| 1. |
- Fergelot, Patricia, et al.
(författare)
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Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations
- 2016
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 170:12, s. 3069-3082
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Tidskriftsartikel (refereegranskat)abstract
- Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia.
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| 2. |
- Jarviaho, Tekla, et al.
(författare)
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Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6
- 2019
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:18, s. 2722-2731
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic germline variants in ETV6 have been associated with familial predisposition to thrombocytopenia and hematological malignancies, predominantly childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In addition, overrepresentation of a high hyperdiploid subtype and older age at diagnosis have been reported among sporadic BCP-ALL cases with germline variants in ETV6. We studied a family with 2 second-degree relatives who developed childhood high hyperdiploid BCP-ALL at ages 8 and 12 years, respectively. A constitutional balanced reciprocal translocation t(12;14)(p13.2;q23.1) was discovered in both patients by routine karyotyping at diagnosis and, subsequently, in 7 healthy family members who had not experienced hematological malignancies. No carriers had thrombocytopenia. Whole-genome sequencing confirmed the translocation, resulting in 2 actively transcribed but nonfunctional fusion genes, causing heterozygous loss and consequently monoallelic expression of ETV6. Whole-genome sequencing analysis of the affected female subjects' leukemia excluded additional somatic aberrations in ETV6 and RTN1 as well as shared somatic variants in other genes. Expression studies, performed to confirm decreased expression of ETV6, were not conclusive. We suggest that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of ETV6 is required for developing THC5. To our knowledge, this report is the first of a constitutional translocation disrupting ETV6 causing predisposition to childhood ALL.
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| 3. |
- Kiiski, Heikki, et al.
(författare)
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Increased plasma UCH-L1 after aneurysmal subarachnoid hemorrhage is associated with unfavorable neurological outcome
- 2016
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Ingår i: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X .- 1878-5883. ; 361, s. 144-149
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Aneurysmal subarachnoid hemorrhage (aSAH) is a common cause of long-term disability and death. After primary hemorrhage, secondary brain injury is the main cause of mortality and morbidity. Despite extensive research, reliable prognostic biomarkers are lacking. We measured ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) levels in aSAH patients to evaluate its prognostic potential. This is the first time that plasma UCH-L1 has been studied as a potential prognostic biomarker in patients with aSAH. Methods: In this prospective population-based study, UCH-L1 levels were measured in aSAH patients (n = 47) for up to five days. UCH-L1 was measured at 0, 12 and 24 h after the admission to the intensive care unit (ICU) and daily thereafter until the patient was transferred from the ICU. Only patients whose UCH-L1 was measured within 24 h from aSAH were included in the study. The patients' neurological outcome was evaluated with the modified Rankin Scale (mRS) at six months after aSAH. Results: UCH-L1 levels during the first 24 h after aSAH were not significantly different between the groups with favorable (mRS 0-2) and unfavorable (mRS 3-6) neurological outcome. In 22 patients, UCH-L1 levels were obtained for up to five days. In this subgroup, UCH-L1 measured at day five showed significant elevation from baseline levels in patients with unfavorable outcome (p = 0.026). Elevated UCH-L1 levels at day five were higher in patients with unfavorable outcome than in patients with favorable outcome (p = 0.001). Conclusions: Elevated UCH-L1 levels during the five-day follow-up were associated with unfavorable neurological outcome. Repetitive measurements of UCH-L1 concentrations with an emphasis on change relative to the individual baseline could be the optimal approach for future clinical studies.
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| 4. |
- Kiiski, Heikki, et al.
(författare)
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Plasma soluble Urokinase-Type Plasminogen activator receptor is not associated with neurological Outcome in Patients with aneurysmal subarachnoid hemorrhage
- 2017
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Ingår i: Frontiers in Neurology. - : FRONTIERS MEDIA SA. - 1664-2295. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Object: Aneurysmal subarachnoid hemorrhage (aSAH) is a common cause of death or long-term disability. Despite advances in neurocritical care, there is still only a very limited ability to monitor the development of secondary brain injury or to predict neurological outcome after aSAH. Soluble urokinase-type plasminogen activator receptor (suPAR) has shown potential as a prognostic and as an inflammatory biomarker in a wide range of critical illnesses since it displays an association with overall immune system activation. This is the first time that suPAR has been evaluated as a prognostic biomarker in aSAH. Methods: In this prospective population-based study, plasma suPAR levels were measured in aSAH patients (n = 47) for up to 5 days. suPAR was measured at 0, 12, and 24 h after patient admission to the intensive care unit (ICU) and daily thereafter until he/ she was transferred from the ICU. The patients' neurological outcome was evaluated with the modified Rankin Scale (mRS) at 6 months after aSAH. Results: suPAR levels (n = 47) during the first 24 h after aSAH were comparable in groups with a favorable (mRS 0-2) or an unfavorable (mRS 3-6) outcome. suPAR levels during the first 24 h were not associated with the findings in the primary brain CT, with acute hydrocephalus, or with antimicrobial medication use during 5-days' follow-up. suPAR levels were associated with generally accepted inflammatory biomarkers (C-reactive protein, leukocyte count). Conclusion: Plasma suPAR level was not associated with either neurological outcome or selected clinical conditions. While suPAR is a promising biomarker for prognostication in several conditions requiring intensive care, it did not reveal any value as a prognostic biomarker after aSAH.
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| 5. |
- Kiiski, Heikki, et al.
(författare)
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S100B, NSE and MMP-9 fail to predict neurologic outcome while elevated S100B associates with milder initial clinical presentation after aneurysmal subarachnoid hemorrhage
- 2018
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Ingår i: Journal of the Neurological Sciences. - : ELSEVIER SCIENCE BV. - 0022-510X .- 1878-5883. ; 390, s. 129-134
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Despite advances in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) one-year mortality remains approximately 50%. Making an accurate prognosis at the early phase of the disease is notoriously difficult. A clinically reliable biomarker that could be used for better prediction of prognosis and/or as a surrogate for developing complications after aSAH is still lacking. In this study, we evaluated the prognostic values of three promising biomarkers, i.e. S100B, NSE, and MMP-9 in aSAH.Methods: In this prospective population-based study, S100B, NSE, and MMP-9 levels were measured in 47 aSAH patients for up to five days. Blood samples were taken at 0, 12 and 24 h after the admission to the intensive care unit (ICU) and daily after that until the patient was transferred from the ICU. The patients' neurological outcome was evaluated with the modified Rankin Scale (mRS) at six months after aSAH.Results: Biomarker-levels measured during the first 24 h were not associated with neurological outcome. S100B levels during the first 24 h were elevated in patients with a non-severe initial clinical presentation. Otherwise, there was no association between selected clinical variables and the early biomarker levels. In 22 patients, whose ICU follow-up lasted for up to five days, the total release of biomarkers was not associated with the neurological outcome.Conclusions: None of the measured biomarkers were associated with the neurological outcome evaluated at six months after aSAH. Elevated levels of S100B in patients with non-severe initial presentation suggest an adaptive role of this biomarker in aSAH. Based on our findings it is not advisable to use these biomarkers to guide clinical decision-making in patients with aSAH.
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| 6. |
- Konttinen, Jukka, et al.
(författare)
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Trace element behavior in the fluidized bed gasification of solid recovered fuels : a thermodynamic study
- 2013
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Ingår i: Fuel. - : Elsevier BV. - 0016-2361 .- 1873-7153. ; 106, s. 621-631
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Tidskriftsartikel (refereegranskat)abstract
- Gasification of biomass and recycled fuels is of particular interest for the efficient production of power and heat. Trace elements present as impurities in the product gas should be removed very efficiently. The objective of this work has been to develop and test thermodynamic models for the reactions of trace elements with chlorine and sulfur in the gasification processes of recycled fuels. In particular, the chemical reactions of trace elements with main thermochemical conversion products, main ash components, and bed and sorbent material are implemented into the model. The possibilities of gas cleaning devices in condensing and removing the trace element compounds are studied by establishing the volatilization tendency of trace element compounds in reducing gases. The results obtained with the model are compared with the measured data of trace elements of gasification experiments using solid recovered fuel as feedstock. Some corresponding studies in the literature are also critically reviewed and compared. The observed discrepancies may be attributed to differences in thermodynamic databases applied and experimental arrangements. The method of removing gaseous trace elements by condensation is already in use in the 160 MWth waste gasification plant in Lahti, Finland.
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| 7. |
- Kramb, Jason, et al.
(författare)
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Modeling biomass char gasification kinetics for improving prediction of carbon conversion in a fluidized bed gasifier
- 2014
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Ingår i: Fuel. - : Elsevier BV. - 0016-2361 .- 1873-7153. ; 132, s. 107-115
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Tidskriftsartikel (refereegranskat)abstract
- Gasification of biomass in a fluidized bed (FB) was modeled based on kinetic data obtained from previously conducted thermogravimetric analysis. The thermogravimetric analysis experiments were designed to closely resemble conditions in a real FB gasifier by using high sample heating rates, in situ devolatilization and gas atmospheres of H2O/H2 and CO2/CO mixtures. Several char kinetic models were evaluated based on their ability to predict char conversion based on the thermogravimetric data. A modified version of the random pore model was shown to provide good fitting of the char reactivity and suitability for use in a reactor model. An updated FB reactor model which incorporates the newly developed char kinetic expression and a submodel for the estimation of char residence time is presented and results from simulations were compared against pilot scale gasification data of pine sawdust. The reactor model showed good ability for predicting char conversion and product gas composition.
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| 8. |
- Norberg, Anna, et al.
(författare)
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Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
- 2018
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 26:6, s. 858-867
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Tidskriftsartikel (refereegranskat)abstract
- Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.
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| 9. |
- Nordstrom, Tanja, et al.
(författare)
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Comorbidity of disruptive behavioral disorders and attention-deficit hyperactivity disorder-Indicator of severity in problematic behavior?
- 2013
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Ingår i: Nordic Journal of Psychiatry. - : Informa UK Limited. - 0803-9488 .- 1502-4725. ; 67:4, s. 240-248
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disruptive behavioral disorders (DBD) and attention-deficit hyperactivity disorder (ADHD) are both characterized by certain patterns of misbehavior among adolescents. Aims: The aim of this study was to examine how the comorbidity of DBD and ADHD affects in misbehavior among adolescents. Methods: A total of 158 adolescents aged 16-18 years, from a subsample of the Northern Finland Birth Cohort 1986 (NFBC 1986), were interviewed with the Finnish translation of the semi-structured Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime (K-SADS-PL) in order to obtain DBD, including conduct disorder (CD) and oppositional defiant disorder (ODD), and ADHD diagnoses. The structure of the CD symptoms, obtained from the K-SADS-PL, was compared with the previously formed model about the development of the problematic behavior. The severity of the CD symptoms was compared with adolescents diagnosed with only DBD, only ADHD and with both DBD and ADHD. Also, the associations with other psychiatric disorders diagnosed at age 16 were evaluated. Results: The boys in the study sample were diagnosed with ADHD or with comorbid DBD and ADHD more often than girls. The severity of CD symptoms was statistically significantly associated with the comorbid DBD and ADHD group. The adolescents diagnosed with comorbid DBD and ADHD had an increased risk for anxiety disorders, depressive disorders and substance abuse disorders. Conclusions: The comorbidity of DBD and ADHD seems to indicate the severity of CD symptoms. Clinical implications: The comorbidity between DBD and ADHD should be considered in clinical practice because it could indicate more serious problematic behavior than pure disorders alone.
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| 10. |
- Nordström, Tanja, et al.
(författare)
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Different Risk Factors Between Disruptive Behavior Disorders and ADHD in Northern Finland Birth Cohort 1986
- 2017
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Ingår i: Journal of Attention Disorders. - : SAGE Publications. - 1087-0547 .- 1557-1246. ; 21:11, s. 904-912
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine different risk factors between disruptive behavior disorders (DBD) and ADHD or combined DBD and ADHD. Method: The study population was derived from the Northern Finland Birth Cohort 1986. Psychiatric diagnoses were defined from the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL) interview. The study sample was divided into four groups—people with DBD (n = 44), with ADHD (n = 91), with both (n = 72), and without either (n = 250)—to evaluate the different risk factors behind these disorders. Results: After adjusting with possible confounding factors, female gender and paternal admittance to inpatient psychiatric care increased the odds that an adolescent was having DBD. Childhood hyperactivity symptoms increased the odds of having ADHD and childhood hyperactivity symptoms and scholastic impairment increased the odds of having both disorders. Conclusion: Our study indicates DBD and ADHD have clearly different risk factors, and the impact of the paternal factors on DBD should be noted more than has been before.
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