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  • 1.
    Abdul-Hussein, Saba
    et al.
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Rahl, Karin
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg, Sweden.
    Phenotypes of myopathy-related beta-tropomyosin mutants in human and mouse tissue cultures2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 9, article id e72396Article in journal (Refereed)
    Abstract [en]

    Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of β-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-β-TM(EGFP) mutant showed perinuclear aggregates. The G53ins-β-TM(EGFP) mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-β-TM(EGFP) and E122K-β-TM(EGFP) mutants induced the formation of rod-like structures in human cells. The N202K-β-TM(EGFP) mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant β-TM(EGFP) in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related β-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.

  • 2.
    Abdul-Hussein, Saba
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Expression profiles of muscle disease-associated genes and their isoforms during differentiation of cultured human skeletal muscle cells2012In: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 13, article id 262Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The formation of contractile myofibrils requires the stepwise onset of expression of muscle specific proteins. It is likely that elucidation of the expression patterns of muscle-specific sarcomeric proteins is important to understand muscle disorders originating from defects in contractile sarcomeric proteins.

    METHODS: We investigated the expression profile of a panel of sarcomeric components with a focus on proteins associated with a group of congenital disorders. The analyses were performed in cultured human skeletal muscle cells during myoblast proliferation and myotube development.

    RESULTS: Our culture technique resulted in the development of striated myotubes and the expression of adult isoforms of the sarcomeric proteins, such as fast TnI, fast TnT, adult fast and slow MyHC isoforms and predominantly skeletal muscle rather than cardiac actin. Many proteins involved in muscle diseases, such as beta tropomyosin, slow TnI, slow MyBPC and cardiac TnI were readily detected in the initial stages of muscle cell differentiation, suggesting the possibility of an early role for these proteins as constituent of the developing contractile apparatus during myofibrillogenesis. This suggests that in disease conditions the mechanisms of pathogenesis for each of the mutated sarcomeric proteins might be reflected by altered expression patterns, and disturbed assembly of cytoskeletal, myofibrillar structures and muscle development.

    CONCLUSIONS: In conclusion, we here confirm that cell cultures of human skeletal muscle are an appropriate tool to study developmental stages of myofibrillogenesis. The expression of several disease-associated proteins indicates that they might be a useful model system for studying the pathogenesis of muscle diseases caused by defects in specific sarcomeric constituents.

  • 3.
    Alhardallo, Mutaz
    et al.
    Department of Orthopedic Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    El Ansari, Walid
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Department of Surgery, Hamad General Hospital, Doha, Qatar ; College of Medicine, Qatar University, Doha, Qatar.
    Baco, Abdul M.
    Department of Orthopedic Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.
    Second ever reported case of central cause of unilateral foot drop due to cervical disc herniation: Case report and review of literature2021In: International Journal of Surgery Case Reports, E-ISSN 2210-2612, Vol. 83, article id 105928Article in journal (Refereed)
    Abstract [en]

    Background: Foot drop is defined as a weakness in the ankle and foot dorsiflexors. A disruption of the neural pathway starting from the motor prefrontal cortex and ending in the peroneal nerve can lead to foot drop. Foot drop due to lower motor neuron injury is well documented. However, foot drop due to a central cause of cervical disc prolapse is very rare. Case presentation: A 55-year-old male presenting with neck pain, right and left arms radicular pain and numbness, and unilateral right foot drop following cervical disc prolapse. The patient presented with upper motor neuron lesion signs. MRI showed cervical disc prolapse at two levels, confirming central cause of foot drop. The patient underwent anterior cervical decompression and fusion surgery. Discussion: Following decompression and fusion of involved cervical spine disc pathology, the patient had complete recovery of his right foot drop. Conclusions: Central causes, although rare, should be considered in the differential diagnosis of foot drop. Causes could be due to the compression effect of the cortico-spinal tract of the cervical spinal cord. Satisfactory results can be achieved upon correcting the causative lesion. 

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  • 4.
    Arnoldussen, Ilse A. C.
    et al.
    Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands / Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.
    Gustafson, Deborah R.
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Department of Neurology, The State University of New York Downstate Health Sciences University, Brooklyn, USA.
    Leijsen, Esther M. C.
    Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    de Leeuw, Frank-Erik
    Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    Kiliaan, Amanda J.
    Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands / Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.
    Adiposity is related to cerebrovascular and brain volumetry outcomes in the RUN DMC study2019In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 93, no 9, p. e864-e878Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Adiposity predictors, body mass index (BMI), waist circumference (WC), and blood leptin and total adiponectin levels were associated with components of cerebral small vessel disease (CSVD) and brain volumetry in 503 adults with CSVD who were ≥50 years of age and enrolled in the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC).

    METHODS: RUN DMC participants were followed up for 9 years (2006-2015). BMI, WC, brain imaging, and dementia diagnoses were evaluated at baseline and follow-up. Adipokines were measured at baseline. Brain imaging outcomes included CSVD components, white matter hyperintensities, lacunes, microbleeds, gray and white matter, hippocampal, total brain, and intracranial volumes.

    RESULTS: Cross-sectionally among men at baseline, higher BMI, WC, and leptin were associated with lower gray matter and total brain volumes, and higher BMI and WC were associated with lower hippocampal volume. At follow-up 9 years later, higher BMI was cross-sectionally associated with lower gray matter volume, and an obese WC (>102 cm) was protective for ≥1 lacune or ≥1 microbleed in men. In women, increasing BMI and overweight or obesity (BMI ≥25 kg/m2 or WC >88 cm) were associated with ≥1 lacune. Longitudinally, over 9 years, a baseline obese WC was associated with decreasing hippocampal volume, particularly in men, and increasing white matter hyperintensity volume in women and men.

    CONCLUSIONS: Anthropometric and metabolic adiposity predictors were differentially associated with CSVD components and brain volumetry outcomes by sex. Higher adiposity is associated with a vascular-neurodegenerative spectrum among adults at risk for vascular forms of cognitive impairment and dementias.

  • 5.
    Behrens, Anders
    et al.
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Sanmartin Berglund, Johan
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Anderberg, Peter
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    CoGNIT Automated Tablet Computer Cognitive Testing in Patients With Mild Cognitive Impairment: Feasibility Study2022In: JMIR Formative Research, E-ISSN 2561-326X, Vol. 6, no 3, article id e23589Article in journal (Refereed)
    Abstract [en]

    Background: Early diagnosis of cognitive disorders is becoming increasingly important. Limited resources for specialist assessment and an increasing demographical challenge warrants the need for efficient methods of evaluation. In response, CoGNIT, a tablet app for automatic, standardized, and efficient assessment of cognitive function, was developed. Included tests span the cognitive domains regarded as important for assessment in a general memory clinic (memory, language, psychomotor speed, executive function, attention, visuospatial ability, manual dexterity, and symptoms of depression). Objective: The aim of this study was to assess the feasibility of automatic cognitive testing with CoGNIT in older patients with symptoms of mild cognitive impairment (MCI). Methods: Patients older than 55 years with symptoms of MCI (n=36) were recruited at the research clinic at the Blekinge Institute of Technology (BTH), Karlskrona, Sweden. A research nurse administered the Mini-Mental State Exam (MMSE) and the CoGNIT app on a tablet computer. Technical and testing issues were documented. Results: The test battery was completed by all 36 patients. One test, the four-finger-tapping test, was performed incorrectly by 42% of the patients. Issues regarding clarity of instructions were found in 2 tests (block design test and the one finger-tapping test). Minor software bugs were identified. Conclusions: The overall feasibility of automatic cognitive testing with the CoGNIT app in patients with symptoms of MCI was good. The study highlighted tests that did not function optimally. The four-finger-tapping test will be discarded, and minor improvements to the software will be added before further studies and deployment in the clinic. © 2022 JMIR Publications Inc.. All right reserved.

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  • 6.
    Berggren, Elisabeth
    University of Skövde, School of Life Sciences. School of Health Sciences, Jönköping University, Sweden.
    Daily life after Subarachnoid Haemorrhage: Identity construction, patients' and relatives' statements about patients' memory, emotional status and activities of living2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of this thesis was to describe patients’ experience and reconstruction regarding the onset of, and events surrounding being struck by a Subarachnoid Haemorrhage (SAH), and to describe patients’ and relatives’ views of patients’ memory ability, emotional status and activities of living, in a long-term perspective.

    Methods: Both inductive and deductive approaches were used. Nine open interviews were carried out in home settings, in average 1 year and 7 seven months after the patients’ onset, and discourse analysis was used to interpret the data. Eleven relatives and 11 patients, 11 years after the onset, and 15 relatives and 15 patients, 6 years after the onset, participated in two studies. Interviews using a questionnaire with structured questions and memory tests were used to collect data. Fischer’s exact test and Z-scores were used for the statistical analysis.

    Results: Patients with experience of a SAH were able to judge their own memory for what happened when they became ill. The reconstruction of the illness event may be interpreted as an identity creating process. The process of meaning-making is both a matter of understanding SAH as a pathological event and a social and communicative matter, where the SAH is construed into a meaningful life history, in order to make life complete (I). Memory problems, changes in emotional status and problems with activities of living were common (II-IV). There was correspondence between relatives’ and patients’ statements regarding the patients’ memory in general and long-term memory. Patients judged their own memory ability better than relatives, compared with results on memory tests. Relatives stated that some patients had meta-memory problems (II). The episodic memory seemed to be well  reserved, both concerning the onset and in the long-term perspective (I, II). There were more problems with social life than with P- and I-ADL (III), and social company habits had changed due to concentration difficulties, mental fatigue, and  patients’ sensitivity to noisy environments and uncertainty (IV). Relatives rated the patients’ ability concerning activities of living and emotional status, and in a similar manner to patients’ statements (III-IV).

    Conclusions: The reconstruction of the illness event can be used as a tool in nursing for understanding the patient’s identity-construction. Relatives and patients stated the patients’ memory, emotional status and activities of living in a similar manner, and therefore both patients’ and relatives’ statements can be used as a tool in nursing care, in order to support the patient. However, the results showed: meta-memory problems (relatives’ statements) and that the patients’ judged their own memory ability better than relatives in comparison with results on memory tests. Nevertheless, there was a high degree of concordance between relatives’ and patients’ evaluations concerning patients´ memory ability, emotional status, emotional problems, social company habits and activities of living. Therefore both relatives’ and patients’ statements can be considered to be reliable. However, sometimes the patients and the relatives judge the patients’ memory differently. Consequently, memory tests and formalized dialogues between the patient, the relative and a professional might be required, in order to improve the mutual family relationship in a positive way. Professionals however, must first assume that patients can judge their own memory, emotional status and ability in daily life.

  • 7.
    Berggren, Elisabeth
    University of Skövde, School of Life Sciences. Jönköping University.
    Identity construction and memory after Subarachnoid Haemorrhage: Patients' accounts and relatives' and patients' statements in relation to memory tests2010Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: A Subarachnoid haemorrhage (SAH) is a complex pathophysiological event and most patients have, before the onset, felt completely well. Being stricken by a SAH is a dramatic event, often followed by unconsciousness and memory problems. This may influence the adjustment to daily life. Supporting patients and relatives in nursing care therefore requires knowledge concerning patients' experience of the onset of the SAH event, and knowledge concerning patients' memory after a SAH.

    Aim: The general aim of this thesis was to study patients' experiences and reconstruction of the onset of, and events surrounding, a SAH and to study patients' and relatives' experience of patients' memory ability, in a long-term perspective.

    Specific aims:

    (I) The aim of this study was to analyse people's accounts of SAH, and to describe how they initiate and create meaning for the onset and events surrounding the SAH. The specific questions were : (i) What is highlighted in the accounts of SAH? (II) How is the illness reconstructed? (iii) How is meaning created through communicative interaction with others about SAH?

    (II) The aim was to describe memory after a SAH from the perspective of relatives and patients in two cohorts. In this study, the researchers also aimed to evaluate the application of relatives' statements as a tool in nursing care and rehabilitation, in order to support the patients. This was achieved by comparing: (i) Relatives' statements with patients' statements and (ii) Relatives' and patients' statements with the patients' memory test results.

    Methods: Both an inductive and a deductive approach were used. Nine open interviews were carried out in home settings, 1 year and 7 months (ranging 14-24 months) after the patients' onset and discourse analysis was used to interpret the data (I). Eleven relatives and 11 patients, 11 years and 15 relatives and 15 patients, 6 years after the onset participated in two studies. Interview questions and memory tests were used to collect data. Fischer's exact test was used for the statistical analysis (II).

    Findings:Patient with experience of a SAH were able to judge their own memory for what happened when they became ill. Both conscious irrational and rational actions were expressed in relation to experienced sensations. Critical events related to SAH were "existential insights" and "time as waiting and time as structuring meaning". The reconstruction of the illness event may be interpreted as an identity ceating process. The process of meaning-making is both a matter of understanding SAH as a pathological event, and a social and communicative matter, where the SAH is constructed into a meaningful life history, in order to make life complete (I). Memory problems were common according to relatives' and patients' statements and from memory test results. There was correspondence between relatives' and patients' statements regarding the patients' memory in general and long-term memory. Patients judged their own memory ability better than relatives, compared with results on memory tests. Both relatives and patients underestimated older patients' memory ability and underrated younger patients' memory problems, when compared with results on memory tests. Relatives stated that some patients had meta-memory problems (II). The episodic memory seemed to be well preserved, both concerning the onset (I) and in the long-term perspective (II).

    Conclusions: The reconstruction of the illness is a tool in nursing for understanding the patient's self-positioning and identity-construction. (I) Relatives' and patients' statements regarding patients' memory can also be used as tools in nursing care. However, the results showed: meta-memory problems (relatives' statements); that patients' judged their own memory ability better than relatives in comparison with results on memory tests. Consequently, memory tests and formalized dialogues, between the patient, the relative and a professional are required in order to prevent complications in the patient's mutual family relationships. However, professionals must assume that patients can judge their own memory (II). Dialogues between the patient, the relative and a professional, with focus on how to manage daily life in patients' home context, due to the patient's experience of the onset of the SAH and possible memory problems after the SAH, will probably improve the mutual family relationship in a positive way (I,II).

  • 8.
    Berggren, Elisabeth
    et al.
    University of Skövde, School of Life Sciences.
    Sidenvall, Birgitta
    School of Health Sciences, Department of Nursing Science, Jönköping University, Sweden.
    Hellström Muhli, Ulla
    University of Skövde, School of Life Sciences.
    Identity construction and meaning-making after subarachnoid haemorrhage2010In: British Journal of Neuroscience Nursing, ISSN 1747-0307, E-ISSN 2052-2800, Vol. 6, no 2, p. 86-93Article in journal (Refereed)
    Abstract [en]

    Aim: The aim was to analyse people's accounts of subarachnoid haemorrhage (SAH) and to describe how they initiate and create meaning for the onset and events surrounding the SAH.

    Background: Being struck by a SAH is a dramatic event, often followed by unconsciousness. There is therefore a special need for a patient to try to create some kind of meaning for the event during recovery and afterwards.

    Method: Nine interviews were carried out in home settings and discourse analysis was used to interpret the data.

    Findings: People stricken by SAH seem to be able to judge from memory for when they were becoming ill. Critical events related to SAH were existential threats and existential insights; and time as 'waiting' and time as 'structuring meaning'. The reconstruction of the illness event may be interpreted as an identity-creating process.

    Conclusion: The reconstruction of the illness is a tool that can be used by nurses and other health professionals to understand a patient's self-positioning and identity-construction.

  • 9.
    Berggren, Elisabeth
    et al.
    University of Skövde, School of Life Sciences. School of Health Sciences, Jönköping University, Sweden.
    Sidenvall, Birgitta
    School of Health Sciences, Jönköping University, Sweden.
    Larsson, Dennis
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Memory ability after subarachnoid haemorrhage: Relatives' and patients' statements in relation to test results2010In: British Journal of Neuroscience Nursing, ISSN 1747-0307, E-ISSN 2052-2800, Vol. 6, no 8, p. 383-391Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to describe memory after a subarachnoid haemorrhage (SAH) from the perspective of relatives and patients in two cohorts and also to evaluate the application of relatives' statements as a tool in nursing care and rehabilitation, in order to support the patient.

    Background: Cognitive sequelae due to SAH are a large disability and may influence the adjustment to daily life. Supporting patients and relatives requires knowledge concerning the patients' memory both from the perspective of patients and relatives.

    Method: Eleven relatives and 11 patients (Cohort 1), 11 years after the onset of a SAH and 15 relatives and 15 patients (Cohort 2) 6 years after the onset of a SAH, participated in the study. Interview questions and memory tests were used to collect data.

    Findings: Problems with memory, including meta-memory problems regarding relatives' statements, were common. Relatives and patients stated patients' memory in a similar manner. However, patients' statements concerning their memory corresponded in higher degree with memory test results, in comparison with relatives' statements.

    Conclusions: Relatives' and patients' statements are useful as tools in nursing care and rehabilitation. However, from results showing meta-memory problems and that patients' statements concerning their memory corresponded better with memory test results (in comparison with relatives' statements), it is vital to offer patients memory tests in order to prevent complications in mutual family relationships.

  • 10.
    Berggren, Elisabeth
    et al.
    University of Skövde, School of Life Sciences. School of Health Sciences, Jönköping University, Sweden.
    Sidenvall, Birgitta
    School of Health Sciences, Jönköping University, Sweden.
    Larsson, Dennis
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Subarachnoid haemorrhage has long-term effects on social life2011In: British Journal of Neuroscience Nursing, ISSN 1747-0307, E-ISSN 2052-2800, Vol. 7, no 1, p. 429-435Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to describe memory after a subarachnoid haemorrhage (SAH) from the perspective of relatives and patients in two cohorts and also to evaluate the application of relatives' statements as a tool in nursing care and rehabilitation, in order to support the patient. Background: Cognitive sequelae due to SAH are a large disability and may influence the adjustment to daily life. Supporting patients and relatives requires knowledge concerning the patients' memory both from the perspective of patients and relatives. Method: Eleven relatives and 11 patients (Cohort 1), 11 years after the onset of an SAH and 15 relatives and 15 patients (Cohort 2) 6 years after the onset of an SAH, participated in the study. Interview questions and memory tests were used to collect data. Findings: Problems with memory, including meta-memory problems regarding relatives' statements, were common. Relatives and patients stated patients' menory in a similar manner. However, patients' statements concerning their memory corresponded in higher degree with memory test results, in comparison with relatives' statements. Conclusions: Relatives' and patients' statements are useful as tools in nursing care and rehabilitation. However, from results showing meta-memory problems and that patients' statements concerning their memory corresponded better with memory test results (in comparison with relatives' statements), it is vital to offer patients memory tests in order to prevent complications in mutual family relationships.

  • 11.
    Bokenberger, Kathleen
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sjölander, Arvid
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dahl Aslan, Anna K.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; School of Health and Welfare, Institute of Gerontology, Jönköping University, Sweden.
    Karlsson, Ida K.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Åkerstedt, Torbjörn
    Stress Research Institute, Stockholm University, Sweden ; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pedersen, Nancy Lee
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles, USA.
    Shift work and risk of incident dementia: a study of two population-based cohorts2018In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 33, no 10, p. 977-987Article in journal (Refereed)
    Abstract [en]

    This study aimed to investigate the association between shift work and incident dementia in two population-based cohorts from the Swedish Twin Registry (STR). The STR-1973 sample included 13,283 participants born 1926–1943 who received a mailed questionnaire in 1973 that asked about status (ever/never) and duration (years) of shift work employment. The Screening Across the Lifespan Twin (SALT) sample included 41,199 participants born 1900–1958 who participated in a telephone interview in 1998–2002 that asked about night work status and duration. Dementia diagnoses came from Swedish patient registers. Cox proportional-hazards regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Potential confounders such as age, sex, education, diabetes, cardiovascular disease and stroke were included in adjusted models. In genotyped subsamples (n = 2977 in STR-1973; n = 10,366 in SALT), APOE ε4 status was considered in models. A total of 983 (7.4%) and 1979 (4.8%) dementia cases were identified after a median of 41.2 and 14.1 years follow-up in the STR-1973 and SALT sample, respectively. Ever shift work (HR 1.36, 95% CI 1.15–1.60) and night work (HR 1.12, 95% CI 1.01–1.23) were associated with higher dementia incidence. Modest dose-response associations were observed, where longer duration shift work and night work predicted increased dementia risk. Among APOE ε4 carriers, individuals exposed to ≥ 20 years of shift work and night work had increased dementia risk compared to day workers. Findings indicate that shift work, including night shift work, compared to non-shift jobs is associated with increased dementia incidence. Confirmation of findings is needed. 

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  • 12.
    Bokenberger, Kathleen
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ström, Peter
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dahl Aslan, Anna K.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Institute of Gerontology, School of Health and Welfare, Jönköping University, Sweden.
    Johansson, Anna L. V.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gatz, Margaret
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles CA, USA.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles CA, USA.
    Åkerstedt, Torbjörn
    Stress Research Institute, Stockholm University, Sweden ; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Association between sleep characteristics and incident dementia accounting for baseline cognitive status: A prospective population-based study2017In: The journals of gerontology. Series A, Biological sciences and medical sciences, ISSN 1079-5006, E-ISSN 1758-535X, Vol. 72, no 1, p. 134-139Article in journal (Refereed)
    Abstract [en]

    Background: While research has shown that sleep disorders are prevalent among people with dementia, the temporal relationship is unclear. We investigated whether atypical sleep characteristics were associated with incident dementia while accounting for baseline cognitive functioning.

    Methods: Screening Across the Lifespan Twin Study (SALT) participants were 11,247 individuals from the Swedish Twin Registry who were at least 65 years at baseline (1998-2002). Sleep and baseline cognitive functioning were assessed via the SALT telephone screening interview. Data on dementia diagnoses came from national health registers. Cox regression was performed to estimate hazard ratios (HR) for dementia.

    Results: After 17 years of follow-up, 1,850 dementia cases were identified. Short (≤ 6 hours) and extended (> 9 hours) time-in-bed (TIB) compared to the middle reference group (HR=1.40, 95% CI=1.06-1.85, HR=1.11, 95% CI=1.00-1.24, respectively) and rising at 8:00AM or later compared to earlier rising (HR=1.12, 95% CI=1.01-1.24) were associated with higher dementia incidence. Bedtime, sleep quality, restorative sleep, and heavy snoring were not significant predictors. Findings stratified by baseline cognitive status indicated that the association between short TIB and dementia remained in those cognitively intact at the start.

    Conclusions: Short and extended TIB as well as delayed rising among older adults predicted increased dementia incidence in the following 17 years. The pattern of findings suggests that extended TIB and late rising represent prodromal features whereas short TIB appeared to be a risk factor for dementia.

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  • 13.
    Calame, Daniel G.
    et al.
    Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA ; Texas Children’s Hospital, Houston, TX, USA.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Lupski, James R.
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA ; Texas Children’s Hospital, Houston, TX, USA ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA ; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
    Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia2022In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 92, no 2, p. 304-321Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683).

    METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.

    RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.

    INTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022.

  • 14.
    Celik, Yeliz
    et al.
    Department of Pulmonary Medicine, Koc University School of Medicine, Koc University Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Turkey.
    Peker, Yüksel
    Department of Pulmonary Medicine, Koc University School of Medicine, Koc University Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Turkey ; Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Sciences, Respiratory Medicine and Allergology, Faculty of Medicine, Lund University, Sweden ; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States ; Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States.
    Yucel-Lindberg, Tülay
    Department of Dental Medicine, Karolinska Institute, Stockholm, Sweden.
    Thelander, Tilia
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Behboudi, Afrouz
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Association of TNF-α (-308G/A) Gene Polymorphism with Changes in Circulating TNF-α Levels in Response to CPAP Treatment in Adults with Coronary Artery Disease and Obstructive Sleep Apnea2023In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 12, no 16, article id 5325Article in journal (Refereed)
    Abstract [en]

    Rationale: We recently demonstrated that patients with coronary artery disease (CAD) and obstructive sleep apnea (OSA) carrying the tumor necrosis factor-alpha (TNF-α) A allele had increased circulating TNF-α levels compared with the ones carrying the TNF-α G allele. In the current study, we addressed the effect of TNF-α (-308G/A) gene polymorphism on circulating TNF-α levels following continuous positive airway pressure (CPAP) therapy. Methods: This study was a secondary analysis of the RICCADSA trial (NCT00519597) conducted in Sweden. CAD patients with OSA (apnea–hypopnea index) of ≥15 events/h and an Epworth Sleepiness Scale (ESS) score of <10 were randomized to CPAP or no-CPAP groups, and OSA patients with an ESS score of ≥10 were offered CPAP treatment. Blood samples were obtained at baseline and 12-month follow-up visits. TNF-α was measured by immunoassay (Luminex, R&D Systems). Genotyping of TNF-α-308G/A (single nucleotide polymorphism Rs1800629) was performed by polymerase chain reaction–restriction fragment length polymorphism. Results: In all, 239 participants (206 men and 33 women; mean age 64.9 (SD 7.7) years) with polymorphism data and circulating levels of TNF-α at baseline and 1-year follow-up visits were included. The median circulating TNF-α values fell in both groups between baseline and 12 months with no significant within- or between-group differences. In a multivariate linear regression model, a significant change in circulating TNF-α levels from baseline across the genotypes from GA to GA and GA to AA (standardized β-coefficient −0.129, 95% confidence interval (CI) −1.82; −0.12; p = 0.025) was observed in the entire cohort. The association was more pronounced among the individuals who were using the device for at least 4 h/night (n = 86; standardized β-coefficient −2.979 (95% CI −6.11; −1.21); p = 0.004)), whereas no significant association was found among the patients who were non-adherent or randomized to no-CPAP. The participants carrying the TNF-α A allele were less responsive to CPAP treatment regarding the decline in circulating TNF-α despite CPAP adherence (standardized β-coefficient −0.212, (95% CI −5.66; −1.01); p = 0.005). Conclusions: Our results suggest that TNF-α (-308G/A) gene polymorphism is associated with changes in circulating TNF-α levels in response to CPAP treatment in adults with CAD and OSA. 

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  • 15.
    Cuisset, J. M.
    et al.
    Service de Neuropédiatrie, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    Maurage, C. A.
    Service d'Anatomie Pathologique, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    Pellissier, J. F.
    Laboratoire de Biopathologie Neuromusculaire, JE 2053, Centre hospitalier universitaire et faculté de médecine de La Timone, Marseille, France.
    Barois, A.
    Service de réanimation pédiatrique, Hôpital Raymond-Poincaré, Garches, France.
    Urtizberea, J. A.
    Institut de Myologie, Hôpital Pitié-Salpétrière, Paris, France.
    Laing, N.
    Center for neuromuscular and neurological disorders, Australian neuromuscular research institute, University of Western Australia, Nedlands, WA, Australia.
    Tajsharghi, H
    Department of pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Vallée, L.
    Service de Neuropédiatrie, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    'Cap myopathy': case report of a family2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 4, p. 277-281Article in journal (Refereed)
    Abstract [en]

    We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

  • 16.
    Dahl-Halvarsson, Martin
    et al.
    University of Gothenburg, Gothenburg, Sweden.
    Olive, Montse
    Institut Investigació Biomèdica de Bellvitge – Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
    Pokrzywa, Malgorzata
    University of Gothenburg, Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Palmer, Ruth H.
    University of Gothenburg, Gothenburg, Sweden.
    Uv, Anne Elisabeth
    University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 28, p. E6566-E6575Article in journal (Refereed)
    Abstract [en]

    Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

  • 17.
    Dahl-Halvarsson, Martin
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Olive, Montse
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
    Pokrzywa, Malgorzata
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Norum, Michaela
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase2020In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 13, no 12, article id dmm047886Article in journal (Refereed)
    Abstract [en]

    Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/ß-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases with myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of R1845W mutation. This study shows that higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase.This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities including extensive loss of thick filaments with selective A-band loss and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Further, the impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase. These findings suggest that modification of ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

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  • 18.
    Dallora, Ana Luiza
    et al.
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Minku, Leandro
    School of Computer Science, University of Birmingham, United Kingdom.
    Mendes, Emilia
    Department of Computer Science, Blekinge Institute of Technology, Karlskrona, Sweden.
    Rennemark, Mikael
    Faculty of Health and Life Sciences, Linnaeus University, Kalmar, Sweden.
    Anderberg, Peter
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Berglund, Johan Sanmartin
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Multifactorial 10-year prior diagnosis prediction model of dementia2020In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 17, no 18, p. 1-18, article id 6674Article in journal (Refereed)
    Abstract [en]

    Dementia is a neurodegenerative disorder that affects the older adult population. To date, no cure or treatment to change its course is available. Since changes in the brains of affected individuals could be evidenced as early as 10 years before the onset of symptoms, prognosis research should consider this time frame. This study investigates a broad decision tree multifactorial approach for the prediction of dementia, considering 75 variables regarding demographic, social, lifestyle, medical history, biochemical tests, physical examination, psychological assessment and health instruments. Previous work on dementia prognoses with machine learning did not consider a broad range of factors in a large time frame. The proposed approach investigated predictive factors for dementia and possible prognostic subgroups. This study used data from the ongoing multipurpose Swedish National Study on Aging and Care, consisting of 726 subjects (91 presented dementia diagnosis in 10 years). The proposed approach achieved an AUC of 0.745 and Recall of 0.722 for the 10-year prognosis of dementia. Most of the variables selected by the tree are related to modifiable risk factors; physical strength was important across all ages. Also, there was a lack of variables related to health instruments routinely used for the dementia diagnosis. 

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  • 19.
    Darin, Niklas
    et al.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden / Department of Pediatrics, Queen Silvia Children's Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Östman-Smith, I.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Gilljam, T.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    New skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH72007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 23, p. 2041-2042Article in journal (Refereed)
  • 20.
    Frost, Morgan
    University of Skövde, School of Bioscience.
    Social perception in Autism: An eye tracking and pupillometric study2018Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Typically developing humans innately place subjective value on social information and orient attention to it. This can be shown through eye tracking and pupillometry, a method used to show attentional engagement. Social brain development and social preference is present from infancy, and is thought to rely on a carefully balanced network of neurotransmitters and neural connections. Autism Spectrum Disorder (ASD) presents altered neural systems which cause individuals to perceive and process social information differently, but the neurophysiology of this difference remains unclear. Previous research shows atypical gaze patterns, hyperarousal, and lack of orienting to social stimuli in ASD. Since autism is highly comorbid and shares traits with other neurodevelopmental disorders, it is difficult to distinguish aspects of these social processing differences. This study used a group of 35 neuropsychiatric patients to investigate how individuals with autism process social and non-social scenes. Eye tracking and pupillometry measures were collected while participants observed images of natural scenes with or without a person. Participants with autism did not show a pupillary response to social images and were slower to fixate on the face  region than the other participants. Additionally there were correlations between clinical measures of social functioning and the length of time it took to fixate to faces. The results highlight important distinctions of social processing in autism. This thesis proposes a new perspective of looking at the social deficits present in autism spectrum disorder. It suggests reframing the current discussion from two leading hypotheses to a unified approach and formally considering the limitations of differing types of stimuli.

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  • 21.
    Gerafi, Joel
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Long-term functional outcome after ischemic stroke: Prognostic value of early identification of neglect and aphasia2017Licentiate thesis, comprehensive summary (Other academic)
  • 22.
    Gerafi, Joel
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Göteborgs universitet. Samhällsvetenskapliga fakulteten University of Gothenburg. Faculty of Social Sciences.
    Visuospatial inattention and processing speed: Predictors of long-term outcome and patterns of change after ischemic stroke2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Impairments of visuospatial attention, language, and processing speed (PS) are common early after stroke and have been associated with unfavorable short-term functional outcomes but little is known about this relationship in the long-term. This thesis investigates 1) the potential importance of visuospatial inattention (VSI) and language impairments (LI) as predictors of functional outcomes 7 years after an ischemic stroke (studies I-II) and 2) presence of lateralized inattention 7 years after stroke and potential predictors of this phenomenon (study III). Study IV gives a detailed description of the long-term course of PS across 3 months and 7 years after an ischemic stroke. A cohort of 375 consecutive stroke patients was assessed early after stroke for the occurrence (studies I–II and IV) and severity (studies III-IV) of VSI using the Star Cancellation Test (SCT, studies I-IV) and Letter Cancellation Test (LCT, studies III-IV). Language impairments were investigated (studies I-II) by the language item from the Scandinavian Stroke Scale (SSS). At the 7-year follow-up, functional outcomes were measured by the modified Rankin Scale (mRS), the Frenchay Activities Index (FAI) (studies I-II and IV), and the recovery item of Stroke Impact Scale (SIS) (study IV). Patients with a recurrent stroke during the follow-up period were excluded (all studies). The presence of lateralized inattention at the 7-year follow-up (study III) was assessed with the SCT, the LCT, and the neglect item from the NIH Stroke Scale (NIHSS). The long-term course of PS (study IV) was measured by a mirrored copy of the SCT with a time limit of 30 seconds, follow-up assessments of SCT, LCT, and NIHSS were also included in this study. In study I, 235 stroke survivors were included at the follow-up and VSI and stroke severity (SSS) were identified as the significant independent predictors of unfavorable outcomes in mRS and FAI. The early screening of LI did not provide independent prognostic information beyond the information provided by VSI and stroke severity. In study II, 105 individuals with left hemispheric stroke were included at the 7-year follow-up. It was found that the presence of VSI was rather common observed in about one of five patients. VSI was the most important independent predictor of unfavorable outcomes in mRS and FAI. Individuals with both VSI and LI had increased risk of poor outcome compared to those with signs of one of these symptoms. In study III, 188 stroke survivors were included at the 7-year follow-up and about one of ten had signs of lateralized inattention. Independent baseline predictors for these long-term signs were total omissions in target cancellations and inferior performance on visual processing speed. In study IV, 148 subjects were included at follow-up and impaired PS was observed in about one of three individuals at baseline with significant improvement in scores at 3 months followed by a clear decline at 7 years. It was also found that slow PS was related with inferior functional outcome at the 7-year follow-up, also after adjusting for age. Age was related with scores in PS but did not explain the scores of PS for those with lowest speed. Conclusions: Studies I-II emphasize the importance of identifying early symptoms of VSI not only after right hemispheric stroke but also after left hemispheric stroke and particularly for individuals with severe symptoms of LI. A combination of attention and language deficits at the acute phase seems to be rather common among patients with left hemispheric stroke and indicates an increased risk of unfavorable outcomes. Studies III-IV are the first studies to recognize PS as a significant predictor of long-term lateralized inattention and to describe changes in speed across two follow-ups up to 7 years in a stroke cohort. The results from these two studies emphasize the importance of further long-term studies of PS after stroke.

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  • 23.
    Gerafi, Joel
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Faculty of Social Sciences, Department of Psychology, University of Gothenburg, Sweden / Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden / The Skaraborg Institute for Research and Development, Skövde, Sweden.
    Samuelsson, Hans
    Faculty of Social Sciences, Department of Psychology, University of Gothenburg, Sweden / Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Viken, Jo I.
    Faculty of Social Sciences, Department of Psychology, University of Gothenburg, Sweden / Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Jern, Christina
    Department of Laboratory Medicine, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Blomstrand, Christian
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Jood, Katarina
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden / Department of Neurology, The Sahlgrenska University Hospital, Gothenburg, Sweden.
    The presence and prediction of lateralized inattention 7 years post-stroke2020In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 141, no 5, p. 423-430Article in journal (Refereed)
    Abstract [en]

    Objective: Lateralized inattention is a typical sign of neglect and related to poor functional outcome. Knowledge of the long-term course of this phenomenon is limited. The purpose of this study was to investigate presence and predictors for signs of lateralized inattention 7 years after stroke. Methods: From a cohort of acute ischemic stroke patients, aged 18-69 years (n = 297), a consecutive series of 188 survivors without recurrent stroke at follow-up 7 years later were included. Within the first week after stroke onset, stroke severity was assessed according to the Scandinavian Stroke Scale. Target omissions, asymmetry of omissions, and perceptual speed according to Star- and Letter Cancellation Tests were also assessed. Presence of lateralized inattention at the 7-year follow-up was investigated with the Star- and Letter Cancellation Tests and with the neglect item in the National Institutes of Health Stroke Scale. Results: At the follow-up, 22 (11.7%) participants had lateralized inattention and the multivariable regression showed that independent significant baseline predictors were total omissions in target cancellations (P <.001) and inferior baseline performance on visual processing speed (P =.008). Conclusion: About one of ten individuals exhibited signs of lateralized inattention 7 years after stroke. Baseline performance in perceptual processing speed and target omissions independently predicted presence of late signs of lateralized inattention. This is the first time processing speed is recognized as a significant predictor of lateralized inattention several years after the stroke incidence, indicating that the longitudinal course of processing speed following stroke is a critical subject for future research. © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

  • 24.
    Gharibi, Farid
    et al.
    Social Determinants of Health Research Center, Semnan University of Medical Sciences, Semnan, Iran.
    Imani, Ali
    Tabriz Health Services Management Research Center, Tabriz University of Medical Sciences, Iran.
    Haghi, Mehdi
    Social Determinants of Health Research Center, School of Health and Nutrition, Lorestan University of Medical Sciences, Khorramabad, Iran.
    Khezri, Ali
    Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Iran.
    Joudyian, Nasrin
    Department of Health Services Management, School of Management and Medical Informatics, Tabriz University of Medical Sciences, Iran.
    Ebrahimi Tavani, Masoumeh
    Department of Quality Improvement, Monitoring and Evaluation, Center of Health Network Management, Deputy of Public Health, Ministry of Health & Medical Education, Tehran, Iran.
    Dalal, Koustuv
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Higher School of Public Health, Kazakh National University, Almaty, Kazakhstan.
    Quality of Life and Its Relative Factors Among Patients With Multiple Sclerosis: A Cross-sectional Study in Northwest Iran2023In: Journal of Research and Health, ISSN 2423-5717, Vol. 13, no 4, p. 263-272Article in journal (Refereed)
    Abstract [en]

    Background: Multiple sclerosis (MS) is one of the critical diseases due to its adverse clinical, social, and economic consequences for affected people. This study aims to assess the quality of life (QoL) of patients with MS in East Azerbaijan, Iran. Methods: This cross-sectional study was conducted using the multiple sclerosis quality of life-54 (MSQoL-54) questionnaires to interview 300 randomly selected MS patients in East Azarbaijan Province, Iran. The independent t-test, analysis of variance (ANOVA), and Tukey post hoc test were used to examine the relationship between demographic variables, and QoL, and all analyses were performed using SPSS software, version 19. Results: The QoL score in MS patients is 48.22±22.48. The “life satisfaction” is the best and “physical role limitation” is the worst QoL aspect. Significant relationships were observed between marital status, education level, employment status, age of symptoms onset, and years of illness with QoL (P<0.05). Conclusion: The QoL of the MS patients in East Azarbaijan Province is lower than in other parts of Iran and much lower than in Organization for Economic Co-operation and Development (OECD) countries.

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  • 25.
    Hurme, Mikko
    et al.
    Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Koivisto, Mika
    Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Revonsuo, Antti
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Railo, Henry
    Department of Psychology, University of Turku, Finland / Centre for Cognitive Neuroscience, University of Turku, Finland / Turku Brain and Mind Centre, University of Turku, Finland.
    Early processing in primary visual cortex is necessary for conscious and unconscious vision while late processing is necessary only for conscious vision in neurologically healthy humans2017In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 150, p. 230-238Article in journal (Refereed)
    Abstract [en]

    The neural mechanisms underlying conscious and unconscious visual processes remain controversial. Blindsight patients may process visual stimuli unconsciously despite their VI lesion, promoting anatomical models, which suggest that pathways bypassing the VI support unconscious vision. On the other hand, physiological models argue that the major geniculostriate pathway via VI is involved in both unconscious and conscious vision, but in different time windows and in different types of neural activity. According to physiological models, feedforward activity via VI to higher areas mediates unconscious processes whereas feedback loops of recurrent activity from higher areas back to VI support conscious vision. With transcranial magnetic stimulation (TMS) it is possible to study the causal role of a brain region during specific time points in neurologically healthy participants. In the present study, we measured unconscious processing with redundant target effect, a phenomenon where participants respond faster to two stimuli than one even when one of the stimuli is not consciously perceived. We tested the physiological feedforward-feedback model of vision by suppressing conscious vision by interfering selectively either with early or later VI activity with TMS. Our results show that early VI activity (60 ms) is necessary for both unconscious and conscious vision. During later processing stages (90 ms), VI contributes selectively to conscious vision. These findings support the feedforward-feedback-model of consciousness.

  • 26.
    Javeed, Ashir
    et al.
    Aging Research Center, Karolinska Institutet, Stockholm, Sweden ; Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Dallora, Ana Luiza
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Sanmartin Berglund, Johan
    Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Ali, Arif
    Department of Computer Science, University of Science and Technology Bannu, Pakistan.
    Anderberg, Peter
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Department of Health, Blekinge Institute of Technology, Karlskrona, Sweden.
    Ali, Liaqat
    Department of Electrical Engineering, University of Science and Technology Bannu, Pakistan.
    Predicting Dementia Risk Factors Based on Feature Selection and Neural Networks2023In: Computers, Materials and Continua, ISSN 1546-2218, E-ISSN 1546-2226, Vol. 75, no 2, p. 2491-2508Article in journal (Refereed)
    Abstract [en]

    Dementia is a disorder with high societal impact and severe consequences for its patients who suffer from a progressive cognitive decline that leads to increased morbidity, mortality, and disabilities. Since there is a consensus that dementia is a multifactorial disorder, which portrays changes in the brain of the affected individual as early as 15 years before its onset, prediction models that aim at its early detection and risk identification should consider these characteristics. This study aims at presenting a novel method for ten years prediction of dementia using on multifactorial data, which comprised 75 variables. There are two automated diagnostic systems developed that use genetic algorithms for feature selection, while artificial neural network and deep neural network are used for dementia classification. The proposed model based on genetic algorithm and deep neural network had achieved the best accuracy of 93.36%, sensitivity of 93.15%, specificity of 91.59%, MCC of 0.4788, and performed superior to other 11 machine learning techniques which were presented in the past for dementia prediction. The identified best predictors were: age, past smoking habit, history of infarct, depression, hip fracture, single leg standing test with right leg, score in the physical component summary and history of TIA/RIND. The identification of risk factors is imperative in the dementia research as an effort to prevent or delay its onset. 

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  • 27.
    Jensen, Poul Erik H.
    et al.
    Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmar.
    Warnke, Clemens
    Department of Neurology, University Hospital Köln, Germany / University of Düsseldorf, Medical Faculty, Department of Neurology, Germany.
    Ingenhoven, Kathleen
    University of Düsseldorf, Medical Faculty, Department of Neurology, Germany.
    Piccoli, Luca
    Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Bellinzona, Switzerland.
    Gasis, Marcia
    University of Düsseldorf, Medical Faculty, Department of Neurology, Germany.
    Hermanrud, Christina
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fernandez-Rodriguez, Blanca M.
    Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Bellinzona, Switzerland.
    Ryner, Malin
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kramer, Daniel
    Sanofi-Aventis Germany, Frankfurt Am Main, Germany.
    Link, Jenny
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ramanujam, Ryan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden / KTH – Royal Institute of Technology, Stockholm, Sweden.
    Auer, Michael
    Innsbruck Medical University, Innsbruck, Austria.
    Buck, Dorothea
    Department of Neurology, Technische Universität München, Munich, Germany.
    Grummel, Verena
    Department of Neurology, Technische Universität München, Munich, Germany.
    Bertotti, Elisa
    Merck NBE Bioanalytics Ivrea, Colleretto Giacosa, Italy.
    Fissolo, Nicolas
    Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Barcelona, Spain.
    Oliver-Martos, Begoña
    Hospital Regional Universitario de Málaga, Instituto de investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain.
    Nytrova, Petra
    MS Center, Department of Neurology and Center Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
    Khalil, Michael
    Department of Neurology, Medical University of Graz, Austria.
    Guger, Michael
    Clinic for Neurology 2, Kepler University Clinic, Med Campus III, Linz, Austria.
    Rathmaier, Sandra
    Clinic for Neurology 2, Kepler University Clinic, Med Campus III, Linz, Austria.
    Sievers-Stober, Claudia
    Departments of Biomedicine and Neurology, University Hospital Basel and University of Basel, Switzerland.
    Lindberg, Raija L. P.
    Departments of Biomedicine and Neurology, University Hospital Basel and University of Basel, Switzerland.
    Hässler, Signe
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay, University UVSQ, Villejuif, France.
    Bachelet, Delphine
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay, University UVSQ, Villejuif, France.
    Aktas, Orhan
    University of Düsseldorf, Medical Faculty, Department of Neurology, Germany.
    Donnellan, Naoimh
    Ipsen Biopharm Ltd., Berkshire, United Kingdom.
    Lawton, Andy
    GlaxoSmithKline R&D, Uxbridge, Middlesex, United Kingdom.
    Hemmer, Bernhard
    Department of Neurology, Technische Universität München, Germany / Munich Cluster for systems Neurology (SyNergy), Germany.
    Havrdova, Eva Kubala
    MS Center, Department of Neurology and Center Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
    Kieseier, Bernd
    University of Düsseldorf, Medical Faculty, Department of Neurology, Germany.
    Hartung, Hans-Peter
    University of Düsseldorf, Medical Faculty, Department of Neurology, Germany.
    Comabella, Manuel
    Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Barcelona, Spain.
    Montalban, Xavier
    Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Barcelona, Spain.
    Derfuss, Tobias
    Departments of Biomedicine and Neurology, University Hospital Basel and University of Basel, Switzerland.
    Sellebjerg, Finn
    Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
    Dönnes, Pierre
    SciCross AB, Skövde, Sweden.
    Pallardy, Marc
    INSERM UMR 996, Univ. Paris-Sud, Faculty of Pharmacy, Université Paris-Saclay, Châtenay-Malabry, France.
    Spindeldreher, Sebastian
    Drug Metabolism Pharmacokinetics-Biologics, Novartis Institutes for Biomedical Research, Basel, Switzerland.
    Broët, Philippe
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, Paris-Saclay, University UVSQ, Villejuif, France / Assistance Publique - Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France.
    Deisenhammer, Florian
    Innsbruck Medical University, Austria.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Sorensen, Per Soelberg
    Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
    Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis: Results from the ABIRISK prospective cohort study2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 326, p. 19-27Article in journal (Refereed)
    Abstract [en]

    Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.

  • 28.
    Karlsson, Christina
    University of Skövde, School of Life Sciences.
    Undersköterskans tolkningar av tecken på smärta hos personer med demens2013In: BestPractice, ISSN 1177-5645, Vol. 2, no 6, p. 14-16Article in journal (Refereed)
  • 29.
    Karlsson, Ida K.
    et al.
    Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Sweden ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gatz, Margaret
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA.
    Arpawong, Thalida Em
    Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
    Dahl Aslan, Anna K.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Sweden ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Reynolds, Chandra A.
    Department of Psychology, University of California, Riverside, United States.
    The dynamic association between body mass index and cognition from midlife through late-life, and the effect of sex and genetic influences2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1Article in journal (Refereed)
    Abstract [en]

    Body mass index (BMI) is associated with cognitive abilities, but the nature of the relationship remains largely unexplored. We aimed to investigate the bidirectional relationship from midlife through late-life, while considering sex differences and genetic predisposition to higher BMI. We used data from 23,892 individuals of European ancestry from the Health and Retirement Study, with longitudinal data on BMI and three established cognitive indices: mental status, episodic memory, and their sum, called total cognition. To investigate the dynamic relationship between BMI and cognitive abilities, we applied dual change score models of change from age 50 through 89, with a breakpoint at age 65 or 70. Models were further stratified by sex and genetic predisposition to higher BMI using tertiles of a polygenic score for BMI (PGSBMI). We demonstrated bidirectional effects between BMI and all three cognitive indices, with higher BMI contributing to steeper decline in cognitive abilities in both midlife and late-life, and higher cognitive abilities contributing to less decline in BMI in late-life. The effects of BMI on change in cognitive abilities were more evident in men compared to women, and among those in the lowest tertile of the PGSBMI compared to those in the highest tertile, while the effects of cognition on BMI were similar across groups. In conclusion, these findings highlight a reciprocal relationship between BMI and cognitive abilities, indicating that the negative effects of a higher BMI persist from midlife through late-life, and that weight-loss in late-life may be driven by cognitive decline.

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  • 30.
    Kimber, Eva
    et al.
    Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden / .
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Sweden.
    Kroksmark, A.-K.
    Queen Silvia Children's Hospital, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Sweden.
    Tulinius, M.
    Queen Silvia Children's Hospital, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
    A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis.2006In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 67, no 4, p. 597-601Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe a three-generation family with distal arthrogryposis associated with myopathy and caused by a mutation in the gene encoding for sarcomeric thin filament protein troponin I, TNNI2.

    METHODS: The authors performed clinical investigations and reviewed medical records. Muscle biopsy specimens were obtained for morphologic analysis. Genomic DNA was extracted from blood and analyzed for mutations in TNNI2.

    RESULTS: The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement (mild micrognathia, narrow palpebral fissures), and no detectable muscle weakness. The four affected adults had slightly increased levels of creatine kinase in blood, and muscle biopsy specimens showed findings of myopathy with changes restricted to type 2 fibers. These included variability of muscle fiber size, internalized nuclei, and increased interstitial connective tissue. Analysis of TNNI2 encoding the troponin I isoform expressed in type 2 muscle fibers disclosed a heterozygous three-base in-frame deletion, 2,918-2,920del, skipping the highly conserved lysine at position 176. The mutation was present in all 5 affected individuals but was not identified in any of the 11 unaffected family members.

    CONCLUSION: Distal arthrogryposis type 1 is genetically heterogeneous, and myopathy due to sarcomeric protein dysfunction may be one underlying cause of the disease.

  • 31.
    Kimber, Eva
    et al.
    Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, Uppsala, Sweden / Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kroksmark, Anna-Karin
    Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tulinius, Már
    Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Distal arthrogryposis: clinical and genetic findings2012In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 101, no 8, p. 877-887Article in journal (Refereed)
    Abstract [en]

    AIM: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation.

    METHOD: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed.

    RESULTS: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection.

    CONCLUSION: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.

  • 32.
    Knez, Rajna
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Pediatrics, Skaraborg Hospital, Skövde, Sweden.
    Stevanovic, Dejan
    Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Fernell, Elisabeth
    Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Gillberg, Cristopher
    Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations)2022In: Neuropsychiatric Disease and Treatment, ISSN 1176-6328, E-ISSN 1178-2021, Vol. 18, p. 2683-2702Article in journal (Refereed)
    Abstract [en]

    Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE) is an umbrella term covering a wide range of neurodevelopmental difficulties and disorders. Thus, ESSENCE includes attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental disorders (NDDs) and difficulties, with a variety of symptoms in cognitive, motor, sensory, social, arousal, regulatory, emotional, and behavioral developmental domains, frequently co-occurring and likely having partly common neurobiological substrates. The ESSENCE concept is a clinical paradigm that promotes organizing NDDs in everyday clinical practice according to their coexistence, symptom dimensions overlapping, and treatment possibilities. Despite increased knowledge regarding NDDs, the neurobiological mechanisms that underlie them and other ESSENCE-related problems, are not well understood. With its wide range of neural circuits and interactions with numerous neurotransmitters, the orexin/hypocretin system (Orx-S) is possibly associated with a variety of neurocognitive, psychobiological, neuroendocrine, and physiological functions and behaviors. Dysfunction of Orx-S has been implicated in various psychiatric and neurological disorders. This article provides an overview of Orx-S dysfunctions' possible involvement in the development, presentation, and maintenance of ESSENCE. We provide a focused review of current research evidence linking orexin neuropeptides with specific clinical NDDs symptoms, mostly in ADHD and ASD, within the Research Domain Criteria (RDoC) framework. We propose that Orx-S dysfunction might have an important role in some of these neurodevelopmental symptom domains, such as arousal, wakefulness, sleep, motor and sensory processing, mood and emotional regulation, fear processing, reward, feeding, attention, executive functions, and sociability. Our perspective is presented from a clinical point of view. Further, more thorough systematic reviews are needed as well as planning of extensive new research into the Orx-S’s role in ESSENCE, especially considering RDoC elements. 

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  • 33.
    Li, M.
    et al.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Department of Neurology, Qilu Hospital, Shandong University, Jinan, China.
    Lionikas, A.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Yu, F.
    Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Larsson, L.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 11, p. 782-791Article in journal (Refereed)
    Abstract [en]

    The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analyzed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.

  • 34.
    Lossos, Alexander
    et al.
    Department of Neurology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Fellig, Yakov
    Department of Pathology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Meiner, Vardiella
    Department of Genetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Argov, Zohar
    Department of Neurology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    MYH2 mutation in recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p122013In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 136, no 7, article id e238Article in journal (Refereed)
  • 35.
    Lundh, Dan
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Coleman, Scott
    Baylor University Medical Center, Dallas, USA.
    Riad, Jacques
    Orthopedic Department, Skaraborgs Hospital, Skövde, Sweden.
    Addressing homogeneity between affected and unaffected sides and upper and lower extremities in unilateral cerebral palsy2012In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 36, no Supplement 1, p. S14-S15Article in journal (Refereed)
  • 36.
    Lundh, Dan
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Coleman, Scott
    Baylor University Medical Center, Dallas, USA.
    Riad, Jacques
    Ortopaedic, Skaraborgs Hospital Skövde, Skövde, Sweden.
    The relationship between arm posturing and gait deviation in teenagers and young adults with spastic unilateral cerebral palsy2012In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 36, no Supplement 1, p. S13-Article in journal (Refereed)
  • 37.
    Maroofian, Reza
    et al.
    Department of Neuromuscular Diseases, University College London, Institute of Neurology, United Kingdom.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Severino, Mariasavina
    Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
    Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders2023In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 12, p. 5031-5043Article in journal (Refereed)
    Abstract [en]

    MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. 

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  • 38.
    Mohammad, Sameh
    University of Skövde, School of Life Sciences.
    Long-term depression in the rat hippocampus as a memory model: Interrogating the role of protein synthesis in NMDA- and mGluR-dependent synaptic plasticity2010Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Long-term potentiation (LTP) and depression (LTD) are important forms of activity-dependent synaptic plasticity believed to play a role in memory at the cellular level. It has previously been described that synthesis of new proteins is needed to maintain LTP longer than a few hours. Other reports argue that sufficient proteins for stable LTP are already available. The present study aims to examine the role of protein synthesis in LTD, the presumed mirror mechanism of LTP.

    Experiments were carried out in hippocampal slices from young (12-45 days) and old (12-18 weeks) Sprague-Dawley rats. Extracellular techniques were used to study synaptic responses in the Schaffer-collateral-commissural pathway. Plasticity was induced electrically by low frequency stimulation (2-3 trains at 1 Hz for 15 min) or chemically by brief exposure to certain glutamate receptor agonists (NMDA at 20 µM for 3 min or DHPG at 100 µM for 10 min). Whole slice protein synthesis was quantified by assessing 3H-leucine incorporation.

    Stable LTD (> 8 h) was be obtained by either electrical or chemical activation. Protein synthesis inhibitors anisomycin (40 uM) and cycloheximide (100 uM) both failed to influence the magnitude of LTD. Moreover, no age difference was found, in terms of stable LTD in both young and old rats under inhibition of protein synthesis. The potency of the inhibitors was found to be high, depressing synthesis down to a few percent. It is concluded that sufficient proteins for generating stable LTD are normally present in the brain, implying a large safety-margin for cellular memory.

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  • 39.
    Moslemi, Ali-Reza
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Institute of Physiology and Neurological Sciences, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Johanna
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Bert
    Department of Cardiology, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Glycogenin-1 deficiency and inactivated priming of glycogen synthesis2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 13, p. 1203-1210Article in journal (Refereed)
    Abstract [en]

    Glycogen, which serves as a major energy reserve in cells, is a large, branched polymer of glucose molecules. We describe a patient who had muscle weakness, associated with the depletion of glycogen in skeletal muscle, and cardiac arrhythmia, associated with the accumulation of abnormal storage material in the heart. The skeletal muscle showed a marked predominance of slow-twitch, oxidative muscle fibers and mitochondrial proliferation. Western blotting showed the presence of unglucosylated glycogenin-1 in the muscle and heart. Sequencing of the glycogenin-1 gene, GYG1, revealed a nonsense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.

  • 40.
    Nilipour, Yalda
    et al.
    Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Iran.
    Nafissi, Shahriar
    Tehran University of Medical Sciences, Iran.
    Tjust, Anton E.
    Umeå University, Sweden.
    Ravenscroft, Gianina
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Hossein-Nejad Nedai, Hamid
    Shahid Beheshti University of Medical Sciences, Iran.
    Taylor, Rhonda L.
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia.
    Varasteh, Vahid
    Shahid Beheshti University of Medical Sciences, Iran.
    Pedrosa Domellöf, Fatima
    Umeå University, Sweden.
    Zangi, Mahdi
    National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Iran.
    Tonekaboni, Seyed Hassan
    Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Iran.
    Olivé, M.
    IDIBELL-Hospital de Bellvitge, Barcelona, Spain.
    Kiiski, Kirsi
    Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Finland.
    Sagath, L.
    Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Finland.
    Davis, Mark R.
    Pathwest, QEII Medical Centre, Nedlands, Western Australia.
    Laing, Nigel G.
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies2018In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 25, no 6, p. 841-847Article in journal (Refereed)
    Abstract [en]

    Background: Nemaline myopathy has been associated with mutations in twelve genes to date. However, for some patients diagnosed with nemaline myopathy, definitive mutations are not identified in the known genes, suggesting there are other genes involved. This study describes compound heterozygosity for rare variants in RYR3 in one such patient.

    Results: Clinical examination of the patient at 22 years of age revealed a long-narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear areas, subsarcolemmal and within the cytoplasm. No likely pathogenic mutations in known nemaline myopathy genes were identified. Copy number variation in known nemaline myopathy genes was excluded by nemaline myopathy targeted array-CGH. Next generation sequencing revealed compound heterozygous missense variants in the ryanodine receptor type 3 gene (RYR3).  RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain or cauda equina samples. Immunofluorescence of human skeletal muscle revealed a "single-row" appearance of RYR3, interspaced between the "double-rows" of RYR1 at each A-I junction.

    Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

  • 41.
    Nilsson, J.
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Beta-tropomyosin mutations alter tropomyosin isoform composition2008In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 15, no 6, p. 573-578Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Tropomyosin (TM) is an actin-binding protein, which is localized head to tail along the length of the actin filament. There are three major TM isoforms in human striated muscle. Mutations in beta-tropomyosin (TPM2) have recently been identified as an important cause of neuromuscular disorders.

    MATERIALS AND METHODS: The expression of TM isoforms in patients carrying mutations in TPM2 was detected using a combination of SDS-PAGE, Western blotting, and a new method to measure the relative abundance of the various TM transcripts.

    RESULTS: The level of gamma-TM is reduced in patients with mutations in TPM2. Beta-tropomyosin was expressed at high levels in muscle specimens of the patients.

    DISCUSSION: Our study indicates that beta-TM gene mutations can alter the expression of other sarcomeric TM isoforms and that the perturbation of TM isoform levels may affect the dimer preference within the thin filaments, which may contribute to muscle weakness as a result of both functional and structural changes in muscle.

  • 42.
    Ochala, Julien
    et al.
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden.
    Li, Mingxin
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden / Department of Neurology, Qilu Hospital, Shandong University, Shandong, China.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Department of Neuropaediatrics, Uppsala University Children's Hospital, Sweden.
    Tulinius, Mar
    The Queen Silvia Children's Hospital, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Larsson, Lars
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden / Center for Development and Health Genetics, Pennsylvania State University, University Park, PA, United States.
    Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres2007In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, p. 1283-1292Article in journal (Refereed)
    Abstract [en]

    A novel R133W beta-tropomyosin (beta-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the beta-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force-pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the beta-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P<0.05) and ktr (P<0.01), and a faster V0 (P<0.05). The force-pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W beta-Tm mutation. It is suggested that the R133W beta-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

  • 43.
    Ohlsson, M.
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Quijano-Roy, S.
    AP-HP, Service de Pédiatrie, Centre National de Référence des Maladies Neuromusculaires GNMH, Garches, France.
    Darin, N.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Brochier, G.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Lacène, E.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Avila-Smirnow, D.
    AP-HP, Service de Pédiatrie, Centre National de Référence des Maladies Neuromusculaires GNMH, Garches, France.
    Fardeau, M.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations2008In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 23, p. 1896-1901Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2.

    METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis.

    RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys).

    CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.

  • 44.
    Ohlsson, M.
    et al.
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, N.
    Department of Pediatrics, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kyllerman, M.
    Department of Pediatrics, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1)2004In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 14, no 8-9, p. 471-475Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.

  • 45.
    Ohlsson, Monica
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hedberg, Carola
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Brådvik, Björn
    Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden.
    Lindberg, Christopher
    Department of Neurology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Danielsson, Olof
    Division of Neurology, Department of Clinical and Experimental Medicine, University Hospital Linköping, Linköping, Sweden.
    Melberg, Atle
    Department of Neuroscience, Neurology, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Udd, Bjarne
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Folkhälsan Genetic Institute, Department of Medical Genetics, Helsinki University, Helsinki, Finland.
    Martinsson, Tommy
    Department of Clinical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 135, no 6, p. 1682-1694Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

  • 46.
    Oldfors, Anders
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    Department of Paediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Myopathies associated with myosin heavy chain mutations2004In: Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases, ISSN 1128-2460, Vol. 23, no 2, p. 90-96Article in journal (Refereed)
    Abstract [en]

    Myosin, a molecular motor, converts chemical energy into mechanical force. The motor domain of myosin heavy chain (MyHC) includes an ATP binding region with ATPase activity and an actin-binding region. Motor function is achieved by conformational changes, at hydrolysis, of ATP causing a shift in the angle between the actin binding head and the rod region of the molecule. The elongated alpha-helical coiled-coil rod region of MyHC molecules constitutes the major part of the thick filaments of the sarcomere. Three major MyHC isoforms are expressed in human skeletal muscle (type I, MYH7, expressed in type 1 fibres; IIa, MYH2, expressed in 2A fibres; IIx, MYH1, expressed in 2B fibres). While mutations in slow/beta cardiac MyHC (MYH7) are a common cause of familial hypertrophic cardiomyopathy, no skeletal myopathies have, until recently, been associated with mutations in MyHC. A heterozygous mutation, Glu706Lys, in the core of the head of MyHC IIa is associated with a familial congenital myopathy, which, in most instances, has shown mild phenotypic expression in children but progressive course in some adults. There is a relationship between the level of expression of mutated MyHC IIa and muscle pathology. Some adults with a progressive course show muscle fibres with rimmed vacuoles and filaments of the type seen in inclusion body myositis/myopathy (IBM). Endurance training in a group of affected patients caused a shift in the expression of myosin from fast (IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa. A heterozygous mutation, Arg1845Trp, in the distal rod region of slow myosin (type I, MYH7) is associated with familial congenital myopathy, with large deposits of MyHC I in the subsarcolemmal region of type 1 muscle fibres, "Myosin storage myopathy". These patients showed slowly progressive muscle weakness but no overt cardiomyopathy. These two muscle diseases, which are caused by mutations in MyHC, form the basis of a novel entity: "Myosin myopathies".

  • 47.
    Oldfors, Anders
    et al.
    Göteborg, Sweden.
    Tajsharghi, Homa
    Göteborg, Sweden.
    Thornell, L. E.
    Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy2005In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 64, no 3, p. 580-581Article in journal (Refereed)
  • 48.
    Olivé, Montse
    et al.
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Abdul-Hussein, Saba
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    González-Costello, José
    Department of Cardiology, Barcelona, Spain.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Fürst, Dieter O.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    González, Laura
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology.
    Moreno, Dolores
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain.
    Torrejón-Escribano, Benjamín
    Scientific and Technical Services Facility, Biology Unit, CCiTUB, IDIBELL-University of Barcelona, Barcelona, Spain.
    Alió, Josefina
    Department of Cardiology, Barcelona, Spain.
    Pou, Adolf
    Department of Neurology, Hospital del Mar, Barcelona, Spain.
    Ferrer, Isidro
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations: [Human Molecular Genetics, 24, 13, (2015) 3638-3650] DOI: 10.1093/hmg/ddv108 [Erratum]2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 21, p. 6264-6264Article in journal (Refereed)
  • 49.
    Rizzuto, Debora
    et al.
    Department of Neurobiology, Care Sciences and Society, Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Feldman, Adina L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Ida K.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dahl Aslan, Anna K.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Institute of Gerontology and Aging Research Network – Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Sweden.
    Gatz, Margaret
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles, California.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles, California.
    Detection of dementia cases in two Swedish health registers: A validation study2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 4, p. 1301-1310Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial.

    OBJECTIVE: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies.

    METHODS: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two decades of follow-up.

    RESULTS: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR.

    CONCLUSIONS: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases.

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  • 50.
    Rosenhahn, Erik
    et al.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    O'Brien, Thomas J.
    MRC London Institute of Medical Sciences, United Kingdom.
    Zaki, Maha S.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Sorge, Ina
    Department of Pediatric Radiology, University Hospital Leipzig, Germany.
    Wieczorek, Dagmar
    Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany.
    Rostasy, Kevin
    Department of Pediatric Neurology, Children's and Adolescents’ Hospital Datteln, Witten/Herdecke University, Germany.
    Vitobello, Antonio
    UF6254 Innovation en Diagnostic Genomique des Maladies Rares, CHU Dijon Bourgogne, FHU translad, Génétique des Anomalies du Développement, INSERM UMR 1231, Université de Bourgogne-Franche Comté, Dijon, France.
    Nambot, Sophie
    Centre de Génétique et Centre de référence des Maladies rare, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, France.
    Alkuraya, Fowsan S.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
    Hashem, Mais O.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
    Alhashem, Amal
    Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia ; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Tabarki, Brahim
    Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Alamri, Abdullah S.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Al Safar, Ayat H.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Bubshait, Dalal K.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Alahmady, Nada F.
    Biology Department, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Gleeson, Joseph G.
    Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA ; Rady Children’s Institute for Genomic Medicine, San Diego, La Jolla, CA, USA.
    Abdel-Hamid, Mohamed S.
    Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Lesko, Nicole
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Ygberg, Sofia
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Neuropediatric Unit, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Correia, Sandrina P.
    Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Wredenberg, Anna
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Alavi, Shahryar
    Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran ; Palindrome, Isfahan, Iran.
    Seyedhassani, Seyed M.
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Ebrahimi Nasab, Mahya
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Hussien, Haytham
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Omar, Tarek E. I.
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Harzallah, Ines
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Touraine, Renaud
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Morsy, Heba
    UCL Queen Square Institute of Neurology, University College London, UK.
    Houlden, Henry
    UCL Queen Square Institute of Neurology, University College London, UK.
    Shahrooei, Mohammad
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran ; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Belgium.
    Ghavideldarestani, Maryam
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
    Abdel-Salam, Ghada M. H.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Torella, Annalaura
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy ; Telethon Institute of Genetics and Medicine, Naples, Italy.
    Zanobio, Mariateresa
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
    Terrone, Gaetano
    Child Neurology Unit, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
    Brunetti-Pierri, Nicola
    Telethon Institute of Genetics and Medicine, Naples, Italy ; Department of Translational Medicine, Section of Pediatrics, University of Naples Federico II, Italy.
    Omrani, Abdolmajid
    Division of Clinical Studies, The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Iran.
    Hentschel, Julia
    Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
    Lemke, Johannes R.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany ; Center for Rare Diseases, University of Leipzig Medical Center, Germany.
    Sticht, Heinrich
    Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Abou Jamra, Rami
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Brown, Andre E. X.
    MRC London Institute of Medical Sciences, UK ; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, UK ; .
    Maroofian, Reza
    UCL Queen Square Institute of Neurology, University College London, UK.
    Platzer, Konrad
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications2022In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, no 8, p. 1421-1435Article in journal (Refereed)
    Abstract [en]

    PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications. 

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