| 1. |
- Andersen, Peter M., et al.
(författare)
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Clinical genetics of amyotrophic lateral sclerosis : what do we really know?
- 2011
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Ingår i: Nature Reviews Neurology. - : Nature Publishing Group. - 1759-4758 .- 1759-4766. ; 7:11, s. 603-615
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Forskningsöversikt (refereegranskat)abstract
- Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most common being SOD1, FUS and TARDBP-mutations in the other genes are rare. The identified genes explain 25-35% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can be inherited in an autosomal dominant, autosomal recessive or X-linked manner, and families with low disease penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing the specific gene defect and the disease penetrance in the particular family.
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| 2. |
- Benatar, Michael, et al.
(författare)
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Presymptomatic ALS genetic counseling and testing : Experience and recommendations
- 2016
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 86:24, s. 2295-2302
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Forskningsöversikt (refereegranskat)abstract
- Remarkable advances in our understanding of the genetic contributions to amyotrophic lateral sclerosis (ALS) have sparked discussion and debate about whether clinical genetic testing should routinely be offered to patients with ALS. A related, but distinct, question is whether presymptomatic genetic testing should be offered to family members who may be at risk for developing ALS. Existing guidelines for presymptomatic counseling and testing are mostly based on small number of individuals, clinical judgment, and experience from other neurodegenerative disorders. Over the course of the last 8 years, we have provided testing and 317 genetic counseling sessions (including predecision, pretest, posttest, and ad hoc counseling) to 161 first-degree family members participating in the Pre-Symptomatic Familial ALS Study (Pre-fALS), as well as testing and 75 posttest counseling sessions to 63 individuals with familial ALS. Based on this experience, and the real-world challenges we have had to overcome in the process, we recommend an updated set of guidelines for providing presymptomatic genetic counseling and testing to people at high genetic risk for developing ALS. These recommendations are especially timely and relevant given the growing interest in studying presymptomatic ALS.
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| 3. |
- Benatar, Michael, et al.
(författare)
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Preventing amyotrophic lateral sclerosis : insights from pre-symptomatic neurodegenerative diseases
- 2022
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:1, s. 27-44
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Forskningsöversikt (refereegranskat)abstract
- Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned - more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers - we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.
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| 4. |
- Benatar, Michael, et al.
(författare)
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The Miami Framework for ALS and related neurodegenerative disorders : an integrated view of phenotype and biology
- 2024
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Ingår i: Nature Reviews Neurology. - : Springer Nature. - 1759-4758 .- 1759-4766. ; 20:6, s. 364-376
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Forskningsöversikt (refereegranskat)abstract
- Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.
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| 5. |
- Godoy, Patricio, et al.
(författare)
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
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Forskningsöversikt (refereegranskat)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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| 6. |
- Jons, Daniel, 1974, et al.
(författare)
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Targeting Epstein-Barr virus infection as an intervention against multiple sclerosis
- 2015
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Ingår i: Acta Neurologica Scandinavica. - : Wiley-Blackwell. - 0001-6314 .- 1600-0404. ; 131:2, s. 69-79
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Forskningsöversikt (refereegranskat)abstract
- We here review contemporary data on genetic and environmental risk factors, particularly Epstein-Barr virus infection, for multiple sclerosis. There is an important immunogenetic etiological factor for multiple sclerosis. However, a general assumption is that immune defense genes are activated by the environment, basically by infections. We contend that the relationship between infectious mononucleosis and multiple sclerosis cannot be completely explained by genetics and inverse causality. Epstein-Barr infection as indicated by positive serology is an obligatory precondition for multiple sclerosis, which is a stronger attribute than a risk factor only. Data on events in the early pathogenesis of multiple sclerosis are cumulating from bio-banks with presymptomatic specimens, but there is only little information from the critical age when Epstein-Barr infection including infectious mononucleosis is acquired, nor on the detailed immunological consequences of this infection in individuals with and without multiple sclerosis. We discuss how focused bio-banking may elaborate a rationale for the development of treatment or vaccination against Epstein-Barr virus infection. A cohort in which intervention against Epstein-Barr infections was performed should be the object of neurological follow-up.
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| 7. |
- Kuraszkiewicz, B., et al.
(författare)
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Potential Preventive Strategies for Amyotrophic Lateral Sclerosis
- 2020
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 14
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Forskningsöversikt (refereegranskat)abstract
- It may seem useless to propose preventive measures for a disease without established pathogenesis and successful therapy, such as amyotrophic lateral sclerosis (ALS). However, we will show that ALS shares essential molecular mechanisms with aging and that established anti-aging strategies, such as healthy diet or individually adjusted exercise, may be successfully applied to ameliorate the condition of ALS patients. These strategies might be applied for prevention if persons at ALS risk could be identified early enough. Recent research advances indicate that this may happen soon.
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| 8. |
- Lok, Veeleah, et al.
(författare)
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Changes in anxiety and depression during the COVID-19 pandemic in the European population : A meta-analysis of changes and associations with restriction policies
- 2023
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Ingår i: European psychiatry. - 0924-9338 .- 1778-3585. ; 66:1
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Forskningsöversikt (refereegranskat)abstract
- Background. Early studies of common mental disorders (CMDs) during the COVID-19 pandemic mainly report increases; however, more recent findings have been mixed. Also, studies assessing the effects of restriction measures on CMDs show varied results. The aim of this meta-analysis was to assess changes in levels of CMDs from pre-/early to during the pandemic and the effects of restriction policies in the European population.Methods. We searched for studies assessing both pre-pandemic and peri-pandemic self-reported emotional distress and symptoms of depression or anxiety among nationally/regionally representative samples in Europe and collected microdata from those studies. Estimates of corona containment index were related to changes in CMDs using random-effects meta-regression.Results. Our search strategy resulted in findings from 15 datasets drawn from 8 European countries being included in the meta-analysis. There was no evidence of change in the prevalence of emotional distress, anxiety, or depression from before to during the pandemic; but from early pandemic periods to later periods, there were significant decreases in emotional distress and anxiety. Increased school restrictions and social distancing were associated with small increases in self-reported emotional distress.Conclusions. Despite initial concerns of increased emotional distress and mental illness due to the COVID-19 pandemic, the results from this meta-analysis indicate that there was a decrease in emotional distress and no change in anxiety or depression in the general population in Europe. Overall, our findings support the importance of strong governance when implementing periodic and robust restriction measures to combat the spread of COVID-19.
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| 9. |
- Lundgren, Edvin, et al.
(författare)
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Surface oxides on close-packed surfaces of late transition metals
- 2006
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Ingår i: Journal of Physics: Condensed Matter. - 1361-648X. ; 18:30, s. 481-499
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Forskningsöversikt (refereegranskat)abstract
- In recent years, the formation of thin, well-ordered but complex surface oxides on late transition metals has been discovered. The driving force for this line of research has been the strong incentive to increase the partial pressure of oxygen from ultra-high vacuum to conditions more relevant for heterogeneous catalysis. Here we review the present status of the research field. Compared to oxygen adatom superstructures, the structure of the surface oxides has proven to be extremely complex, and the investigations have therefore relied on a combination of several experimental and theoretical techniques. The approach to solving the structures formed on close-packed surfaces of Pd and Rh is presented in some detail. Focusing on the structures found, we show that the surface oxides share some general properties with the corresponding bulk oxides. Nevertheless, of all surface oxide structures known today, only the two-dimensional surface oxides on Pd(100) and Pt(110) have the same lattice as the bulk oxides (PdO and PtO, respectively). In addition to two-dimensional oxides, including the O-Rh-O trilayers found on Rh, one-dimensional oxides were observed at ridges or steps of open surfaces such as (110) or vicinal surfaces. Finally, we briefly report on a few studies of the reactivity of surface oxides with well-known structure.
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| 10. |
- Pongpairoj, Korbkarn, et al.
(författare)
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Proposed ICDRG Classification of the Clinical Presentation of Contact Allergy
- 2016
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Ingår i: Dermatitis. - 1710-3568. ; 27:5, s. 248-258
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Forskningsöversikt (refereegranskat)abstract
- The International Contact Dermatitis Research Group proposes a classification for the clinical presentation of contact allergy. The classification is based primarily on the mode of clinical presentation. The categories are direct exposure/contact dermatitis, mimicking or exacerbation of preexisting eczema, multifactorial dermatitis including allergic contact dermatitis, by proxy, mimicking angioedema, airborne contact dermatitis, photo-induced contact dermatitis, systemic contact dermatitis, noneczematous contact dermatitis, contact urticaria, protein contact dermatitis, respiratory/mucosal symptoms, oral contact dermatitis, erythroderma/exfoliative dermatitis, minor forms of presentation, and extracutaneous manifestations.
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