 2017)
K Lähteenmäki, P Wacklin, M Taskinen, E Tuovinen, O Lohi, J Partanen, J Mättö, K Vettenranta



Spillover improved survival in non-invited patients of the colorectal cancer screening programme.

2017-08-09T05:22:23-00:00

Journal of medical screening (01 January 2017)

Objectives In colorectal cancer screening, randomized clinical trials have shown a 16% mean reduction in colorectal cancer mortality, but the Finnish randomized health services study showed no effect. We quantified spillover (the total indirect effect caused by the programme on the non-invited) and corrected the effectiveness estimate of the Finnish programme. Methods We retrieved from the Finnish Cancer Registry data on all non-invited colorectal cancer patients diagnosed in 1999-2013 in municipalities that adopted screening ( n = 18,948). Patients were stratified by three 5-year diagnostic periods and two calendar periods of programme adoption in the municipality of residence. Follow-up ended on 31 December 2013. We measured the spillover effect in patient survival, based on differences of adjusted estimates of the colorectal cancer-related hazard of death between pairs of consecutive diagnostic periods. Results The spillover effect was estimated as 9 percentage points (95% confidence interval: -1 to 19 percentage points). It was 13 percentage points in men (-1 to 26 percentage points) and 5 percentage points in women (-9 to 20 percentage points). The corrected effect estimate of implementing screening in Finland was 5 percentage points. Conclusions The corrected Finnish effectiveness estimate was consistent with estimates from randomized trials. Indirect effects (spillover) bias the invitee-control contrast. In this case, spillover was an inherent benefit of the Finnish programme.
Joonas Miettinen, Nea Malila, Matti Hakama, Janne Pitkäniemi



SLUG transcription factor: a pro-survival and prognostic factor in gastrointestinal stromal tumour.

2017-08-09T05:20:12-00:00

British journal of cancer, Vol. 116, No. 9. (25 April 2017), pp. 1195-1202

The SLUG transcription factor has been linked with the KIT signalling pathway that is important for gastrointestinal stromal tumour (GIST) tumourigenesis. Its clinical significance in GIST is unknown. Influence of SLUG expression on cell proliferation and viability were investigated in GIST48 and GIST882 cell lines. The association between tumour SLUG expression in immunohistochemistry and recurrence-free survival (RFS) was studied in two clinical GIST series, one with 187 patients treated with surgery alone, and another one with 313 patients treated with surgery and adjuvant imatinib. SLUG downregulation inhibited cell proliferation, induced cell death in both cell lines, and sensitised GIST882 cells to lower imatinib concentrations. SLUG was expressed in 125 (25.0%) of the 500 clinical GISTs evaluated, and expression was associated with several factors linked with unfavourable prognosis. SLUG expression was associated with unfavourable RFS both when patients were treated with surgery alone (HR=3.40, 95% CI=1.67-6.89, P=0.001) and when treated with surgery plus adjuvant imatinib (HR=1.83, 95% CI=1.29-2.60, P=0.001). GIST patients with high tumour SLUG expression have unfavourable RFS. SLUG may mediate pro-survival signalling in GISTs.
Olli-Pekka Pulkka, Bengt Nilsson, Maarit Sarlomo-Rikala, Peter Reichardt, Mikael Eriksson, Kirsten Sundby Hall, Eva Wardelmann, Aki Vehtari, Heikki Joensuu, Harri Sihto



Comparison of relationships between four common anthropometric measures and incident diabetes.

2017-08-08T11:01:04-00:00

Diabetes research and clinical practice, Vol. 132 (22 July 2017), pp. 36-44

First, to conduct a detailed exploration of the prospective relations between four commonly used anthropometric measures with incident diabetes and to examine their consistency across different population subgroups. Second, to compare the ability of each of the measures to predict five-year risk of diabetes. We conducted a meta-analysis of individual participant data on body mass index (BMI), waist circumference (WC), waist-hip and waist-height ratio (WHtR) from the Obesity, Diabetes and Cardiovascular Disease Collaboration. Cox proportional hazard models were used to estimate the association between a one standard deviation increment in each anthropometric measure and incident diabetes. Harrell's concordance statistic was used to test the predictive accuracy of each measure for diabetes risk at five years. Twenty-one studies with 154,998 participants and 9342 cases of incident diabetes were available. Each of the measures had a positive association with incident diabetes. A one standard deviation increment in each of the measures was associated with 64-80% higher diabetes risk. WC and WHtR more strongly associated with risk than BMI (ratio of hazard ratios: 0.95 [0.92,0.99] - 0.97 [0.95,0.98]) but there was no appreciable difference between the four measures in the predictive accuracy for diabetes at five years. Despite suggestions that abdominal measures of obesity have stronger associations with incident diabetes and better predictive accuracy than BMI, we found no overall advantage in any one measure at discriminating the risk of developing diabetes. Any of these measures would suffice to assist in primary diabetes prevention efforts. Copyright © 2017 Elsevier B.V. All rights reserved.
Crystal Man Ying Lee, Mark Woodward, Nirmala Pandeya, Robert Adams, Elizabeth Barrett-Connor, Edward Boyko, Mats Eliasson, Laercio Franco, Wilfred Fujimoto, Clicerio Gonzalez, Barbara Howard, David Jacobs, Sirkka Keinanen-Kiukaanniemi, Dianna Magliano, Pamela Schreiner, Jonathan Shaw, June Stevens, Anne Taylor, Jaakko Tuomilehto, Lynne Wagenknecht, Rachel Huxley,



Primary decompressive craniectomy is associated with worse neurological outcome in patients with traumatic brain injury requiring acute surgery.

2017-08-08T05:44:23-00:00

Surgical neurology international, Vol. 8 (2017)

The role of decompressive craniectomy in treating raised intracranial pressure (ICP) after traumatic brain injuries (TBI) is controversial. The aim of this study was to assess the differences in prognosis of patients initially treated by decompressive craniectomy, craniotomy, or conservatively. We conducted a single-center retrospective study on adult blunt TBI patients admitted to a neurosurgical intensive care unit during 2009-2012. Patients were divided into three groups based on their initial treatment - decompressive craniectomy, craniotomy, and conservative. Primary outcome was 6-month Glasgow Outcome Scale (GOS) dichotomized to favorable outcome (independent) and unfavorable outcome (dependent). The association between initial treatment and outcome was assessed using a logistic regression model adjusting for case-mix using known predictors of outcome. Of the 822 included patients, 58 patients were in the craniectomy group, 401 patients in the craniotomy group, and 363 patients in the conservatively treated group. Overall, 6-month unfavorable outcome was 48%. After adjusting for case-mix, patients in the decompressive craniectomy group had a statistical significantly higher risk for poor neurological outcome compared to patients in the conservative group (OR 3.06, 95% CI 1.45-6.42) and craniotomy group (OR 3.61, 95% CI 1.74-7.51). In conclusion, patients requiring primary decompressive craniectomy had a higher risk for poor neurological outcome compared to patients undergoing craniotomy or were conservatively treated. It is plausible that the poor prognosis is related to the TBI severity itself rather than the intervention. Further prospective randomized trials are required to establish the role of decompressive craniectomy in the treatment of patients with TBI.
Julius Tapper, Markus Skrifvars, Riku Kivisaari, Jari Siironen, Rahul Raj



Relationship between physical activity and physical performance in later life in different birth weight groups.

2017-08-08T05:42:06-00:00

Journal of developmental origins of health and disease (07 August 2017), pp. 1-7

There is strong evidence that physical activity (PA) has an influence on physical performance in later life. Also, a small body size at birth has been associated with lower physical functioning in older age and both small and high birth weight have shown to be associated with lower leisure time physical activity. However, it is unknown whether size at birth modulates the association between PA and physical performance in old age. We examined 695 individuals from the Helsinki Birth Cohort Study born in Helsinki, Finland between 1934 and 1944. At a mean age of 70.7 years PA was objectively assessed with a multisensory activity monitor and physical performance with the Senior Fitness Test (SFT). Information on birth weight and gestational age was retrieved from hospital birth records. The study participants were divided in three birth weight groups, that is <3000 g, 3000-3499 g and ⩾3500 g. The volume of PA was significantly associated with the physical performance in all birth weight groups. However, the effect size of the association was large and significant only in men with a birth weight <3000 g (β 0.59; 95% confidence interval 0.37-0.81, P<0.001). Our study shows that the association between PA and physical performance is largest in men with low birth weight. Our results suggest that men with low birth weight might benefit most from engaging in PA in order to maintain a better physical performance.
H Jantunen, NS Wasenius, MK Salonen, M-M Perälä, H Kautiainen, M Simonen, P Pohjolainen, E Kajantie, MB von Bonsdorff, JG Eriksson



PLS3 deletions lead to severe spinal osteoporosis and disturbed bone matrix mineralization.

2017-08-07T11:44:18-00:00

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (04 August 2017)

Mutations in the PLS3 gene, encoding Plastin 3, were described in 2013 as a cause for X-linked primary bone fragility in children. The specific role of PLS3 in bone metabolism remains inadequately understood. Here we describe for the first time PLS3 deletions as the underlying cause for childhood-onset primary osteoporosis in three boys from two families. We carried out thorough clinical, radiological and bone tissue analyses to explore the consequences of these deletions and to further elucidate the role of PLS3 in bone homeostasis. In Family 1 the two affected brothers had a deletion of exons 4-16 (NM_005032) in PLS3, inherited from their healthy mother. In Family 2 the index patient had a deletion involving the entire PLS3 gene (exons 1-16), inherited from his mother who had osteoporosis. The three patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies. The two brothers in Family 1 also displayed subtle dysmorphic facial features and both had developed a myopathic gait. Extensive analyses of a transiliac bone biopsy from one patient showed a prominent increase in osteoid volume, osteoid thickness and in mineralizing lag time. Results from quantitative backscattered electron imaging and Raman microspectroscopy showed a significant hypomineralization of the bone. Together our results indicate that PLS3 deletions lead to severe childhood-onset osteoporosis due to defective bone matrix mineralization, suggesting a specific role for PLS3 in the mineralization process. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Kämpe Aj, Costantini A, Levy-Shraga Y, Zeitlin L, Roschger P, Taylan F, Lindstrand A, Paschalis Ep, Gamsjaeger S, Raas-Rothschild A, Hövel M, Jiao H, Klaushofer K, Grasemann C, Mäkitie O



The evolution of the Helsinki frostbite management protocol.

2017-08-07T11:35:15-00:00

Burns : journal of the International Society for Burn Injuries (01 August 2017)

Severe frostbite can result in devastating injuries leading to significant morbidity and loss of function from distal extremity amputation. The modern day management approach to frostbite injuries is evolving from a historically very conservative approach to the increasingly reported use of early interventional angiography and fibrinolysis with tPA. The aim of this study was to evaluate the results of our frostbite treatment protocol introduced 3 years ago. All frostbite patients underwent first clinical and then Doppler ultrasound examination. Angiography was conducted if certain clinical criteria indicated a severe frostbite injury and if there were no contraindications to fibrinolysis. Intra-arterial tissue plasminogen activator (tPA) was then administered at 0.5-1mg/h proximal to the antecubital fossa (brachial artery) or popliteal fossa (femoral artery) if angiography confirmed thrombosis, as well as unfractionated intravenous heparin at 500 units/h. The vasodilator iloprost was administered intravenously (0.5-2.0ng/kg/min) in selected cases. 20 patients with frostbite were diagnosed between 2013-2016. Fourteen patients had a severe injury and angiography was performed in 10 cases. The total number of digits at risk was 111. Nine patients underwent fibrinolytic treatment with tPA (including one patient who received iloprost after initial non response to tPA), 3 patients were treated with iloprost alone and 2 patients received neither treatment modality (due to contraindications). The overall digital salvage rate was 74.8% and the Hennepin tissue salvage rate was 81.1%. One patient developed a catheter-site pseudoaneurysm that resolved after conservative treatment. Prompt referral to a facility where interventional radiology and 24/7 laboratory services are available, and the combined use of tPA and iloprost, may improve outcome after severe frostbite. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.
Andrew Lindford, Jussi Valtonen, Maarit Hult, Heli Kavola, Kimmo Lappalainen, Riitta Lassila, Pekka Aho, Jyrki Vuola



Fast-track vs. delayed insertion of the levonorgestrel-releasing intrauterine system after early medical abortion - a randomized trial.

2017-08-07T11:23:55-00:00

Contraception (31 July 2017)

To compare levonorgestrel (LNG) 52-mg intrauterine system (IUS) expulsion rates with fast track (≤ three days) or delayed (2-4weeks) insertion following mifepristone and misoprostol medical abortion. In this pilot trial we randomized 108 women≤63days gestation to fast-track (n=55) or delayed (n=53) insertion. Follow-up visits occurred at 2-4weeks, three months and one year. We assessed total and partial expulsion at three months and one year, adverse effects and bleeding profiles. We had follow-up data at three months and one year for 41 (74.5%) and 37 (69.8%) women in the fast-track group, and 31 (56.4%) and 28 (52.8%) women in the delayed group. By three months, expulsion occurred in six (12.5%) women after fast-track and one (2.3%) woman after delayed insertion (RR 5.50, 95%CI 0.69-43.90), most (n=5) of these were partial expulsions in the fast-track group. By one year, expulsion had occurred in seven (14.6%) and five (11.5%) women in the fast-track and delayed groups, respectively (RR 1.28, 95%CI 0.44-3.75). We found no differences in rates of vacuum aspiration, residual tissue, infection and bleeding or bleeding patterns within three months of insertion. Fast-track insertion of the LNG 52-mg IUS after medical abortion is feasible, but may result in higher expulsion rates compared to delayed insertion. Due to lack of statistical power and high lost-to-follow-up rates, we were unable to fully address this question. Fast-tract initiation of LNG 52-mg IUS contraception after medical abortion is feasible. It results in higher expulsion rates than delayed insertion, but may improve post-abortal intrauterine contraception uptake. Copyright © 2017. Published by Elsevier Inc.
Riina Korjamo, Maarit Mentula, Oskari Heikinheimo



Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

2017-08-07T07:31:09-00:00

Gut (04 August 2017)

Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Rudi Alberts, Elisabeth de Vries, Elizabeth Goode, Xiaojun Jiang, Fotis Sampaziotis, Krista Rombouts, Katrin Böttcher, Trine Folseraas, Tobias Weismüller, Andrew Mason, Weiwei Wang, Graeme Alexander, Domenico Alvaro, Annika Bergquist, Niklas Björkström, Ulrich Beuers, Einar Björnsson, Kirsten Muri Boberg, Christopher Bowlus, Maria Bragazzi, Marco Carbone, Olivier Chazouillères, Angela Cheung, Georgios Dalekos, John Eaton, Bertus Eksteen, David Ellinghaus, Martti Färkkilä, Eleonora Festen, Annarosa Floreani, Irene Franceschet, Daniel Nils Gotthardt, Gideon Hirschfield, Bart van Hoek, Kristian Holm, Simon Hohenester, Johannes Roksund Hov, Floris Imhann, Pietro Invernizzi, Brian Juran, Henrike Lenzen, Wolfgang Lieb, Jimmy Liu, Hanns-Ulrich Marschall, Marco Marzioni, Espen Melum, Piotr Milkiewicz, Tobias Müller, Albert Pares, Christian Rupp, Christian Rust, Richard Sandford, Christoph Schramm, Stefan Schreiber, Erik Schrumpf, Mark Silverberg, Brijesh Srivastava, Martina Sterneck, Andreas Teufel, Ludovic Vallier, Joanne Verheij, Arnau Vich Vila, Boudewijn de Vries, Kalliopi Zachou, , Roger Chapman, Michael Manns, Massimo Pinzani, Simon Rushbrook, Konstantinos Lazaridis, Andre Franke, Carl Anderson, Tom Karlsen, Cyriel Ponsioen, Rinse Weersma



Maternal blood contamination of collected cord blood can be identified using DNA methylation at three CpGs.

2017-08-07T07:29:21-00:00

Clinical epigenetics, Vol. 9 (2017)

Cord blood is a commonly used tissue in environmental, genetic, and epigenetic population studies due to its ready availability and potential to inform on a sensitive period of human development. However, the introduction of maternal blood during labor or cross-contamination during sample collection may complicate downstream analyses. After discovering maternal contamination of cord blood in a cohort study of 150 neonates using Illumina 450K DNA methylation (DNAm) data, we used a combination of linear regression and random forest machine learning to create a DNAm-based screening method. We identified a panel of DNAm sites that could discriminate between contaminated and non-contaminated samples, then designed pyrosequencing assays to pre-screen DNA prior to being assayed on an array. Maternal contamination of cord blood was initially identified by unusual X chromosome DNA methylation patterns in 17 males. We utilized our DNAm panel to detect contaminated male samples and a proportional amount of female samples in the same cohort. We validated our DNAm screening method on an additional 189 sample cohort using both pyrosequencing and DNAm arrays, as well as 9 publically available cord blood 450K data sets. The rate of contamination varied from 0 to 10% within these studies, likely related to collection specific methods. Maternal blood can contaminate cord blood during sample collection at appreciable levels across multiple studies. We have identified a panel of markers that can be used to identify this contamination, either post hoc after DNAm arrays have been completed, or in advance using a targeted technique like pyrosequencing.
Alexander Morin, Evan Gatev, Lisa McEwen, Julia MacIsaac, David Lin, Nastassja Koen, Darina Czamara, Katri Räikkönen, Heather Zar, Karestan Koenen, Dan Stein, Michael Kobor, Meaghan Jones



Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S2TOP-BLEED.

2017-08-07T07:24:48-00:00

Neurology (02 August 2017)

To develop and externally validate a prediction model for major bleeding in patients with a TIA or ischemic stroke on antiplatelet agents. We combined individual patient data from 6 randomized clinical trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS) investigating antiplatelet therapy after TIA or ischemic stroke. Cox regression analyses stratified by trial were performed to study the association between predictors and major bleeding. A risk prediction model was derived and validated in the PERFORM trial. Performance was assessed with the c statistic and calibration plots. Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed 3-year risk of major bleeding was 4.6% (95% confidence interval [CI] 4.4%-4.9%). Predictors were male sex, smoking, type of antiplatelet agents (aspirin-clopidogrel), outcome on modified Rankin Scale ≥3, prior stroke, high blood pressure, lower body mass index, elderly, Asian ethnicity, and diabetes (S2TOP-BLEED). The S2TOP-BLEED score had a c statistic of 0.63 (95% CI 0.60-0.64) and showed good calibration in the development data. Major bleeding risk ranged from 2% in patients aged 45-54 years without additional risk factors to more than 10% in patients aged 75-84 years with multiple risk factors. In external validation, the model had a c statistic of 0.61 (95% CI 0.59-0.63) and slightly underestimated major bleeding risk. The S2TOP-BLEED score can be used to estimate 3-year major bleeding risk in patients with a TIA or ischemic stroke who use antiplatelet agents, based on readily available characteristics. The discriminatory performance may be improved by identifying stronger predictors of major bleeding. © 2017 American Academy of Neurology.
Nina Hilkens, Ale Algra, Hans-Christoph Diener, Johannes Reitsma, Philip Bath, Laszlo Csiba, Werner Hacke, Jaap Kappelle, Peter Koudstaal, Didier Leys, Jean-Louis Mas, Ralph Sacco, Pierre Amarenco, Leila Sissani, Jacoba Greving,



Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family.

2017-08-07T07:22:55-00:00

Atherosclerosis, Vol. 264 (22 July 2017), pp. 58-66

Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs. Copyright © 2017 Elsevier B.V. All rights reserved.
Elina Nikkola, Arthur Ko, Marcus Alvarez, Rita Cantor, Kristina Garske, Elliot Kim, Stephanie Gee, Alejandra Rodriguez, Reinhard Muxel, Niina Matikainen, Sanni Söderlund, Mahdi Motazacker, Jan Borén, Claudia Lamina, Florian Kronenberg, Wolfgang Schneider, Aarno Palotie, Markku Laakso, Marja-Riitta Taskinen, Päivi Pajukanta



Questionnaire survey of detrimental fur animal epidemic necrotic pyoderma in Finland.

2017-08-07T07:19:14-00:00

Acta veterinaria Scandinavica, Vol. 59, No. 1. (03 August 2017)

In 2007, a previously unrecorded disease, fur animal epidemic necrotic pyoderma (FENP), was detected in farmed mink (Neovision vision), foxes (Vulpes lagopus) and Finnraccoons (Nyctereutes procyonoides) in Finland. Symptoms included severe pyoderma with increased mortality, causing both animal welfare problems and economic losses. In 2011, an epidemiologic questionnaire was mailed to all members of the Finnish Fur Breeders' Association to assess the occurrence of FENP from 2009 through the first 6 months of 2011. The aim was to describe the geographical distribution and detailed clinical signs of FENP, as well as sources of infection and potential risk factors for the disease. A total of 239 farmers (25%) returned the questionnaire. Clinical signs of FENP were observed in 40% (95% CI 34-46%) of the study farms. In addition, the survey clarified the specific clinical signs for different animal species. The presence of disease was associated with the importation of mink, especially from Denmark (OR 9.3, 95% CI 2.6-33.0). The transmission route between Finnish farms was associated with fur animal purchases. Some risk factors such as the farm type were also indicated. As such, FENP was detected more commonly on farms with more than one species of fur animal in comparison to farms with, for example, only foxes (OR 4.6, 95% CI 2.4-8.6), and the incidence was higher on farms with over 750 breeder mink compared to smaller farms (OR 3.8, 95% CI 1.6-9.0). Contact between fur animals and birds and other wildlife increased the risk of FENP on farms. Responses also indicated that blocking the entry of wildlife to the animal premises protected against FENP. FENP was most likely introduced to Finland by imported mink and spread further within the country via domestically purchased fur animals. Some potential risk factors, such as the type and size of the farm and contact with wildlife, contributed to the spread of FENP. Escape-proof shelter buildings block the entry of wildlife, thus protecting fur animals against FENP.
Heli Nordgren, Katariina Vapalahti, Olli Vapalahti, Antti Sukura, Anna-Maija Virtala



Evaluation of novel computerized tomography scoring systems in human traumatic brain injury: An observational, multicenter study.

2017-08-07T07:16:53-00:00

PLoS medicine, Vol. 14, No. 8. (August 2017)

Traumatic brain injury (TBI) is a major contributor to morbidity and mortality. Computerized tomography (CT) scanning of the brain is essential for diagnostic screening of intracranial injuries in need of neurosurgical intervention, but may also provide information concerning patient prognosis and enable baseline risk stratification in clinical trials. Novel CT scoring systems have been developed to improve current prognostic models, including the Stockholm and Helsinki CT scores, but so far have not been extensively validated. The primary aim of this study was to evaluate the Stockholm and Helsinki CT scores for predicting functional outcome, in comparison with the Rotterdam CT score and Marshall CT classification. The secondary aims were to assess which individual components of the CT scores best predict outcome and what additional prognostic value the CT scoring systems contribute to a clinical prognostic model. TBI patients requiring neuro-intensive care and not included in the initial creation of the Stockholm and Helsinki CT scoring systems were retrospectively included from prospectively collected data at the Karolinska University Hospital (n = 720 from 1 January 2005 to 31 December 2014) and Helsinki University Hospital (n = 395 from 1 January 2013 to 31 December 2014), totaling 1,115 patients. The Marshall CT classification and the Rotterdam, Stockholm, and Helsinki CT scores were assessed using the admission CT scans. Known outcome predictors at admission were acquired (age, pupil responsiveness, admission Glasgow Coma Scale, glucose level, and hemoglobin level) and used in univariate, and multivariable, regression models to predict long-term functional outcome (dichotomizations of the Glasgow Outcome Scale [GOS]). In total, 478 patients (43%) had an unfavorable outcome (GOS 1-3). In the combined cohort, overall prognostic performance was more accurate for the Stockholm CT score (Nagelkerke's pseudo-R2 range 0.24-0.28) and the Helsinki CT score (0.18-0.22) than for the Rotterdam CT score (0.13-0.15) and Marshall CT classification (0.03-0.05). Moreover, the Stockholm and Helsinki CT scores added the most independent prognostic value in the presence of other known clinical outcome predictors in TBI (6% and 4%, respectively). The aggregate traumatic subarachnoid hemorrhage (tSAH) component of the Stockholm CT score was the strongest predictor of unfavorable outcome. The main limitations were the retrospective nature of the study, missing patient information, and the varying follow-up time between the centers. The Stockholm and Helsinki CT scores provide more information on the damage sustained, and give a more accurate outcome prediction, than earlier classification systems. The strong independent predictive value of tSAH may reflect an underrated component of TBI pathophysiology. A change to these newer CT scoring systems may be warranted.
Eric Peter Thelin, David Nelson, Juho Vehviläinen, Harriet Nyström, Riku Kivisaari, Jari Siironen, Mikael Svensson, Markus Skrifvars, Bo-Michael Bellander, Rahul Raj



Prognostic factors for return to work after depression-related work disability: A systematic review and meta-analysis.

2017-08-07T07:14:39-00:00

Journal of psychiatric research, Vol. 95 (26 July 2017), pp. 28-36

Knowledge about factors influencing return to work (RTW) after depression-related absence is highly relevant, but the evidence is scattered. We performed a systematic search of PubMed and Embase databases up to February 1, 2016 to retrieve cohort studies on the association between various predictive factors and return to work among employees with depression for review and meta-analysis. We also analyzed unpublished data from the Finnish Public Sector study. Most-adjusted estimates were pooled using fixed effects meta-analysis. Eleven published studies fulfilled the eligibility criteria, representing 22 358 person-observations from five different countries. With the additional unpublished data from the 14 101 person-observations from the Finnish Public Sector study, the total number of person-observations was 36 459. The pooled estimates were derived from 2 to 5 studies, with the number of observations ranging from 260 to 26 348. Older age (pooled relative risk [RR] 0.95; 95% confidence interval [CI] 0.84-0.87), somatic comorbidity (RR = 0.80, 95% CI 0.77-0.83), psychiatric comorbidity (RR = 0.86, 95% CI 0.83-0.88) and more severe depression (RR = 0.96, 95% CI 0.94-0.98) were associated with a lower rate of return to work, and personality trait conscientiousness with higher (RR = 1.06, 95% CI 1.02-1.10) return to work. While older age and clinical factors predicted slower return, significant heterogeneity was observed between the studies. There is a dearth of observational studies on the predictors of RTW after depression. Future research should pay attention to quality aspects and particularly focus on the role of workplace and labor market factors as well as individual and clinical characteristics on RTW. Copyright © 2017 Elsevier Ltd. All rights reserved.
Jenni Ervasti, Matti Joensuu, Jaana Pentti, Tuula Oksanen, Kirsi Ahola, Jussi Vahtera, Mika Kivimäki, Marianna Virtanen



Uncoupling protein 2 haplotype does not affect human brain structure and function in a sample of community-dwelling older adults.

2017-08-07T07:12:38-00:00

PloS one, Vol. 12, No. 8. (2017)

Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that plays a role in uncoupling electron transport from adenosine triphosphate (ATP) formation. Polymorphisms of the UCP2 gene in humans affect protein expression and function and have been linked to survival into old age. Since UCP2 is expressed in several brain regions, we investigated in this study whether UCP2 polymorphisms might 1) affect occurrence of neurodegenerative or mental health disorders and 2) affect measures of brain structure and function. We used structural magnetic resonance imaging (MRI), diffusion-weighted MRI and resting-state functional MRI in the neuroimaging sub-study of the Whitehall II cohort. Data from 536 individuals aged 60 to 83 years were analyzed. No association of UCP2 polymorphisms with the occurrence of neurodegenerative disorders or grey and white matter structure or resting-state functional connectivity was observed. However, there was a significant effect on occurrence of mood disorders in men with the minor alleles of -866G>A (rs659366) and Ala55Val (rs660339)) being associated with increasing odds of lifetime occurrence of mood disorders in a dose dependent manner. This result was not accompanied by effects of UCP2 polymorphisms on brain structure and function, which might either indicate that the sample investigated here was too small and underpowered to find any significant effects, or that potential effects of UCP2 polymorphisms on the brain are too subtle to be picked up by any of the neuroimaging measures used.
Verena Heise, Enikő Zsoldos, Sana Suri, Claire Sexton, Anya Topiwala, Nicola Filippini, Abda Mahmood, Charlotte Allan, Archana Singh-Manoux, Mika Kivimäki, Clare Mackay, Klaus Ebmeier



Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.

2017-08-07T07:10:57-00:00

BioData mining, Vol. 10 (2017)

The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
Emily Holzinger, Shefali Verma, Carrie Moore, Molly Hall, Rishika De, Diane Gilbert-Diamond, Matthew Lanktree, Nathan Pankratz, Antoinette Amuzu, Amber Burt, Caroline Dale, Scott Dudek, Clement Furlong, Tom Gaunt, Daniel Seung Kim, Helene Riess, Suthesh Sivapalaratnam, Vinicius Tragante, Erik van Iperen, Ariel Brautbar, David Carrell, David Crosslin, Gail Jarvik, Helena Kuivaniemi, Iftikhar Kullo, Eric Larson, Laura Rasmussen-Torvik, Gerard Tromp, Jens Baumert, Karen Cruickshanks, Martin Farrall, Aroon Hingorani, GK Hovingh, Marcus Kleber, Barbara Klein, Ronald Klein, Wolfgang Koenig, Leslie Lange, Winfried Mӓrz, Kari North, N Charlotte Onland-Moret, Alex Reiner, Philippa Talmud, Yvonne van der Schouw, James Wilson, Mika Kivimaki, Meena Kumari, Jason Moore, Fotios Drenos, Folkert Asselbergs, Brendan Keating, Marylyn Ritchie



Transport injuries and deaths in the Eastern Mediterranean Region: findings from the Global Burden of Disease 2015 Study.

2017-08-07T07:09:22-00:00

International journal of public health (03 August 2017)

Transport injuries (TI) are ranked as one of the leading causes of death, disability, and property loss worldwide. This paper provides an overview of the burden of TI in the Eastern Mediterranean Region (EMR) by age and sex from 1990 to 2015. Transport injuries mortality in the EMR was estimated using the Global Burden of Disease mortality database, with corrections for ill-defined causes of death, using the cause of death ensemble modeling tool. Morbidity estimation was based on inpatient and outpatient datasets, 26 cause-of-injury and 47 nature-of-injury categories. In 2015, 152,855 (95% uncertainty interval: 137,900-168,100) people died from TI in the EMR countries. Between 1990 and 2015, the years of life lost (YLL) rate per 100,000 due to TI decreased by 15.5%, while the years lived with disability (YLD) rate decreased by 10%, and the age-standardized disability-adjusted life years (DALYs) rate decreased by 16%. Although the burden of TI mortality and morbidity decreased over the last two decades, there is still a considerable burden that needs to be addressed by increasing awareness, enforcing laws, and improving road conditions.
, Ali Mokdad



Burden of cancer in the Eastern Mediterranean Region, 2005-2015: findings from the Global Burden of Disease 2015 Study.

2017-08-07T07:07:42-00:00

International journal of public health (03 August 2017)

To estimate incidence, mortality, and disability-adjusted life years (DALYs) caused by cancer in the Eastern Mediterranean Region (EMR) between 2005 and 2015. Vital registration system and cancer registry data from the EMR region were analyzed for 29 cancer groups in 22 EMR countries using the Global Burden of Disease Study 2015 methodology. In 2015, cancer was responsible for 9.4% of all deaths and 5.1% of all DALYs. It accounted for 722,646 new cases, 379,093 deaths, and 11.7 million DALYs. Between 2005 and 2015, incident cases increased by 46%, deaths by 33%, and DALYs by 31%. The increase in cancer incidence was largely driven by population growth and population aging. Breast cancer, lung cancer, and leukemia were the most common cancers, while lung, breast, and stomach cancers caused most cancer deaths. Cancer is responsible for a substantial disease burden in the EMR, which is increasing. There is an urgent need to expand cancer prevention, screening, and awareness programs in EMR countries as well as to improve diagnosis, treatment, and palliative care services.
, Christina Fitzmaurice



Intentional injuries in the Eastern Mediterranean Region, 1990-2015: findings from the Global Burden of Disease 2015 study.

2017-08-07T07:03:28-00:00

International journal of public health (03 August 2017)

We used GBD 2015 findings to measure the burden of intentional injuries in the Eastern Mediterranean Region (EMR) between 1990 and 2015. The Global Burden of Disease (GBD) study defines intentional injuries as a combination of self-harm (including suicide), interpersonal violence, collective violence (war), and legal intervention. We estimated number of deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) for each type of intentional injuries. In 2015, 28,695 individuals (95% UI: 25,474-37,832) died from self-harm, 35,626 (95% UI: 20,947-41,857) from interpersonal violence, and 143,858 (95% UI: 63,554-223,092) from collective violence and legal interventions. In 2015, collective violence and legal intervention was the fifth-leading cause of DALYs in the EMR and the leading cause in Syria, Yemen, Iraq, Afghanistan, and Libya; they account for 49.7% of total DALYs in Syria. Our findings call for increased efforts to stabilize the region and assist in rebuilding the health systems, as well as increasing transparency and employing preventive strategies to reduce self-harm and interpersonal injuries.
, Ali Mokdad



Burden of cardiovascular diseases in the Eastern Mediterranean Region, 1990-2015: findings from the Global Burden of Disease 2015 study.

2017-08-07T07:00:39-00:00

International journal of public health (03 August 2017)

To report the burden of cardiovascular diseases (CVD) in the Eastern Mediterranean Region (EMR) during 1990-2015. We used the 2015 Global Burden of Disease study for estimates of mortality and disability-adjusted life years (DALYs) of different CVD in 22 countries of EMR. A total of 1.4 million CVD deaths (95% UI: 1.3-1.5) occurred in 2015 in the EMR, with the highest number of deaths in Pakistan (465,116) and the lowest number of deaths in Qatar (723). The age-standardized DALY rate per 100,000 decreased from 10,080 in 1990 to 8606 in 2015 (14.6% decrease). Afghanistan had the highest age-standardized DALY rate of CVD in both 1990 and 2015. Kuwait and Qatar had the lowest age-standardized DALY rates of CVD in 1990 and 2015, respectively. High blood pressure, high total cholesterol, and high body mass index were the leading risk factors for CVD. The age-standardized DALY rates in the EMR are considerably higher than the global average. These findings call for a comprehensive approach to prevent and control the burden of CVD in the region.
, Ali Mokdad



Persistent Hyperglycemia Is Associated With Increased Mortality After Intracerebral Hemorrhage.

2017-08-07T06:55:32-00:00

Journal of the American Heart Association, Vol. 6, No. 8. (02 August 2017)

Hyperglycemia may be associated with worse outcome after intracerebral hemorrhage (ICH). We assessed the association of early glycemic trajectory on ICH mortality and edema growth. We included patients from the Helsinki ICH study with glucose measurements at least once between both 0 to 24 and 24 to 72 hours from onset. Hyperglycemia was defined as blood glucose ≥8 mmol/L (144 mg/dL) based on the local threshold for treatment. Glycemic trajectory was defined on maximum values 0 to 24 and 24 to 72 hours after ICH: (1) persistent normoglycemia in both epochs; (2) late hyperglycemia (only between 24 and 72 hours); (3) early hyperglycemia (only before 24 hours); and (4) persistent hyperglycemia in both epochs. Logistic regression with known predictors of outcome estimated the association of glycemic trajectory and 6-month mortality. A generalized linear model assessed the association of glycemic trajectory and interpolated 72-hour edema extension distance. A total of 576 patients met eligibility criteria, of whom 214 (37.2%) had persistent normoglycemia, 44 (7.6%) late hyperglycemia, 151 (26.2%) early hyperglycemia, and 167 (29.0%) persistent hyperglycemia. Six-month mortality was higher in the persistent (51.1%) and early (26.3%) hyperglycemia groups than the normoglycemia (19.0%) and late hyperglycemia (3.6%) groups. Persistent hyperglycemia was associated with 6-month mortality (odds ratio 3.675, 95% CI 1.989-6.792; P<0.001). Both univariate (P=0.426) and multivariable (P=0.493) generalized linear model analyses showed no association between glycemic trajectory and 72-hour edema extension distance. Early hyperglycemia after ICH is harmful if it is persistent. Strategies to achieve glycemic control after ICH may influence patient outcome and need to be assessed in clinical trials. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
Teddy Wu, Jukka Putaala, Gagan Sharma, Daniel Strbian, Turgut Tatlisumak, Stephen Davis, Atte Meretoja



Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial.

2017-08-07T06:50:15-00:00

Journal of Alzheimer's disease : JAD (29 July 2017)

Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.
Shireen Sindi, Tiia Ngandu, Iiris Hovatta, Ingemar Kåreholt, Riitta Antikainen, Tuomo Hänninen, Esko Levälahti, Tiina Laatikainen, Jaana Lindström, Teemu Paajanen, Markku Peltonen, Dharma Singh Khalsa, Benjamin Wolozin, Timo Strandberg, Jaakko Tuomilehto, Hilkka Soininen, Miia Kivipelto, Alina Solomon,



Chimeric NUP98-NSD1 transcripts from the cryptic t(5;11)(q35.2;p15.4) in adult de novo acute myeloid leukemia.

2017-08-07T06:23:48-00:00

Leukemia & lymphoma (04 August 2017), pp. 1-8

The t(5;11)(q35;p15.4) is a clinically significant marker of poor prognosis in acute myeloid leukemia (AML), which is difficult to detect due to sub-telomeric localization of the breakpoints. To facilitate the detection of this rearrangement, we studied NUP98-NSD1 transcript variants in patients with the t(5;11) using paired-end RNA sequencing and standard molecular biology techniques. We discovered three NUP98-NSD1 transcripts with two fusion junctions (NUP98 exon 11-12/NSD1 exon 6), alternative 5' donor site in NUP98 exon 7, and NSD1 exon 7 skipping. Two of the transcripts were in-frame and occurred in all t(5;11) samples (N = 5). The exonic splicing events were present in all samples (N = 23) regardless of the NUP98-NSD1 suggesting that these novel splice events are unassociated with t(5;11). In conclusion, we provide evidence of two different NUP98-NSD1 fusion transcripts in adult AML, which result in functional proteins and represent suitable molecular entities for monitoring t(5;11) AML patients.
Jarno Kivioja, Jesus Lopez Martí, Ashwini Kumar, Mika Kontro, Henrik Edgren, Alun Parsons, Tuija Lundán, Maija Wolf, Kimmo Porkka, Caroline Heckman



Evaluation of the budding and depth of invasion (BD) model in oral tongue cancer biopsies.

2017-08-04T06:39:00-00:00

Virchows Archiv : an international journal of pathology (02 August 2017)

It is of great clinical importance to identify simple prognostic markers from preoperative biopsies that could guide treatment planning. Here, we compared tumor budding (B), depth of invasion (D), and the combined scores (i.e., budding and depth of invasion (BD) histopathologic model) in preoperative biopsies and the corresponding postoperative specimens of oral tongue squamous cell carcinoma (OTSCC). Tumor budding and depth of invasion were evaluated in the pre- and postoperative samples from 100 patients treated for OTSCC. Sensitivity and specificity statistics were used. Our results showed statistically significant (P < 0.001) relationship between pre- and postoperative BD scores. There was an agreement between the pre- and postoperative BD model scores in 83 cases (83%) with 57.1% sensitivity (95% CI 39.4 to 73.7%) and 96.9% specificity (95% CI 89.3 to 99.6%). Our findings suggest that the BD model, analyzed from representative biopsies, could be used for the treatment planning of OTSCC.
Alhadi Almangush, Ilmo Leivo, Maria Siponen, Elias Sundquist, Rayan Mroueh, Antti Mäkitie, Ylermi Soini, Caj Haglund, Pentti Nieminen, Tuula Salo



Plasma Mannose Levels Are Associated with Incident Type 2 Diabetes and Cardiovascular Disease.

2017-08-04T06:37:15-00:00

Cell metabolism, Vol. 26, No. 2. (01 August 2017), pp. 281-283

Plasma mannose levels are elevated in subjects with insulin resistance independently of obesity. Here, we found that elevated plasma mannose levels are strong markers of future risk of several chronic diseases including T2D, CVD, and albuminuria, and that it may contribute to their development rather than just being a novel biomarker. Copyright © 2017 Elsevier Inc. All rights reserved.
Adil Mardinoglu, Alena Stančáková, Luca Lotta, Johanna Kuusisto, Jan Boren, Matthias Blüher, Nicholas Wareham, Ele Ferrannini, Per Henrik Groop, Markku Laakso, Claudia Langenberg, Ulf Smith



mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression.

2017-08-03T11:40:56-00:00

Cell metabolism, Vol. 26, No. 2. (01 August 2017)

Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21. Copyright © 2017 Elsevier Inc. All rights reserved.
Nahid Khan, Joni Nikkanen, Shuichi Yatsuga, Christopher Jackson, Liya Wang, Swagat Pradhan, Riikka Kivelä, Alberto Pessia, Vidya Velagapudi, Anu Suomalainen



An interaction map of circulating metabolites, immune gene networks, and their genetic regulation.

2017-08-03T11:15:26-00:00

Genome biology, Vol. 18, No. 1. (01 August 2017)

Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up. We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus. This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.
Artika Nath, Scott Ritchie, Sean Byars, Liam Fearnley, Aki Havulinna, Anni Joensuu, Antti Kangas, Pasi Soininen, Annika Wennerström, Lili Milani, Andres Metspalu, Satu Männistö, Peter Würtz, Johannes Kettunen, Emma Raitoharju, Mika Kähönen, Markus Juonala, Aarno Palotie, Mika Ala-Korpela, Samuli Ripatti, Terho Lehtimäki, Gad Abraham, Olli Raitakari, Veikko Salomaa, Markus Perola, Michael Inouye