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  • 151. Chen, Mengying
    et al.
    Shi, Xiaoyan
    Chen, Yinhua
    Cao, Zhaolan
    Cheng, Rui
    Xu, Yuxiang
    Liu, Li
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Li, Xiaonan
    A prospective study of pain experience in a neonatal intensive care unit of China2012Inngår i: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 28, nr 8, s. 700-704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: To assess pain burden in neonates during their hospitalization in China and thus provide evidence for the necessity of neonatal pain management. Patients and Methods: The Neonatal Facial Coding System was used to evaluate pain in neonates. We prospectively collected data of all painful procedures performed on 108 neonates (term, 62; preterm, 46) recruited from admission to discharge in a neonatal intensive care unit of a university-affiliated hospital in China. Results: We found that during hospitalization each preterm and term neonate was exposed to a median of 100.0 (range, 11 to 544) and 56.5 (range, 12 to 249) painful procedures, respectively. Most of the painful procedures were performed within the first 3 days. Preterm neonates, especially those born at 28 and 29 weeks' gestational age, experienced more pain than those born at 30 weeks' gestation or later (P < 0.001). Among those painful procedures, tracheal aspiration was the most frequently performed on preterm neonates, and intravenous cannulation was the most common for term neonates. Moreover, tracheal intubations and femoral venous puncture were found to be the most painful. Notably, none of the painful procedures was accompanied by analgesia. Conclusions: Neonates, particularly preterm neonates, were exposed to numerous invasive painful procedures without appropriate analgesia in hospitals in China. The potential long-term impacts of poorly treated pain in neonates call for a change in pediatric practice in China and in countries with similar practices.

  • 152. Chiang, Huei-Hsin
    et al.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Tysnes, Ole-Bjørn
    Gredal, Ole
    Christensen, Peter B
    Graff, Caroline
    Novel TARDBP mutations in Nordic ALS patients2012Inngår i: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 57, nr 5, s. 316-319Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.

  • 153. Chinot, Olivier L.
    et al.
    Nishikawa, Ryo
    Mason, Warren
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Regional Cancer Center Stockholm Gotland, Stockholm, Sweden.
    Saran, Frank
    Cloughesy, Timothy
    Garcia, Josep
    Revil, Cedric
    Abrey, Lauren
    Wick, Wolfgang
    Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio2016Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, nr 9, s. 1313-1318Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy. Methods: Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan-Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated. Results: Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P =.0016) and median OS (HR: 0.67, P =.0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P<.0001); OS was comparable between the treatment arms (HR: 0.88, P =.1502). No significant differences in safety were observed between the 2 groups. Conclusion: This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

  • 154. Chinot, Olivier L.
    et al.
    Wick, Wolfgang
    Mason, Warren
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Reg Canc Ctr Stockholm,.
    Saran, Frank
    Nishikawa, Ryo
    Carpentier, Antoine F.
    Hoang-Xuan, Khe
    Kavan, Petr
    Cernea, Dana
    Brandes, Alba A.
    Hilton, Magalie
    Kerloeguen, Yannick
    Guijarro, Abajo
    Cloughsey, Timothy
    FINAL EFFICACY AND SAFETY RESULTS FROM AVAglio, A PHASE III TRIAL OF BEVACIZUMAB (BEV) PLUS TEMOZOLOMIDE (TMZ) ANDRADIOTHERAPY (RT) IN NEWLY DIAGNOSED GLIOBLASTOMA2013Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr Supplement: 3, s. 105-106Artikkel i tidsskrift (Annet vitenskapelig)
  • 155.
    Christensen, Jens
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Alfredson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin. UCLH, ISEH, London, England; Pure Sports Clin, London, England.
    Andersson, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Protease-activated receptors in the Achilles tendon-a potential explanation for the excessive pain signalling in tendinopathy2015Inngår i: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 11, artikkel-id 13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Aim: Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies. Method: In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns. Results: The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells. Conclusions: This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.

  • 156. Cif, Laura
    et al.
    Hariz, Marwan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap. Unit of Functional Neurosurgery, University College London-Institute of Neurology, Queen Square, London, UK.
    Seventy Years of Pallidotomy for Movement Disorders2017Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, nr 7, s. 972-982Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The year 2017 marks the 70th anniversary of the birth of human stereotactic neurosurgery. The first procedure was a pallidotomy for Huntington's disease. However, it was for Parkinson's disease that pallidotomy was soon adopted worldwide. Pallidotomy was abandoned in the late 1950s in favor of thalamotomy because of the latter's more striking effect on tremor. The advent of levodopa put a halt to all surgery for PD. In the mid-1980s, Laitinen reintroduced the posteroventral pallidotomy of Leksell, and this procedure spread worldwide thanks to its efficacy on most parkinsonian symptoms including levodopa-induced dyskinesias and thanks to basic scientific work confirming the role of the globus pallidus internus in the pathophysiology of PD. With the advent of deep brain stimulation of the subthalamic nucleus, pallidotomy was again abandoned, and even DBS of the GPi has been overshadowed by STN DBS. The GPi reemerged in the late 1990s as a major stereotactic target for DBS in dystonia and, recently, in Tourette syndrome. Lately, lesioning of the GPI is being proposed to treat refractory status dystonicus or to treat DBS withdrawal syndrome in PD patients. Hence, the pallidum as a stereotactic target for either lesioning or DBS has been the phoenix of functional stereotactic neurosurgery, constantly abandoned and then rising again from its ashes. This review is a tribute to the pallidum on its 70th anniversary as a surgical target for movement disorders, analyzing its ebbs and flows and highlighting its merits, its versatility, and its resilience.

  • 157. Coelho, T.
    et al.
    Suhr, Ole
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Conceicao, I
    Waddington-Cruz, M.
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, J.
    Falzone, R.
    White, L.
    Bettencourt, B.
    Cehelsky, J.
    Nochur, S.
    Vaishnaw, A.
    Gollob, J.
    Adams, D.
    Phase 2 open-label extension study (ole) of patisiran, an investigational sIRNA investigational agent for familial amyloid polyneuropathy (fap)2015Inngår i: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 20, nr 2, s. 117-118Artikkel i tidsskrift (Annet vitenskapelig)
  • 158. Coelho, Teresa
    et al.
    Maia, Luis F.
    da Silva, Ana Martins
    Cruz, Marcia Waddington
    Plante-Bordeneuve, Violaine
    Lozeron, Pierre
    Suhr, Ole B.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Campistol, Josep M.
    Conceicao, Isabel Maria
    Schmidt, Hartmut H. -J.
    Trigo, Pedro
    Kelly, Jeffery W.
    Labaudinie, Richard
    Chan, Jason
    Packman, Jeff
    Wilson, Amy
    Grogan, Donna R.
    Tafamidis for transthyretin familial amyloid polyneuropathy: A randomized, controlled trial2012Inngår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 79, nr 8, s. 785-792Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. Neurology (R) 2012;79:785-792

  • 159. Coelho, Teresa
    et al.
    Maia, Luis F
    da Silva, Ana Martins
    Cruz, Márcia W
    Planté-Bordeneuve, Violaine
    Suhr, Ole B
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Conceiçao, Isabel
    Schmidt, Hartmut H-J
    Trigo, Pedro
    Kelly, Jeffery W
    Labaudinière, Richard
    Chan, Jason
    Packman, Jeff
    Grogan, Donna R
    Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy2013Inngår i: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, nr 11, s. 2802-2814Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

  • 160. Coelho, Teresa
    et al.
    Suhr, Ole
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Quan, Dianna
    Brannagan, Thomas
    Gollob, Jared
    Goyal, Sunita
    Altincatal, Arman
    Agarwal, Sonalee
    Lin, Hollis
    Adams, David
    Longitudinal changes in mNIS+7 are associated with changes in ambulatory status in hereditary transthyretin-mediated amyloidosis2018Inngår i: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, nr 4, s. 354-355Artikkel i tidsskrift (Annet vitenskapelig)
  • 161. Conceicao, I
    et al.
    Coelho, T
    Plante-Bordeneuve, V
    Waddington Cruz, M
    Ericzon, BG
    Falk, RN
    Ikeda, S
    Maurer, M
    Suhr, Ole B
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ando, Y
    Mazzeo, A
    Grogan, DR
    Baseline neurologic function in symptomatic patients in the Transthyretin Amyloidosis Outcomes Survey (THAOS)2011Konferansepaper (Fagfellevurdert)
  • 162. Conceicao, I.
    et al.
    Suhr, Ole
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Coelho, T.
    Waddington Cruz, M.
    Schmidt, H.
    Buades, J.
    Campistol, J.
    Pouget, J.
    Berk, I.
    Adams, D.
    Phase 2 open-label extension study of patisiran, an investigational siRNA agent for hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN)2016Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 26, s. S142-S142Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease that can cause sensory, motor, and autonomic dysfunction, resulting in significant disability and death. Patisiran is an investigational, systemically administered small interfering RNA (siRNA) targeting wild-type and mutant TTR. A recently completed multi-center, multi-dose Phase 2 trial of patisiran in hATTR-PN patients (N = 29) showed >80% sustained mean knockdown of serum TTR when administered at a dose of 0.3 mg/kg every 3 weeks with a generally favorable safety profile. Phase 2 open label (OLE) study to evaluate patisiran's safety effect on serum TTR levels, impact on neuropathy impairment scores and QOL. Twenty-seven patients with hATTR-PN were enrolled; median age 64 years (range: 29–77 years). Patisiran was well tolerated throughout the23-months of follow-up. Five patients experienced SAEs (unrelated) including one discontinuation and subsequent death (gastroesophageal cancer). Flushing (25.9%) and infusion-related reactions (18.5%) were mild AEs; and did not result in any discontinuations. Approximately 80% sustained mean serum TTR lowering was obtained with a mean nadir of up to 93% between doses. Among the 20 evaluable patients, neuropathy impairment scores were stable with a mean change in mNIS+7 and NIS of 1.7 and 4.2 points, respectively. This compares favorably to 17–26 point mNIS+7/NIS increase at 18-months from prior hATTR-PN studies. Stabilization of quality of life (QOL) measures and significant improvement of distal thigh sweat gland nerve fiber density was observed. Long-term (>18 months) patisiran administration was generally well tolerated, resulted in sustained mean serum TTR lowering; supporting the hypothesis that TTR knockdown potentially halts neuropathy progression. As of March 2016, dosing continues; updated results will be presented.

  • 163. Corcia, Philippe
    et al.
    Ingre, Caroline
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Blasco, Helene
    Press, Rayomand
    Praline, Julien
    Antar, Catherine
    Veyrat-Durebex, Charlotte
    Guettard, Yves-Olivier
    Camu, William
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Vourc'h, Patrick
    Andres, Christian R
    Homozygous SMN2 deletion is a protective factor in the Swedish ALS population2012Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, nr 5, s. 588-591Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations. European Journal of Human Genetics (2012) 20, 588-591; doi:10.1038/ejhg.2011.255; published online 25 January 2012

  • 164. Crippa, Sylvain, V
    et al.
    Domellöf, Fatima Pedrosa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Kawasaki, Aki
    Chromatic pupillometry in children2018Inngår i: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, artikkel-id 669Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chromatic pupillometry is a technique that is increasingly used to assess retinal disorders. As age may be one of the various factors which can influence the pupillary light reaction, this study aimed to evaluate the pupil responses to colored light stimuli in the pediatric population. Fifty-three children with normal vision and without any history of ocular disorders were tested with a portable pupillometer. Four test sequences were used: five dim blue (470 nm) stimuli presented in half log steps ranging from -3.15 to -1.15 log cd/m(2) after 3 min of dark adaptation, five red (622 nm) stimuli of -1.15, -0.7, -0.15, 0.3, and 0.85 log cd/m(2) after 1 min light adaptation, one bright blue stimulus of 2.2 log cd/m(2) and one bright red of 2 log cd/m(2). The results were grouped by age: a younger group included 27 children aged from 3 to 10 years old and an older group included 26 from 10 and 1 month to 18 years old. The younger group had a smaller pupil diameter after dark adaptation compared with the older group. A linear regression defining the photopic threshold showed that younger subjects had a higher threshold, e.g., needed a brighter red stimulus to evoke a threshold pupil response comparable that of subjects. Age thus seems to influence outer retinal sensitivity at least as evaluated by the pupillary photopic threshold intensity. The post-illumination pupillary reaction was used as a marker of intrinsic melanopsin activity and did not show any difference between the two age groups.

  • 165. Cronin, Simon
    et al.
    Greenway, Matthew J
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Hardiman, Orla
    Screening of hypoxia-inducible genes in sporadic ALS2008Inngår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 9, nr 5, s. 299-305Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic variations in two hypoxia-inducible angiogenic genes, VEGF and ANG, have been linked with sporadic amyotrophic lateral sclerosis (SALS). Common variations in these genes may reduce the levels or functioning of their products. VEGF and ANG belong to a larger group of angiogenic genes that are up-regulated under hypoxic conditions. We hypothesized that common genetic variation across other members of this group may also predispose to sporadic ALS. To screen other hypoxia-inducible angiogenic genes for association with SALS, we selected 112 tagging single nucleotide polymorphisms (tgSNPs) that captured the common genetic variation across 16 VEGF-like and eight ANG-like hypoxia-inducible genes. Screening for association was performed in 270 Irish individuals with typical SALS and 272 ethnically matched unrelated controls. SNPs showing association in the Irish phase were genotyped in a replication sample of 281 Swedish sporadic ALS patients and 286 Swedish controls. Seven markers showed association in the Irish. The one modest replication signal observed in the Swedish replication sample, at rs3801158 in the gene inhibin beta A, was for the opposite allele vs. the Irish cohort. We failed to detect association of common variation across 24 candidate hypoxia-inducible angiogenic genes with SALS.

  • 166. Culverhouse, Robert C
    et al.
    Bowes, Lucy
    Breslau, Naomi
    Nurnberger, John I
    Burmeister, Margit
    Fergusson, David M
    Munafò, Marcus
    Saccone, Nancy L
    Bierut, Laura J
    Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.2013Inngår i: BMC psychiatry, ISSN 1471-244X, Vol. 13, s. 304-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.

    METHODS/DESIGN: To improve understanding of the combined roles of 5-HTTLPR variation and stress in the development of depression, we are conducting a meta-analysis of multiple independent datasets. This coordinated approach utilizes new analyses performed with centrally-developed, standardized scripts. This publication documents the protocol for this collaborative, consortium-based meta-analysis of 5-HTTLPR variation, stress, and depression.

    STUDY ELIGIBILITY CRITERIA: Our goal is to invite all datasets, published or unpublished, with 5-HTTLPR genotype and assessments of stress and depression for at least 300 subjects. This inclusive approach is to minimize potential impact from publication bias.

    DATA SOURCES: This project currently includes investigators from 35 independent groups, providing data on at least N = 33,761 participants.The analytic plan was determined prior to starting data analysis. Analyses of individual study datasets will be performed by the investigators who collected the data using centrally-developed standardized analysis scripts to ensure a consistent analytical approach across sites. The consortium as a group will review and interpret the meta-analysis results.

    DISCUSSION: Variation in 5-HTTLPR is hypothesized to moderate the response to stress on depression. To test specific hypotheses about the role of 5-HTTLPR variation on depression, we will perform coordinated meta-analyses of de novo results obtained from all available data, using variables and analyses determined a priori. Primary analyses, based on the original 2003 report by Caspi and colleagues of a GxE interaction will be supplemented by secondary analyses to help interpret and clarify issues ranging from the mechanism of effect to heterogeneity among the contributing studies. Publication of this protocol serves to protect this project from biased reporting and to improve the ability of readers to interpret the results of this specific meta-analysis upon its completion.

  • 167. Czell, David
    et al.
    Sapp, Peter C.
    Neuwirth, Christoph
    Weber, Markus
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Brown, Robert H.
    Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden2017Inngår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, nr 3-4, s. 302-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.

  • 168.
    Dahlin, Anna M.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hollegaard, Mads V.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hougaard, David M.
    Deltour, Isabelle
    Hjalmars, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma2015Inngår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 125, nr 1, s. 75-78Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P (combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

  • 169. Dahlin, Lars B.
    et al.
    Nennesmo, Inger
    Besjakov, Jack
    Ferencz, Istvan
    Andersson, Gert S.
    Backman, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Case report: Intraneural perineurioma of the sciatic nerve in an adolescent - strategies for revealing the diagnosis2016Inngår i: Clinical Case Reports, E-ISSN 2050-0904, Vol. 4, nr 8, s. 777-781Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diagnosis of intraneural conditions can be revealed by a combination of clinical examination, electrophysiology, magnetic resonance imaging (MRI), and targeted fascicular biopsy with subsequent microscopic analyses.

  • 170.
    Darehed, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Blom, M.
    Glader, Eva-Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Niklasson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Norrving, B.
    Eriksson, M.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Acute stroke patients are subject to seasonal variation in quality of care and survival: a Swedish nationwide registry-based study2018Inngår i: International Journal of Stroke, ISSN 1747-4930, E-ISSN 1747-4949, Vol. 13, s. 177-177Artikkel i tidsskrift (Annet vitenskapelig)
  • 171.
    Darehed, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Blom, Mathias
    Glader, Eva-Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Niklasson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Norrving, Bo
    Bray, Benjamin D.
    Eriksson, Marie
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Diurnal variations in the quality of stroke care in Sweden2019Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 140, nr 2, s. 123-130Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: A recent study of acute stroke patients in England and Wales revealed several patterns of temporal variation in quality of care. We hypothesized that similar patterns would be present in Sweden and aimed to describe these patterns. Additionally, we aimed to investigate whether hospital type conferred resilience against temporal variation.

    MATERIALS & METHODS: We conducted this nationwide registry-based study using data from the Swedish Stroke Register (Riksstroke) including all adult patients registered with acute stroke between 2011 and 2015. Outcomes included process measures and survival. We modeled time of presentation as on/off hours, shifts, day of week, 4h and 12 h time blocks. We studied hospital resilience by comparing outcomes across hospital types.

    RESULTS: 113862 stroke events in 72 hospitals were included. The process indicators and survival all showed significant temporal variation. Door-to-needle (DTN) time within 30 minutes was less likely during nighttime than daytime (OR 0.50; 95% CI 0.41-0.60). Patients admitted during off-hours had lower odds of direct stroke unit (SU) admission (OR 0.72; 95% CI 0.70-0.75). 30-day survival was lower in nighttime versus daytime presentations (OR 0.90, 95% CI 0.84-0.96). The effects of temporal variation differed significantly between hospital types for DTN time within 30 minutes and direct SU admission where university hospitals were more resilient than specialized non-university hospitals.

    CONCLUSIONS: Our study shows that variation in quality of care and survival is present throughout the whole week. We also found that university hospitals were more resilient to temporal variation than specialized non-university hospitals.

  • 172.
    Darehed, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. 1 Department of Medicine, Ga¨llivare Hospital, Sweden.
    Norrving, Bo
    Stegmayr, Birgitta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Zingmark, Karin
    Blom, Mathias C.
    Patients with acute stroke are less likely to be admitted directly to a stroke unit when hospital beds are scarce: a Swedish multicenter register study2017Inngår i: European Stroke Journal, ISSN 2396-9873, E-ISSN 2396-9881, Vol. 2, nr 2, s. 178-186Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: It is well established that managing patients with acute stroke in dedicated stroke units is associated with improved functioning and survival. The objectives of this study are to investigate whether patients with acute stroke are less likely to be directly admitted to a stroke unit from the Emergency Department when hospital beds are scarce and to measure variation across hospitals in terms of this outcome.

    Patients and methods: This register study comprised data on patients with acute stroke admitted to 14 out of 72 Swedish hospitals in 2011-2014. Data from the Swedish stroke register were linked to administrative daily data on hospital bed occupancy (measured at 6 a.m.). Logistic regression analysis was used to analyse the association between bed occupancy and direct stroke unit admission.

    Results: A total of 13,955 hospital admissions were included; 79.6% were directly admitted to a stroke unit from the Emergency Department. Each percentage increase in hospital bed occupancy was associated with a 1.5% decrease in odds of direct admission to a stroke unit (odds ratio = 0.985, 95% confidence interval = 0.978-0.992). The best-performing hospital exhibited an odds ratio of 3.8 (95% confidence interval = 2.6-5.5) for direct admission to a stroke unit versus the reference hospital.

    Discussion and conclusion: We found an association between hospital crowding and reduced quality of care in acute stroke, portrayed by a lower likelihood of patients being directly admitted to a stroke unit from the Emergency Department. The magnitude of the effect varied considerably across hospitals.

  • 173. Davies, G.
    et al.
    Armstrong, N.
    Bis, J. C.
    Bressler, J.
    Chouraki, V.
    Giddaluru, S.
    Hofer, E.
    Ibrahim-Verbaas, C. A.
    Kirin, M.
    Lahti, J.
    van der Lee, S. J.
    Le Hellard, S.
    Liu, T.
    Marioni, R. E.
    Oldmeadow, C.
    Postmus, I.
    Smith, A. V.
    Smith, J. A.
    Thalamuthu, A.
    Thomson, R.
    Vitart, V.
    Wang, J.
    Yu, L.
    Zgaga, L.
    Zhao, W.
    Boxall, R.
    Harris, S. E.
    Hill, W. D.
    Liewald, D. C.
    Luciano, M.
    Adams, H.
    Ames, D.
    Amin, N.
    Amouyel, P.
    Assareh, A. A.
    Au, R.
    Becker, J. T.
    Beiser, A.
    Berr, C.
    Bertram, L.
    Boerwinkle, E.
    Buckley, B. M.
    Campbell, H.
    Corley, J.
    De Jager, P. L.
    Dufouil, C.
    Eriksson, J. G.
    Espeseth, T.
    Faul, J. D.
    Ford, I.
    Gottesman, R. F.
    Griswold, M. E.
    Gudnason, V.
    Harris, T. B.
    Heiss, G.
    Hofman, A.
    Holliday, E. G.
    Huffman, J.
    Kardia, S. L. R.
    Kochan, N.
    Knopman, D. S.
    Kwok, J. B.
    Lambert, J-C
    Lee, T.
    Li, G.
    Li, S-C
    Loitfelder, M.
    Lopez, O. L.
    Lundervold, A. J.
    Lundquist, Anders
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Mather, K. A.
    Mirza, S. S.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Oostra, B. A.
    Palotie, A.
    Papenberg, G.
    Pattie, A.
    Petrovic, K.
    Polasek, O.
    Psaty, B. M.
    Redmond, P.
    Reppermund, S.
    Rotter, J. I.
    Schmidt, H.
    Schuur, M.
    Schofield, P. W.
    Scott, R. J.
    Steen, V. M.
    Stott, D. J.
    Van Swieten, J. C.
    Taylor, K. D.
    Trollor, J.
    Trompet, S.
    Uitterlinden, A. G.
    Weinstein, G.
    Widen, E.
    Windham, B. G.
    Jukema, J. W.
    Wright, A. F.
    Wright, M. J.
    Yang, Q.
    Amieva, H.
    Attia, J. R.
    Bennett, D. A.
    Brodaty, H.
    de Craen, A. J. M.
    Hayward, C.
    Ikram, M. A.
    Lindenberger, U.
    Nilsson, Lars-Göran
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). ARC, Karolinska Institutet, Stockholm.
    Porteous, D. J.
    Raikkonen, K.
    Reinvang, I.
    Rudan, I.
    Sachdev, P. S.
    Schmidt, R.
    Schofield, P. R.
    Srikanth, V.
    Starr, J. M.
    Turner, S. T.
    Weir, D. R.
    Wilson, J. F.
    Van Duijn, C.
    Launer, L.
    Fitzpatrick, A. L.
    Seshadri, S.
    Jr, T. H. Mosley
    Deary, I. J.
    Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)2015Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 20, nr 2, s. 183-192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

  • 174. Dayal, Viswas
    et al.
    Grover, Timothy
    Tripoliti, Elina
    Milabo, Catherine
    Salazar, Maricel
    Candelario-McKeown, Joseph
    Athauda, Dilan
    Zrinzo, Ludvic
    Akram, Harith
    Hariz, Marwan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Limousin, Patricia
    Foltynie, Thomas
    Short Versus Conventional Pulse-Width Deep Brain Stimulation in Parkinson's Disease: A Randomized Crossover Comparison2019Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for selected Parkinson's disease patients with motor fluctuations, but can adversely affect speech and axial symptoms. The use of short pulse width (PW) has been shown to expand the therapeutic window acutely, but its utility in reducing side effects in chronic STN-DBS patients has not been evaluated. Objective To compare the effect of short PW settings using 30-mu s with conventional 60-mu s settings on stimulation-induced dysarthria in Parkinson's disease patients with previously implanted STN-DBS systems. Methods In this single-center, double-blind, randomized crossover trial, we assigned 16 Parkinson's disease patients who had been on STN-DBS for a mean of 6.5 years and exhibited moderate dysarthria to 30-mu s or 60-mu s settings for 4 weeks followed by the alternative PW setting for a further 4 weeks. The primary outcome was difference in dysarthric speech measured by the Sentence Intelligibility Test between study baseline and the 2 PW conditions. Secondary outcomes included motor, nonmotor, and quality of life measures. Results There was no difference in the Sentence Intelligibility Test scores between baseline and the 2 treatment conditions (P = 0.25). There were also no differences noted in motor, nonmotor, or quality of life scores. The 30-mu s settings were well tolerated, and adverse event rates were similar to those at conventional PW settings. Post hoc analysis indicated that patients with dysarthria and a shorter duration of DBS may be improved by short PW stimulation. Conclusions Short PW settings using 30 mu s did not alter dysarthric speech in chronic STN-DBS patients. A future study should evaluate whether patients with shorter duration of DBS may be helped by short PW settings.

  • 175. de Carvalho, Mamede
    et al.
    Pinto, Susana
    Andersen, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Grosskreutz, Julian
    Kuzma-Kozakiewicz, Magdalena
    Petri, Susanne
    Uysal, Hilmil
    Gromicho, Marta
    Peripheral neuropathy in ALS: Phenotype association2018Inngår i: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, nr 4, s. 391-392Artikkel i tidsskrift (Annet vitenskapelig)
  • 176. De Carvalho, Mamede
    et al.
    Ryczkowski, Adam
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Gromicho, Marta
    Grosskreutz, Julian
    Kuzma-Kozakiewicz, Magdalena
    Petri, Susanne
    Piotrkiewicz, Maria
    Miltenberger Miltenyi, Gabriel
    International Survey of ALS Experts about Critical Questions for Assessing Patients with ALS2017Inngår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, nr 7-8, s. 505-510Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To define an applicable dataset for ALS patient registries we weighted specific clinical items as scored by worldwide ALS experts.

    Methods: Sixty participants were invited based on relevant clinical work, publications and personal acquaintance. They rated 160 clinical items consensually agreed by the members of our project, incorporating specialists from five European Centres. Scoring scheme was defined as: 1 - essential; 2 - important; 3 - not very important. A mixed effect model was applied to rank items and to find possible correlations with geographical region (Europe vs. outside Europe).

    Results: We received 40 responses, 20 from Europe and 20 from outside; 42/160 data were scored as essential by >50% of the respondents, including: date of birth, gender, date of disease onset, date of diagnosis, ethnicity, region of onset, predominant upper neuron (UMN) or lower motor neuron (LMN) impairment, proximal versus distal weakness, respiratory symptoms, dysarthria, weight loss, signs of LMN/UMN involvement, emotional incontinence, cognitive changes, respiratory signs, neck weakness, body mass index, ALSFRS-R at entry, ALSFRS-R subscores at entry, timing and pattern of spreading and staging, electromyography, spirometry, MRI, CK level, riluzole intake, genetic background, history of physical exercise and previous and current main occupation. Four components were scored as non-relevant, including place of birth, blood pressure and pain at onset. There was no significant difference between regions (European vs. non-European countries).

    Conclusions: Our study identified a consensual set of clinical data with 42 specific items that can be used as a minimal data set for patient registers and for clinical trials.

  • 177. de Flon, P.
    et al.
    Kumlien, E.
    Reuterwall, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Mattsson, P.
    Empirical evidence of underutilization of referrals for epilepsy surgery evaluation2010Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 17, nr 4, s. 619-625Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Epilepsy surgery is a treatment that can cure patients with intractable epilepsy. This study investigates whether referrals for epilepsy surgery evaluation are underutilized. Methods: Patients with epilepsy aged 18-60 years were identified in a computerized registry held by public health care providers in a Swedish county using ICD codes. Clinical data and data on referral status for epilepsy surgery were obtained from the patients' medical records. Potential candidates for epilepsy surgery evaluation were identified using pre-specified criteria. Obstacles for referral were analysed by comparing clinical data in patients who were considered for referral and those who were not. Appropriateness of non-referral was evaluated against recommendations from the Swedish Council on Technology in Health Care (SBU). Results: Of 378 patients with epilepsy in the registry, 251 agreed to participate. Of 251, 40 were already referred patients and 48 patients were identified as potential candidates for epilepsy surgery evaluation by study criteria. Referral had been considered but not performed in 15 of the potential candidates. Potential candidates not considered for referral were less likely to have seen a neurologist, to have had an EEG, CT and MRI, and more likely to have cognitive disturbances. Following the recommendations by the SBU, 28 of 48 potential candidates were identified as inappropriately not referred patients. Conclusion: The number of missed referrals for epilepsy surgery evaluation was estimated to be 60 per 100 000 inhabitants. Several important obstacles were found for not referring patients for epilepsy surgery evaluation.

  • 178.
    de Flon, Pierre
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Treatment with the monoclonal antibody rituximab in Multiple Sclerosis: a study based on an academic clinical trial2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Multiple sclerosis (MS) is a chronic, inflammatory disease, affecting the central nervous system. A growing number of disease modifying treatment alternatives entails a need for an individualised risk-benefit- convenience analysis in the counselling of patients and methods to monitor the treatment effect, including markers for subclinical inflammation. Today, MRI and the biomarker neurofilament light chain (NFL) in cerebrospinal fluid (CSF- NFL) are commonly used. The development of new techniques for analysing NFL in very low concentrations in serum or plasma provides a promising opportunity for a less invasive method. Rituximab is a chimeric monoclonal antibody with B- cell depleting properties vastly used in rheumatological disease and certain haematological malignancies. Phase II studies have shown a beneficial effect on inflammation also in MS, the detailed mechanisms of action yet to be explained.

    Aims: The aims of this thesis were to evaluate rituximab as a treatment alternative in relapsing remitting MS (RRMS) by describing the clinical effect and patient related outcome measures after a switch of therapy from first-line injectables to rituximab and to explore possible immunological mechanisms of B cell depletion as well as to evaluate the use of neurofilament in plasma (p-NFL) as an end-point in a clinical trial setting.

    Methods: The thesis is based on the open-label phase II multicentre clinical trial Switch-To-RItuXimab in MS (STRIX-MS; EudraCT 2010-023021-38), in which 75 patients completed a therapy switch from first-line injectables to rituximab, and, to some part, the extended follow-up study, STRIX-MS extension (EudraCT 2013-002378-26). The disease modifying effect was evaluated by regular clinical evaluations, MRI and analyses of CSF-NFL. The clinical outcome was evaluated by the EDSS and SDMT scales. The questionnaires MSIS-29, FSMC and TSQM were used for the evaluation of patient related outcome measures. Immunological mechanisms of the B cell depletion were explored by the analysis of a broad panel of cyto- and chemokines in CSF by an electrochemiluminiscens method before and after therapy switch, and in comparison to healthy controls. The concentration of p-NFL was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit and explored for the use as a clinical trial end-point.

    Results: During the follow-up, signs of inflammatory activity decreased. Both the mean number of Gd enhancing lesions (0.03 vs 0.36, p=0.029) and the number of new or enlarged T2 lesions were reduced (0.01 vs 0.28, p=0.01). The mean concentration of CSF-NFL was reduced during the first year (491 vs 387, p=0.01). The corresponding reduction in plasma did not reach the level of statistical significance. The rating of overall treatment satisfaction improved significantly (6.3 vs 4.8, scale range 1-7, p<0.001). In the explorative immunological study, the immunological profile was altered after therapy switch with the most prominent reduction observed in the concentrations of IP-10 and IL-12/23p40.

    Conclusions: The results indicate a disease modifying effect of rituximab in line with other studies and provide support for a superior treatment satisfaction with rituximab as compared with injectable therapies. However, the lack of control group hampers the possibility to draw definite conclusions on the therapy effect. The immunological effects of B cell depletion need to be further explored.

  • 179.
    de Flon, Pierre
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Laurell, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Blennow, Kaj
    Söderström, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Zetterberg, Henrik
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap. Department of Clinical Sciences, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial2019Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, nr 5, s. 462-468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

    Materials and methods: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch-To RItuXimab in MS" (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed up for 2 years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed up for an additional 3 years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

    Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL was 25% during the first year of follow-up (from a mean of 471 [SD 393] to 354 [SD 174] pg/mL; P = 0.006) and was statistically significant. The corresponding reduction in plasma NFL was 18% (from 9.73 [SD 7.04] to 7.94 [SD 3.10] pg/mL; P = 0.055) and did not reach statistical significance.

    Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimize the use in clinical trials.

  • 180.
    de Flon, Pierre
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Laurell, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry; Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Söderström, Lars
    Unit of Research, Education and Development, Region Jämtland Härjedalen, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry; Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 4 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK 5 UK Dementia Research Institute at UCL, London, UK.
    Gunnarsson, Martin
    Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Comparison of plasma and CSF Neurofilament light as outcome in a multiple sclerosis trialManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

    Method: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial “Switch-To RItuXimab in MS” (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed for two years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed for an additional three years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

    Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL with 25% during the first year of follow-up (from a mean of 471 (SD 393) to 354 (SD 174) pg/mL; p=0.006) was statistically significant. The corresponding reduction in plasma-NFL was 18% (from 9.73 (SD 7.04) to 7.94 (SD 3.10) pg/mL; p=0.055) and did not reach the level of statistical significance.

    Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimise the use in clinical trials.

  • 181.
    de Flon, Pierre
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Söderström, Lars
    Laurell, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Dring, Ann
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Sundström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Gunnarsson, Martin
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap. Dept of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm.
    Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 2, artikkel-id e0192516Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC).

    METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.

    RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.

    CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

  • 182.
    de Frias, Cindy M
    et al.
    Stockholm University.
    Marklund, Petter
    Stockholm University, Stockholm Brain Institute.
    Eriksson, Elias
    Göteborg University.
    Larsson, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Öman, Lena
    Umeå universitet.
    Annerbrink, Kristina
    Göteborg University.
    Bäckman, Lars
    Karolinska Institute.
    Nilsson, Lars-Göran
    Stockholm University.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Influence of COMT gene polymorphism on fMRI-assessed sustained and transient activity during a working memory task.2010Inngår i: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 22, nr 7, s. 1614-1622Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The catechol O-methyltransferase (COMT) gene--encoding an enzyme that is essential for the degradation of dopamine (DA) in prefrontal cortex (PFC)--contains a single nucleotide polymorphism (val/met) important for cognition. According to the tonic-phasic hypothesis, individuals carrying the low-enzyme-activity allele (met) are characterized by enhanced tonic DA activity in PFC, promoting sustained cognitive representations in working memory. Val carriers have reduced tonic but enhanced phasic dopaminergic activity in subcortical regions, enhancing cognitive flexibility. We tested the tonic-phasic DA hypothesis by dissociating sustained and transient brain activity during performance on a 2-back working memory test using mixed blocked/event-related functional magnetic resonance imaging. Participants were men recruited from a random sample of the population (the Betula study) and consisted of 11 met/met and 11 val/val carriers aged 50 to 65 years, matched on age, education, and cognitive performance. There were no differences in 2-back performance between genotype groups. Met carriers displayed a greater transient medial temporal lobe response in the updating phase of working memory, whereas val carriers showed a greater sustained PFC activation in the maintenance phase. These results support the tonic-phasic theory of DA function in elucidating the specific phenotypic influence of the COMT val(158)met polymorphism on different components of working memory.

  • 183. Denolf, Petra L.
    et al.
    Vanderveken, Olivier M.
    Marklund, Marie E.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Braem, Marc J.
    The status of cephalometry in the prediction of non-CPAP treatment outcome in obstructive sleep apnea patients2016Inngår i: Sleep Medicine Reviews, ISSN 1087-0792, E-ISSN 1532-2955, Vol. 27, s. 56-73Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Obstructive sleep apnea syndrome (OSAS) is the most common sleep disordered breathing disorder (SDB) in adults and is characterized by a recurrent partial or complete collapse of the upper airway during sleep. This can be caused by many factors, sometimes interacting, such as skeletal malformations, soft tissue crowding, respiratory instability and the various effects of aging, obesity and gender that dictate craniofacial and upper airway anatomy. Research has demonstrated that the majority of patients exhibit at least one anatomical component such as retrognathia or a narrow posterior airway space that predisposes to the development of OSAS. Within the predisposing elements for OSAS many seem to point to anatomical characteristics. A standardized and relatively simple radiologic technique to evaluate anatomical craniofacial relationships is cephalometry. This has been used already for a long time in orthodontics, but is now gradually being introduced in OSAS treatment to envisage optimal treatment selection as well as to predict treatment outcomes. The purpose of the present review is to evaluate the contribution of cephalometry in the prediction of outcomes from OSAS treatments that depend on the upper airway morphology in their mechanisms of action such as oral appliances that advance the mandible as well as various surgical methods. In addition, an overview of imaging modalities and methods that currently are being used in cephalometric analysis in OSAS patients is provided. The findings indicate that isolated cephalometric parameters cannot be used to reliably predict treatment outcomes from mandibular advancement devices and surgical methods for OSAS. Extreme or outlying values of cephalometric parameters may rather be used as contra-indicators or 'red flags' instead of predictors.

  • 184. Devil, M
    et al.
    Andersen, PM
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Van Den Bosch, L
    Robberecht, W
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Genetics of amyotrophic lateral sclerosis2004Inngår i: Clinical Neurophysiology of Motor Neuron Diseases / [ed] Andrew Eisen, Elsevier, 2004Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
  • 185. Di Castelnuovo, Augusto
    et al.
    Veronesi, Giovanni
    Costanzo, Simona
    Zeller, Tanja
    Schnabel, Renate B.
    de Curtis, Amalia
    Salomaa, Veikko
    Borchini, Rossana
    Ferrario, Marco
    Giampaoli, Simona
    Kee, Frank
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Niiranen, Teemu
    Kuulasmaa, Kari
    de Gaetano, Giovanni
    Donati, Maria Benedetta
    Blankenberg, Stefan
    Iacoviello, Licia
    NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) and the Risk of Stroke Results From the BiomarCaRE Consortium2019Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 50, nr 3, s. 610-617Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose: NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a risk factor for atrial fibrillation and a marker of cardiac function used in the detection of heart failure. Given the link between cardiac dysfunction and stroke, NT-proBNP is a candidate marker of stroke risk. Our aim was to evaluate the association of NT-proBNP with stroke and to determine the predictive value beyond a panel of established risk factors. Methods: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe-Consortium, we analyzed data of 58 173 participants (50% men; mean age 52 y) free of stroke from 6 community-based cohorts. NT-proBNP measurements were performed in the central Biomarkers for Cardiovascular Risk Assessment in Europe laboratory. The outcomes considered were total stroke and subtypes of stroke (ischemic/hemorrhagic). Results: During a median follow-up time of 7.9 years, we observed 1550 stroke events (1176 ischemic). Increasing quarters of the NT-proBNP distribution were associated with increasing risk of stroke (P for trend < 0.0001; multivariable Cox regression analysis adjusted for risk factors and cardiac diseases). Individuals in the highest NT-proBNP quarter (NTproBNP > 82.2 pg/mL) had 2-fold (95% CI, 75%-151%) greater risk of stroke than individuals in the lowest quarter (NTproBNP < 20.4 pg/mL). The association remained unchanged when adjusted for interim coronary events during followup, and though it was somewhat heterogeneous across cohorts, it was highly homogenous according to cardiovascular risk profile or subtypes of stroke. The addition of NT-proBNP to a reference model increased the C-index discrimination measure by 0.006 (P=0.0005), yielded a categorical net reclassification improvement of 2.0% in events and 1.4% in nonevents and an integrated discrimination improvement of 0.007. Conclusions: In European individuals free of stroke, levels of NT-proBNP are positively associated with risk of ischemic and hemorrhagic stroke, independently from several other risk factors and conditions. The addition of NT-proBNP to variables of established risk scores improves prediction of stroke, with a medium effect size.

  • 186. Diekstra, Frank P.
    et al.
    Saris, Christiaan G. J.
    van Rheenen, Wouter
    Franke, Lude
    Jansen, Ritsert C.
    van Es, Michael A.
    van Vught, Paul W. J.
    Blauw, Hylke M.
    Groen, Ewout J. N.
    Horvath, Steve
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G.
    Robberecht, Wim
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    Shatunov, Aleksey
    Shaw, Christopher E.
    Leigh, P. Nigel
    Al-Chalabi, Ammar
    Ophoff, Roel A.
    van den Berg, Leonard H.
    Veldink, Jan H.
    Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 4, s. e35333-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 x 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.

  • 187. Diekstra, Frank P.
    et al.
    Van Deerlin, Vivianna M.
    van Swieten, John C.
    Al-Chalabi, Ammar
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    van Es, Michael A.
    Pasterkamp, R. Jeroen
    Koppers, Max
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G.
    van Damme, Philip
    Melki, Judith
    Meininger, Vincent
    Shatunov, Aleksey
    Shaw, Christopher E.
    Leigh, P. Nigel
    Shaw, Pamela J.
    Morrison, Karen E.
    Fogh, Isabella
    Chio, Adriano
    Traynor, Bryan J.
    Czell, David
    Weber, Markus
    Heutink, Peter
    de Bakker, Paul I. W.
    Silani, Vincenzo
    Robberecht, Wim
    van den Berg, Leonard H.
    Veldink, Jan H.
    C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis2014Inngår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 76, nr 1, s. 120-133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

  • 188. Diekstra, Frank P.
    et al.
    van Vught, Paul W. J.
    van Rheenen, Wouter
    Koppers, Max
    Pasterkamp, R. Jeroen
    van Es, Michael A.
    Schelhaas, Helenius J.
    de Visser, Marianne
    Robberecht, Wim
    van Damme, Philip
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    van den Berg, Leonard H.
    Veldink, Jan H.
    UNC13A is a modifier of survival in amyotrophic lateral sclerosis2012Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, nr 3, s. 630.e3-630.e8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis. (C) 2012 Elsevier Inc. All rights reserved.

  • 189. Divanoglou, A
    et al.
    Westgren, N
    Bjelak, S
    Levi, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin.
    Medical conditions and outcomes at 1 year after acute traumatic spinal cord injury in a Greek and a Swedish region: a prospective, population-based study2010Inngår i: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 48, nr 6, s. 470-476Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    STUDY DESIGN: Prospective, population-based study. This paper is part of the Stockholm Thessaloniki Acute Traumatic Spinal Cord Injury Study (STATSCIS).

    OBJECTIVES: To evaluate and compare outcomes, length of stay (LOS), associated conditions and medical complications at 1-year post-trauma.

    SETTINGS: The Greater Thessaloniki region, Greece, and the Greater Stockholm region, Sweden. While Stockholm follows a SCI system of care, Thessaloniki follows a fragmented 'non-system' approach.

    SUBJECTS: Out of the 87 cases in Thessaloniki and the 49 cases in Stockholm who comprised the study population of STATSCIS, 75 and 42 cases respectively were successfully followed-up during the first year post-trauma.

    RESULTS: Significantly superior outcomes (that is, survival with neurological recovery, functional ability and discharge to home) and shorter LOS for initially motor complete cases occurred in Stockholm. Management routines known to increase long-term morbidity, for example, long-term tracheostomy and indwelling urethral catheters were significantly more common in Thessaloniki. Major medical complications, that is, multiple pressure ulcers, heterotopic ossification and bacteremia/sepsis were more frequent in Thessaloniki.

    CONCLUSIONS: Our findings show how two rather similar cohorts of TSCI manifest large discrepancies in terms of 1-year outcomes and complications, depending on the type of management they receive. As the major difference between regions was the presence or absence of a SCI system of care, rather than differences in availability of modern medicine, the mere presence of the latter does not seem to be sufficient to guarantee adequate outcomes. This study provides strong evidence as to the urgent need of implementing a SCI system of care in Greece.

  • 190.
    Divanoglou, Anestis
    et al.
    Division of Neuro-rehabilitation, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm.
    Seiger, A
    Division of Neuro-rehabilitation, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm.
    Richard, Levi
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin. Division of Neuro-rehabilitation, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm.
    Acute management of traumatic spinal cord injury in a Greek and a Swedish region: a prospective, population-based study.2010Inngår i: Spinal Cord, ISSN 1362-4393, E-ISSN 1476-5624, Vol. 48, nr 6, s. 477-482Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    STUDY DESIGN: Prospective, population-based study. This paper is part of the Stockholm Thessaloniki Acute Traumatic Spinal Cord Injury Study (STATSCIS). OBJECTIVES: To characterize patient populations and to compare acute management after traumatic spinal cord injury (TSCI). SETTINGS: The Greater Thessaloniki region in Greece and the Greater Stockholm region in Sweden. METHODS: Inception cohorts with acute TSCI that were hospitalized during the study period, that is September 2006 to October 2007, were identified. Overall, 81 out of 87 cases consented to inclusion in Thessaloniki and 47 out of 49 in Stockholm. Data from Thessaloniki were collected through physical examinations, medical record reviews and communication with TSCI cases and medical teams. Data from Stockholm were retrieved from the Nordic Spinal Cord Injury Registry. RESULTS: There were no significant differences between study groups with regard to core clinical characteristics. In contrast, there were significant differences in (1) transfer logistics from the scene of trauma to a tertiary-level hospital (number of intermediate admissions, modes of transportation and duration of transfer) and (2) acute key therapeutic interventions, that is, the use of mechanical ventilation (49% in Thessaloniki versus 20% in Stockholm), and performance of tracheostomy (36% in Thessaloniki versus 15% in Stockholm); spinal surgery was performed significantly more often and earlier in Stockholm than in Thessaloniki. CONCLUSIONS: Despite largely similar core clinical characteristics, Stockholm and Thessaloniki cases underwent significantly different acute management, most probably to be attributed to adaptations to the differing regional approaches of care one following a systematic approach of SCI care and the other not.

  • 191.
    Divanoglou, Anestis
    et al.
    Karolinska Inst, Div Neurorehabil, Stockholm.
    Westgren, Ninni
    Karolinska Inst, Div Neurorehabil, Stockholm ; Karolinska Univ Hosp, Spinalis SCI Rehabil Unit, Stockholm.
    Seiger, Åke
    Karolinska Inst, Div Neurorehabil, Stockholm.
    Hulting, Claes
    Karolinska Inst, Div Neurorehabil, Stockholm ; Karolinska Univ Hosp, Spinalis SCI Rehabil Unit, Stockholm.
    Levi, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin. Karolinska Inst, Div Neurorehabil, Stockholm ; Rehab Stn Stockholm, Stockholm, Sweden.
    Late mortality during the first year after acute traumatic spinal cord injury: a prospective, population-based study2010Inngår i: Journal of Spinal Cord Medicine (JSCM), ISSN 1079-0268, E-ISSN 2045-7723, Vol. 33, nr 2, s. 117-127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Little is known about the possible impact of the system of care on mortality during the first year after acute traumatic spinal cord injury (TSCI).

    OBJECTIVE: To evaluate late mortality (i.e., >7 days after trauma) during the first year after acute TSCI in 2 European Union (EU) regions, Thessaloniki in Greece and Stockholm in Sweden.

    METHODS: This paper is part of the Stockholm Thessaloniki Acute Traumatic Spinal Cord Injury Study (STATSCIS), which is a prospective, population-based study. Incidence cohorts of TSCI cases were identified and followed up in both study regions through STATSCIS. Data from Thessaloniki region were collected through physical examination, medical records review, and interviews with TSCI individuals and the medical teams. Data from Stockholm were retrieved mainly from the Nordic Spinal Cord Injury Registry, as well as from direct contact with all intensive care facilities of the region.

    RESULTS: The annual case mortality rate after acute TSCI was nearly 20% in Thessaloniki and 0% in Stockholm. The mean time of survival after trauma for the 12 mortality cases of Thessaloniki was 47 days (median = 24, SD +/- 67, range = 8-228). Factors associated with mortality were higher age and presence of comorbid spinal disorders but also the inefficient transfer logistics, initially missed spinal instability, and unsuccessfully treated complications.

    CONCLUSIONS: The annual case mortality rate in Thessaloniki was dramatically higher than in Stockholm. The different approaches to care, one systematic and the other not, is postulated to be an important factor leading to such major discrepancies between the outcomes of these 2 EU regions.

  • 192.
    Domellof, Magdalena Eriksson
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Elgh, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with parkinson's disease2011Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 26, nr 12, s. 2183-2189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent studies have reported cognitive decline to be common in the early phase of Parkinson's disease. Imaging data connect working memory and executive functioning to the dopamine system. It has also been suggested that bradykinesia is the clinical manifestation most closely related to the nigrostriatal lesion. Exploring the relationship between motor dysfunction and cognition can help us find shared or overlapping systems serving different functions. This relationship has been sparsely investigated in population-based studies of untreated Parkinson's disease. The aim of the present study was to investigate the association between motor signs and cognitive performance in the early stages of Parkinson's disease before the intake of dopaminergic medication. Patients were identified in a population-based study of incident cases with idiopathic parkinsonism. Patients with the postural instability and gait disturbances phenotype were compared with patients with the tremor-dominant phenotype on demographics and cognitive measures. Associations between cognitive and motor scores were investigated, with age, education, and sex controlled for. Bradykinesia was associated with working memory and mental flexibility, whereas axial signs were associated with episodic memory and visuospatial functioning. No significant differences in the neuropsychological variables were found between the postural instability and gait disturbances phenotype and the tremor phenotype. Our results indicate a shared system for slow movement and inflexible thinking that may be controlled by a dopaminergic network different from dopaminergic networks involved in tremor and/or rigidity. The association between axial signs and memory and visuospatial function may point to overlapping systems or pathologies related to these abilities.

    (C) 2011 Movement Disorder Society

  • 193.
    Domellöf, Erik
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Rönnqvist, Louise
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Hopkins, Brian
    Functional asymmetries in the stepping response of the human newborn: a kinematic approach2007Inngår i: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 177, nr 3, s. 324-335Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In order to investigate subtle expressions of functional asymmetries in newborn leg movements, kinematic registrations were made on a sample of 40 healthy fullterm newborn infants during performance of the stepping response. Time–position data were collected from markers attached to the hip, knee and ankle joints of the left and right leg, and movements of both legs recorded simultaneously. Findings included evident side differences in terms of smoother trajectories of the right leg as a consequence of less movement segmentation compared to the left leg. Additionally, analyses of intralimb coordination revealed side differences with regard to stronger ankle–knee couplings and smaller phase shifts in the right leg. The findings suggest that asymmetries in newborn stepping responses are present in terms of spatio-temporal parameters and intralimb coordination. No evidence of a lateral preference in terms of frequency of the first foot moved was found. The present study adds new understanding to the lateralized attributes of the stepping response in the human newborn and as such points to new directions of research on the nature of laterality in the future.

  • 194.
    Domellöf, Magdalena E
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Ekman, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Elgh, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Cognitive function in the early phase of Parkinson's disease, a five-year follow-up2015Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 132, nr 2, s. 79-88Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Presence of mild cognitive impairment (MCI) as a predictor for Parkinson's disease dementia (PDD) has been discussed from a clinical perspective. Recently, a Movement Disorder Society (MDS) commissioned Task Force published guidelines for PD-MCI. However, long-term follow-ups of the PD-MCI guidelines for the prediction of PDD have been sparse.

    METHOD: In a community-based cohort of PD, the MDS guidelines for PD-MCI and consensus criteria for PDD were applied on 147 subjects. The predictive ability of PD-MCI for PDD was investigated. Additionally, baseline comparisons were conducted between MCI that converted to PDD and those who did not, and evolvement of motor function was investigated.

    RESULTS: One fourth of the population developed PDD. MCI and age at baseline predicted later occurrence of PDD, and baseline results of tests measuring episodic memory, visuospatial function, semantic fluency, and mental flexibility differed between MCI converters and non-converters. Postural instability/gait (PIGD) phenotype and education did not predict later occurrence of PDD, but increased postural/gait disturbances were shown across time in those developing dementia.

    CONCLUSION: The new PD-MCI guidelines are useful to detect patients at risk for developing PDD. The PIGD phenotype at diagnosis was not a predictor of PDD within 5 years, but the study supports a temporal association between postural/gait disturbances and PDD. Older patients with PD-MCI at baseline with decline in episodic memory, semantic fluency, and mental flexibility need to be carefully monitored regarding cognition and likely also for fall risk.

  • 195.
    Domellöf, Magdalena E
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Elgh, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Persistence of associations between cognitive impairment and motor dysfunction in the early phase of Parkinson's disease2013Inngår i: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, nr 9, s. 2228-2236Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The relation between cognitive and motor functions in Parkinson's disease is not fully understood. In an incidence population of newly diagnosed drug na < ve patients with Parkinson's disease, associations were found between the degree of bradykinesia and postural instability and gait disturbances, measured by the Unified Disease Rating Scale, and different types of cognitive functions. To investigate the stability of these associations over time, we explored the association of differences between baseline and 1-year follow-up in 91 incident cases with Parkinson's disease. The magnitude of change between the two assessments was assessed together with analysis of differences based on which dopaminergic medication was used. Change in bradykinesia was associated with change in working memory and mental flexibility. Changes in postural instability and gait disturbances were associated with change in visuospatial memory. A negative effect of the dopamine agonist pramipexole on phonemic fluency performance was found compared to treatment with other dopaminergic drugs. Change in cognitive and motor functions were associated from time of diagnosis until 1 year after diagnosis. These persisting findings strengthen results from a previous cross-sectional study suggesting similar associations. The effects of dopamine agonists on phonemic fluency should be investigated further.

  • 196.
    Domellöf, Magdalena Eriksson
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Cognitive and motor dysfunction in the early phase of Parkinson's disease2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Background: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease. The diagnosis is based on a combination of the motor signs: tremor, bradykinesia, rigidity and postural abnormalities. Mild Cognitive Impairment (MCI) is common early in the disease and a large proportion of patients with PD develop dementia (PDD). Associations between motor symptoms and cognitive decline have been suggested but the results are inconclusive due to differences in the selection of participants and variables tested. Large population based studies with comprehensive neuropsychological investigation in newly diagnosed cases with PD followed prospectively are rare. The aim of this thesis was to improve characterization and understanding of cognition in PD, and to explore the relationship to motor impairment in the early phase of PD.

    Methods: All new patients with suspected idiopathic parkinsonism in the catchment area (142 ooo inhabitants) were examined during a period of five years and four months. Among other investigations, a comprehensive neuropsychological evaluation was carried out in 119 of 148 patients with PD together with 30 age matched healthy controls. Assessments were repeated after one three and five years.

    Results: Patients performed worse than healthy controls in a majority of neuropsychological tests. MCI at the time of diagnosis were found in 36% according to recently published MCI criteria. Thirty % were cognitively impaired using another definition. One fourth of the patients developed PDD within five years after diagnosis and 25 % of those with MCI at baseline reversed back to normal cognition. Age and MCI were significant predictors of dementia. Education was an independent predictor for severe cognitive dysfunction at diagnosis but did not predict PDD. Patients with MCI converting to PDD had worse performance on visuospatial function, semantic fluency, episodic memory, mental flexibility and conceptual thinking. There were no differences in cognitive performance between patients with predominant Postural and Gait Disturbances (PIGD) and the tremor dominant subtype at the baseline investigation and belonging to the PIGD subgroup at baseline did not predict PDD. Dementia converters declined more rapidly than non-converters in posture/gait function. Associations between bradykinesia and measures of executive functions and working memory were found, and between posture and gait disturbances and visuospatial function. Some of these associations were persistent after one year. Patients receiving the dopamine agonist pramipexole performed significantly worse on a measure of verbal fluency at the one year follow up.

    Conclusions: The differences in proportions of cognitively impaired in the different studies emphasize the value of joint criteria for PD-MCI. Even when using such criteria, a substantial proportion of patients revert back to normal function. The increase in motor disability in patients with PDD could have several different causes that need to be further investigated. Associated motor and cognitive dysfunctions could reflect common pathophysiological processes in partly shared networks. Both dopaminergic and non-dopaminergic motor and cognitive functions seems to be involved in PDD which suggests that pharmacological treatment in PD needs to go beyond the scope of dopaminergic deficiency in search for new therapies that would also be effective for non-motor symptoms.

  • 197.
    Domellöf, Magdalena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Ekman, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Elgh, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Cognitive function in the early phase of Parkinson's disease, a longitudinal follow-upManuskript (preprint) (Annet vitenskapelig)
  • 198.
    Dominguez, Cecilia A
    et al.
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kalliomäki, Maija
    Department of Surgical Sciences, Anaesthesiology/Pain research, Uppsala University, Uppsala, Sweden; Department of Anaesthesiology, University of Tammerfors, Tampere, Finland.
    Gunnarsson, Ulf
    Department of Clinical Science, Intervention and Technology (Surgery), Karolinska Institutet, Huddinge, Sweden.
    Moen, Aurora
    National Institute of Occupational Health, Oslo, Norway; Department of Molecular Biosciences, University of Oslo, Norway.
    Sandblom, Gabriel
    Department of Clinical Science, Intervention and Technology (Surgery), Karolinska Institutet, Huddinge, Sweden.
    Kockum, Ingrid
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lavant, Ewa
    Department of Biomedical Laboratory Science, Faculty of Health and Society, Malmö University/Labmedicine Skåne, Clinical Chemistry, Malmö, Sweden.
    Olsson, Tomas
    Nyberg, Fred
    Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Rygh, Lars Jørgen
    Department of Anesthesiology and Intensive Care, Haukeland University Hospital, Bergen, Norway.
    Røe, Cecilie
    Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Ullevaal, Norway.
    Gjerstad, Johannes
    National Institute of Occupational Health, Oslo, Norway; Department of Molecular Biosciences, University of Oslo, Norway.
    Gordh, Torsten
    Department of Surgical Sciences, Anaesthesiology/Pain research, Uppsala University, Uppsala, Sweden.
    Piehl, Fredrik
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    The DQB1*03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation2013Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, nr 3, s. 427-433Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n=189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1*04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1*03:02 allele together with DRB1*04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n=258), where carriers of the DQB1*03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1*04 - DQB1*03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.

  • 199. Dyck, P. J.
    et al.
    Wang, A. K.
    Kincaid, J. C.
    Wiesman, J. F.
    Chaudhry, V
    Robinson-Papp, J.
    Coelho, T.
    Nordh, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Monia, B. P.
    Hughes, S.
    Ackermann, E. J.
    Litchy, W. J.
    Davies, J.
    Dyck, P. J. B.
    Evaluation of modifications of nis+7 score in oligonucleotide trials in ttr fap2015Inngår i: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 20, nr 2, s. 132-133Artikkel i tidsskrift (Annet vitenskapelig)
  • 200. Dyck, P. James
    et al.
    Adams, David
    Coelho, Teresa
    Kristen, Arnt
    Gonzalez-Duarte, Alejandra
    Berk, John
    Partisano, Angela
    Gollob, Jared
    Sweester, Marianne
    Chen, Jihong
    Suhr, Ole
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Neuropathy progression in patients with hATTR amyloidosis: Analysis of the APOLLO placebo arm2018Inngår i: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 23, nr 4, s. 274-275Artikkel i tidsskrift (Annet vitenskapelig)
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