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- Cinque, Paola, et al.
(författare)
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The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations.
- 2004
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Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 55:5, s. 687-94
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Tidskriftsartikel (refereegranskat)abstract
- The urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in extracellular matrix degradation and cell migration in the central nervous system (CNS). To investigate the role of the uPA/uPAR system in the pathophysiology of acquired immunodeficiency syndrome dementia complex (ADC), we measured soluble uPAR (suPAR) levels in cerebrospinal fluid (CSF) and plasma from human immunodeficiency virus (HIV)-1-infected patients and controls. CSF suPAR levels were significantly higher in HIV-1-infected patients than in controls and in patients with ADC or opportunistic CNS infections (CNS-OIs) than in neurologically asymptomatic patients, irrespective of HIV-1 disease stage. The highest levels of suPAR were found in patients with ADC, and among those with CNS-OIs in patients with cytomegalovirus encephalitis or cryptococcosis. Plasma suPAR levels were higher in HIV-1-infected patients than in controls and increased with HIV-1 disease stage regardless of the presence of CNS disease. In patients with ADC or CNS-OIs, CSF suPAR levels correlated with CSF HIV-1 RNA, but not with plasma suPAR concentrations. Highly active antiretroviral therapy was associated with a significant and parallel decrease of both CSF suPAR and HIV-1 RNA. In brain tissue from patients with HIV-1 encephalitis, uPAR was highly expressed by microglial and multinucleated giant cells staining positively for HIV-1. The overexpression of uPAR in the CNS of patients with ADC suggests that the uPA/uPAR system may contribute to the tissue injury and neuronal damage in this disease.
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| 3. |
- Killestein, Joep, et al.
(författare)
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Antibody-Mediated suppression of Vbeta5.2/5.3+ T Cells in Multiple Sclerosis : Results from an MRI-Monitored Phase II Clinical Trial
- 2002
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 51, s. 467-
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vß5.2/5.3+ T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-? expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm3 at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-? messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vß 5.2/5.3+ T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.
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| 5. |
- Margolis, Russell L, et al.
(författare)
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Huntington's Disease-like 2 (HDL2) in North America and Japan.
- 2004
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 56:5, s. 670-4
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.
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| 6. |
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| 7. |
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| 8. |
- Pedersen, N.L, et al.
(författare)
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How heritable is Alzheimer's disease in late life? Findings in Swedish twins
- 2004
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Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 55:2, s. 180-185
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Tidskriftsartikel (refereegranskat)abstract
- Although genetic effects are known to be important for early onset Alzheimer's disease, little is known about the importance of genetic effects for late-onset disease. Furthermore, previous studies are based on prevalent cases. Our purpose was to characterize the relative importance of genetic and environmental factors for incident Alzheimer's disease late in life, and to test for differences in the importance of genetic effects at different ages. A cohort of 662 pairs of Swedish twins 52 to 98 years of age who were without symptoms of dementia was followed up for an average of 5 years. Incident dementia cases were detected through follow-up at 2 to 3-year intervals using either cognitive testing or telephone screening followed by dementia workups. A physician, psychologist, and nurse gave consensus diagnoses. During the follow-up period, 5.8% of the sample was diagnosed with Alzheimer's disease. Average age of onset was 83.9 years (standard deviation, 6.3). Of the 26 monozygotic pairs in which at least one twin developed Alzheimer's disease, 5 were concordant (probandwise concordance, 32.2%). The concordance rate for dizygotic pairs was 8.7% (2 of 44 pairs). Structural model fitting indicated that 48% of the variation in liability to Alzheimer's disease could be attributed to genetic variation. Estimates did not differ significantly between twins younger than age 80 years and those older than age 80 years at baseline. Although these genetic estimates for incident disease are lower than those for prevalent disease, the importance of genetic factors for liability to Alzheimer's disease is considerable even late in life.
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| 10. |
- Tajsharghi, Homa, 1968, et al.
(författare)
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Myosin storage myopathy associated with a heterozygous missense mutation in MYH7.
- 2003
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Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 54:4, s. 494-500
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Tidskriftsartikel (refereegranskat)abstract
- Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.
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