| 1. |
- Masrori, Pegah, et al.
(författare)
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Respiratory onset of amyotrophic lateral sclerosis in a pregnant woman with a novel SOD1 mutation
- 2022
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Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 29:4, s. 1279-1283
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), the importance of gene testing in ALS is increasing. This will likely lead to the identification of new variants for which the pathogenicity is not established. We aimed to study the pathogenicity of a newly identified variant in superoxide dismutase 1 (SOD1).METHODS: Gene testing was performed using Sanger sequencing. SOD1 activity in erythrocytes was measured using spectrophotometry. Postmortem brain and spinal cord sections were stained with antibodies against phospho-TDP-43 and SOD1.RESULTS: We identified a novel c.416G>T (p.Gly139Val) mutation in SOD1, which caused a rapidly progressive respiratory onset form of ALS. The mutation resulted in a 50% drop of SOD1 activity. Postmortem examination confirmed the absence of TDP-43 pathology and displayed typical SOD1 inclusions in remaining motor neurons, confirming the pathogenic nature of the mutation.CONCLUSIONS: Novel variants of unknown pathogenicity will be identified as a result of a surge in gene testing in people with ALS. An in-depth study of a newly identified p.Gly139Val mutation in SOD1 confirmed the pathogenicity of this mutation. Future patients with this particular mutation should qualify for SOD1 silencing or editing therapies.
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| 2. |
- Behzadi, Arvin, et al.
(författare)
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Myofiber type shift in extraocular muscles in amyotrophic lateral sclerosis
- 2023
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 64:5
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate changes in myofiber composition in the global layer (GL) and orbital layer (OL) of extraocular muscles (EOMs) from terminal amyotrophic lateral sclerosis (ALS) donors.Methods: Medial recti muscles collected postmortem from spinal-onset ALS, bulbar-onset ALS, and healthy control donors were processed for immunofluorescence with antibodies against myosin heavy chain (MyHC) IIa, MyHCI, MyHCeom, laminin, neurofilaments, synaptophysin, acetylcholine receptor γ-subunit, and α-bungarotoxin.Results: The proportion of myofibers containing MyHCIIa was significantly smaller and MyHCeom was significantly larger in the GL of spinal-onset ALS and bulbar-onset ALS donors compared to control donors. Changes in the GL were more prominent in the bulbar-onset ALS donors, with a significantly larger proportion of myofibers containing MyHCeom being present compared to spinal-onset ALS donors. There were no significant differences in the myofiber composition in the OL. In the spinal-onset ALS donors, the proportions of myofibers containing MyHCIIa in the GL and MyHCeom in the OL were significantly correlated with the disease duration. Neurofilament and synaptophysin were present at motor endplates of myofibers containing MyHCeom in ALS donors.Conclusions: The EOMs of terminal ALS donors displayed changes in the fast-type myofiber composition in the GL, with a more pronounced alteration in bulbar-onset ALS donors. Our results align with the worse prognosis and subclinical changes in eye movement function previously observed in bulbar-onset ALS patients and suggest that the myofibers in the OL might be more resistant to the pathological process in ALS.
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| 3. |
- Björkblom, Benny, et al.
(författare)
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Distinct metabolic hallmarks of WHO classified adult glioma subtypes
- 2022
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 24:9, s. 1454-1468
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy.METHODS: Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors - oligodendroglioma (n=31), astrocytoma (n=31) and glioblastoma (n=162) - were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation.RESULTS: Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue.CONCLUSION: Key metabolic differences exist across adult glioma subtypes.
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| 4. |
- Davidson, Thomas, et al.
(författare)
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The costs of human uterus transplantation: a study based on the nine cases of the initial Swedish live donor trial
- 2021
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 36:2, s. 358-366
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: What are the costs of live donor uterus transplantation in a European setting? SUMMARY ANSWER: The total costs for preoperative investigations, including IVF, and live donor uterus transplantation including postoperative costs for 2 months, were calculated to be (sic) 74 564 (mean), with the costs of recipient being somewhat higher than for donor and the cost components of total costs distributed between sick leave (25.7%), postoperative hospitalization (17.8%), surgery (17.1%), preoperative investigations (15.7%), anaesthesia (9.7%), drugs (7.8%), tests after surgery (4.0%) and for re-hospitalization (2.2%). WHAT IS KNOWN ALREADY: Uterus transplantation has proved to be successful by demonstrations of live births, both after live donor and deceased donor procedures. The transplantation is considered as a complex and expensive infertility treatment. There exist no analyses of costs involved in uterus transplantation. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included nine uterus transplantations procedures, performed in Sweden in 2013. Study duration of this health economic study included 6-12 months of pre-transplantation investigations and the time interval from transplantation to 2 months after. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine triads of uterus recipient, partner of recipient and uterus donor participated. All prospective recipients were in stable relationships and performed IVF with their partners before transplantation. The nine donors were relatives or family friends. The recipients and donors underwent pre-transplantation investigations with imaging, laboratory tests and psychological/medical screening prior to transplantation. Transplantation was by laparotomy in both donor and recipient. Standard immunosuppression and postoperative medication were used. After discharge from the hospital, the recipients were followed frequently with laboratory tests and examinations. MAIN RESULTS AND THE ROLE OF CHANCE: The mean costs for preoperative investigations, including IVF, and live donor uterus transplantation with postoperative costs for 2 months, were calculated to be (sic)74 564 (range (sic) 50 960-(sic)99 658), from a societal perspective. The four largest components were cost of sick leave (sic) 19 164), cost of postoperative hospitalization (sic)13 246), surgery cost (sic)12 779) and costs for preoperative investigations, including IVF (sic) 11 739). Smaller components were costs for anaesthesia (sic) 7207), costs for drugs (sic) 5821), costs for post-surgical tests (sic) 2985) and costs for re-hospitalization (sic)1623). The costs of the recipient (sic) 42 984) were somewhat higher than the costs of the donor (sic) 31 580), but in terms of costs, they should be viewed as one entity. By using a health care perspective, excluding cost for productivity loss, the total costs would be reduced by 26%. LIMITATIONS, REASONS FOR CAUTION: A limitation is the restricted sample size and that this is in the experimental, clinical stage of development. WIDER IMPLICATIONS OF THE FINDINGS: The results provide the first information concerning the costs for pre-transplantation investigations and uterus transplantation procedures with postoperative follow-up. We consider the total estimate to be in the higher interval, because of the extensive research protocol. It is likely that the cost of live donor uterus transplantation will vary between countries and that the costs will be lower in a future clinical setting.
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| 5. |
- Forsberg, Karin, et al.
(författare)
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Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation
- 2023
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Ingår i: Acta Neuropathologica. - : Springer-Verlag New York. - 0001-6322 .- 1432-0533. ; 145:1, s. 13-28
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.
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| 6. |
- Keskin, Isil, 1987-, et al.
(författare)
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Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice
- 2021
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Ingår i: Acta neuropathologica communications. - : BioMed Central. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The deposition of aggregated proteins is a common neuropathological denominator for neurodegenerative disorders. Experimental evidence suggests that disease propagation involves prion-like mechanisms that cause the spreading of template-directed aggregation of specific disease-associated proteins. In transgenic (Tg) mouse models of superoxide dismutase-1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), inoculation of minute amounts of human SOD1 (hSOD1) aggregates into the spinal cord or peripheral nerves induces premature ALS-like disease and template-directed hSOD1 aggregation that spreads along the neuroaxis. This infectious nature of spreading pathogenic aggregates might have implications for the safety of laboratory and medical staff, recipients of donated blood or tissue, or possibly close relatives and caregivers. Here we investigate whether transmission of ALS-like disease is unique to the spinal cord and peripheral nerve inoculations or if hSOD1 aggregation might spread from the periphery into the central nervous system (CNS). We inoculated hSOD1 aggregate seeds into the peritoneal cavity, hindlimb skeletal muscle or spinal cord of adult Tg mice expressing mutant hSOD1. Although we used up to 8000 times higher dose—compared to the lowest dose transmitting disease in spinal cord inoculations—the peripheral inoculations did not transmit seeded aggregation to the CNS or premature ALS-like disease in hSOD1 Tg mice. Nor was any hSOD1 aggregation detected in the liver, kidney, skeletal muscle or sciatic nerve. To explore potential reasons for the lack of disease transmission, we examined the stability of hSOD1 aggregates and found them to be highly vulnerable to both proteases and detergent. Our findings suggest that exposed individuals and personnel handling samples from ALS patients are at low risk of any potential transmission of seeded hSOD1 aggregation.
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| 7. |
- Lehmann, Manuela, et al.
(författare)
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Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice
- 2020
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.
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| 8. |
- Vaezghasemi, Masoud, et al.
(författare)
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Multifaceted determinants of social-emotional problems in preschool children in Sweden : An ecological systems theory approach
- 2023
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Ingår i: SSM - Population Health. - : Elsevier. - 2352-8273. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Social-emotional problems occurring early in life can place children at future risk of adverse health, social and economic outcomes. Determinants of social-emotional problems are multi-layered and originate from different contexts surrounding children, though few studies consider them simultaneously. We adopted a holistic approach by using Bronfenbrenner's process-person-context-time model as a structuring device. We aimed to assess what characteristics of families and children from pregnancy, over birth, and up to 3 years of age are associated with social-emotional problems in boys and girls. This study used regional data from the Salut Programme, a universal health promotion programme implemented in Antenatal and Child Health Care, and data from national Swedish registers. The study population included 6033 3-year-olds and their parents during the period 2010-2018. Distinct logistic regression models for boys and girls were used to assess associations between the family social context, parents' lifestyle, parent's mental health, children's birth characteristics, and indicators of proximal processes (the independent variables); and children's social-emotional problems as measured by the parentcompleted Ages and Stages Questionnaire: Social-Emotional between 33 and 41 months of age (the outcome). Overall, a less favourable family social context, detrimental lifestyle of the parents during pregnancy, and parents' mental illness from pregnancy onwards were associated with higher odds of social-emotional problems in 3 -year-olds. Higher screentime and infrequent shared book-reading were associated with higher odds of socialemotional problems. The multifaceted determinants of children's social-emotional problems imply that many diverse targets for intervention exist. Additionally, this study suggests that Bronfenbrenner's process-person-context-time theoretical framework could be relevant for public health research and policy.
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| 9. |
- Zarsky, Vojtech, et al.
(författare)
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Contrasting outcomes of genome reduction in mikrocytids and microsporidians
- 2023
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Ingår i: BMC Biology. - : BioMed Central (BMC). - 1741-7007. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intracellular symbionts often undergo genome reduction, losing both coding and non-coding DNA in a process that ultimately produces small, gene-dense genomes with few genes. Among eukaryotes, an extreme example is found in microsporidians, which are anaerobic, obligate intracellular parasites related to fungi that have the smallest nuclear genomes known (except for the relic nucleomorphs of some secondary plastids). Mikrocytids are superficially similar to microsporidians: they are also small, reduced, obligate parasites; however, as they belong to a very different branch of the tree of eukaryotes, the rhizarians, such similarities must have evolved in parallel. Since little genomic data are available from mikrocytids, we assembled a draft genome of the type species, Mikrocytos mackini, and compared the genomic architecture and content of microsporidians and mikrocytids to identify common characteristics of reduction and possible convergent evolution.Results: At the coarsest level, the genome of M. mackini does not exhibit signs of extreme genome reduction; at 49.7 Mbp with 14,372 genes, the assembly is much larger and gene-rich than those of microsporidians. However, much of the genomic sequence and most (8075) of the protein-coding genes code for transposons, and may not contribute much of functional relevance to the parasite. Indeed, the energy and carbon metabolism of M. mackini share several similarities with those of microsporidians. Overall, the predicted proteome involved in cellular functions is quite reduced and gene sequences are extremely divergent. Microsporidians and mikrocytids also share highly reduced spliceosomes that have retained a strikingly similar subset of proteins despite having reduced independently. In contrast, the spliceosomal introns in mikrocytids are very different from those of microsporidians in that they are numerous, conserved in sequence, and constrained to an exceptionally narrow size range (all 16 or 17 nucleotides long) at the shortest extreme of known intron lengths.Conclusions: Nuclear genome reduction has taken place many times and has proceeded along different routes in different lineages. Mikrocytids show a mix of similarities and differences with other extreme cases, including uncoupling the actual size of a genome with its functional reduction.
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