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Sökning: WFRF:(LeDoux Mark S)

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2.
  • Böhm, Julia K., et al. (författare)
  • Global Characterisation of Coagulopathy in Isolated Traumatic Brain Injury (iTBI) : A CENTER-TBI Analysis
  • 2020
  • Ingår i: Neurocritical Care. - : Encyclopedia of Global Archaeology/Springer Verlag. - 1541-6933 .- 1556-0961.
  • Tidskriftsartikel (refereegranskat)abstract
    • Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood. This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis. Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to − 6, hypothermia and hypotension increased risk significantly. Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.
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3.
  • Prudencio, Mercedes, et al. (författare)
  • Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
  • 2020
  • Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242. ; 12:566
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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4.
  • Francardo, Veronica, et al. (författare)
  • Chapter 22 - Rodent Models of Treatment-Related Complications in Parkinson Disease
  • 2014. - 2nd
  • Ingår i: Movement Disorders : Genetics and Models - Genetics and Models. - : Elsevier. - 9780124051959 ; , s. 373-386
  • Bokkapitel (refereegranskat)abstract
    • Dopamine replacement therapy effectively relieves the typical motor features of Parkinson disease (PD), but it can cause complications that limit its utility. Dyskinesia (abnormal involuntary movements) and motor fluctuations (abrupt changes in the patients' motor status) occur in most PD patients after a few years of 3,4-dihydroxyphenyl-. l-alanine (l-DOPA) pharmacotherapy. Animal models reproducing these motor complications can be obtained in mice and rats if the nigrostriatal dopamine pathway is severely damaged. Within the large arsenal of neurotoxic and genetic models of PD, rodents with unilateral 6-hydroxydopamine lesions have the best characteristics for the sake of modeling l-DOPA-induced dyskinesia. When treated chronically with high doses of l-DOPA, these rodent models may also display motor response alterations reminiscent of the wearing-off fluctuations that occur in PD patients. Because of research performed on these animal models, our understanding of the molecular and biochemical mechanisms of l-DOPA-induced dyskinesia has made great advances, and several pharmacological approaches to treatment have been recently identified and successfully tested in proof-of-concept trials in PD patients. It is now well recognized that dopaminergic therapies for PD also cause nonmotor fluctuations (e.g., abrupt changes in mood and cognitive performance) and impulse control disorders. Valid rodent models of these nonmotor complications need to be developed as an important tool for basic and translational research on the cognitive and psychiatric features of PD.
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5.
  • Hedera, Peter, et al. (författare)
  • Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia
  • 2012
  • Ingår i: BMC Neurology. - : BioMed Central (BMC). - 1471-2377. ; 12:93
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Recently, heterozygous mutations in PRRT2 (Chr 16p11.2) have been identified in Han Chinese, Japanese and Caucasians with paroxysmal kinesigenic dyskinesia. In previous work, a paroxysmal kinesigenic dyskinesia locus was mapped to Chr 16p11.2 - q11.2 in a multiplex African-American family. Methods: Sanger sequencing was used to analyze all four PRRT2 exons for sequence variants in 13 probands (9 Caucasian, 1 Caucasian-Thai, 1 Vietnamese and 2 African-American) with some form of paroxysmal dyskinesia. Results: One patient of mixed Caucasian-Thai background and one African-American family harbored the previously described hotspot mutation in PRRT2 (c.649dupC, p.R217Pfs*8). Another African-American family was found to have a novel mutation (c.776dupG, p.E260*). Both of these variants are likely to cause loss-of-function via nonsense-mediated decay of mutant PRRT2 transcripts. All affected individuals had classic paroxysmal kinesigenic dyskinesia phenotypes. Conclusions: Heterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.
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6.
  • Puschmann, Andreas, et al. (författare)
  • An African-American family with dystonia.
  • 2011
  • Ingår i: Parkinsonism & Related Disorders. - : Elsevier. - 1873-5126. ; 17, s. 547-550
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African-Americans or reports of THAP1 mutations in African-Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African-Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African-Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration.
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7.
  • Puschmann, Andreas, et al. (författare)
  • Genotype-Phenotype Correlations in Parkinson Disease
  • 2014
  • Ingår i: Movement Disorders: Genetics and Models, 2nd Edition. - : Elsevier. - 9780124051959 - 9780124055162 ; , s. 259-285
  • Bokkapitel (refereegranskat)abstract
    • Mutations in four autosomal dominant (SNCA, LRRK2, VPS35, EIF4G1) and three recessive genes (PARK2, PINK1, PARK7/DJ1) are known to cause Parkinson disease (PD). This chapter describes the clinical and pathological phenotypes associated with mutations in these genes. We systematically reviewed the phenotypes associated with all known pathogenic mutations in the dominant genes. SNCA point mutations and genomic multiplications cause a disorder with akinetic-rigid Parkinsonism, dysautonomia, cognitive decline, myoclonus, and pronounced alpha-synuclein pathology. LRRK2 mutations cause tremor-dominant or akinetic-rigid Parkinsonism with variable pathology. Our knowledge about the newly described genes VPS35 and EIF4G1 is still limited. Homozygous or compound heterozygous mutations in the recessive PD genes cause Parkinsonism with an early or very-early onset, but many different mutations are found in these genes and genotype-phenotype correlations are based on low numbers of patients per mutation. Homozygous mutations in GBA may cause Parkinsonism, usually in patients who have Gaucher disease, whereas heterozygous GBA mutations are genetic risk factors for PD. The monogenic forms of PD represent distinct subtypes of this heterogeneous disorder.
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8.
  • Puschmann, Andreas J., et al. (författare)
  • Familial late-onset focal dystonia in an African American family
  • 2010
  • Ingår i: Annals of Neurology. - : John Wiley and Sons. - 1531-8249. ; 68:Suppl. S14, s. 69-69
  • Konferensbidrag (refereegranskat)abstract
    • Recent studies of THAP1 (DYT6) have pointed out that late-onset focal dystonia can have a genetic basis. Familial late-onset primary dystonia has not been described in African- Americans. Six members of an African American family were affected by focal or segmental dystonia with a mean age at onset of 47 years (range, 45-50). Two additional individuals with milder clinical signs were classified as probably affected. Clinical phenotypes included cervical, laryngeal and handforearm (writer's cramp) dystonia, following an autosomal dominant mode of inheritance. TOR1A (DYT1) and THAP1 (DYT6) were screened for sequence variants. There were no abnormalities in TOR1A. A novel THAP1 sequence variant (c.-237-3G>T) was found in both affected and unaffected family members and did not co-segregate with dystonia. This variant was also found in 1/212 African American control alleles. Another variant at the same site (c.-237-3G>A) was found in 2/212 African American control alleles and one African American subject with laryngeal dystonia (1/84 alleles). Therefore, these variants are unlikely to be pathogenic. Familial late-onset primary dystonia does occur in non-Caucasian populations. Future studies of THAP1 and other dystonia genes must take genetic background into consideration.
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9.
  • Vemula, Satya R, et al. (författare)
  • GNAL mutations cause adult-onset primary dystonia
  • 2013
  • Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878. ; 80:1
  • Konferensbidrag (refereegranskat)abstract
    • OBJECTIVE: Identification of the causal mutation in an African-American family with adult-onset primary dystonia. BACKGROUND: The vast majority of patients with dystonia are adults with primary focal or segmental anatomical distributions. Familial and sporadic dystonia appear to share the same genetic etiological background. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large pedigrees suited for linkage analysis are uncommon. In previous work, we excluded THAP1 and TOR1A mutations in an African-American family with clinical phenotypes that included cervical, laryngeal and hand-forearm dystonia. DESIGN/METHODS: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in order to identify the causal mutation (GNAL, c.913G>T) in our African-American family with dystonia. High resolution melting and Sanger sequencing were used to screen 768 additional subjects with primary cervical or segmental dystonia for sequence variants in GNAL. RESULTS: The missense mutation in GNAL (c.913G>T, p.V305F) was found to co-segregate with dystonia in our African-American pedigree. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) is highly expressed in the olfactory bulb, striatum and cerebellar Purkinje cells. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. Screening identified two additional pedigrees with GNAL mutations (c.822-823insA [p.R275T∗13] and c.964C>T [p.R322∗]). None of these sequence variants were found in 760 controls. CONCLUSIONS: Mutations in GNAL are causally-associated with adult-onset primary cervical and segmental dystonia. The prominent expression of Gα(olf) in striatum and cerebellar Purkinje cells points to potential sites of functional pathology in primary dystonia.
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10.
  • Vemula, Satya R, et al. (författare)
  • Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia.
  • 2013
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906. ; 22:12, s. 2510-2519
  • Tidskriftsartikel (refereegranskat)abstract
    • The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1, and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified 3 Caucasian pedigrees with GNAL mutations (c.591dupA [p.R198Tfs*13]; c.733C>T [p.R245*]; and c.3G>A [p.M1?]). These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed up-regulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.
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