| 1. |
- Alping, Peter, et al.
(författare)
-
Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients
- 2020
-
Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 87:5, s. 688-699
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.METHODS: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer.RESULTS: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84).INTERPRETATION: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.
|
|
| 2. |
- Alping, P., et al.
(författare)
-
Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients
- 2016
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:6, s. 950-958
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy. Methods: We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umea, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%). Results: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center). Interpretation: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns.
|
|
| 3. |
- Bennet, Laura, et al.
(författare)
-
Cell therapy for neonatal hypoxia-ischemia and cerebral palsy.
- 2012
-
Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 71:5, s. 589-600
-
Tidskriftsartikel (refereegranskat)abstract
- Perinatal hypoxic-ischemic brain injury remains a major cause of cerebral palsy. Although therapeutic hypothermia is now established to improve recovery from hypoxia-ischemia (HI) at term, many infants continue to survive with disability, and hypothermia has not yet been tested in preterm infants. There is increasing evidence from in vitro and in vivo preclinical studies that stem/progenitor cells may have multiple beneficial effects on outcome after hypoxic-ischemic injury. Stem/progenitor cells have shown great promise in animal studies in decreasing neurological impairment; however, the mechanisms of action of stem cells, and the optimal type, dose, and method of administration remain surprisingly unclear, and some studies have found no benefit. Although cell-based interventions after completion of the majority of secondary cell death appear to have potential to improve functional outcome for neonates after HI, further rigorous testing in translational animal models is required before randomized controlled trials should be considered.
|
|
| 4. |
- Bolouri, Hayde, 1957, et al.
(författare)
-
Innate defence regulator peptide 1018 protects against perinatal brain injury.
- 2014
-
Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 75:3
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury, therefore, the neuroprotective therapeutic potential of innate defence regulator peptides (IDRs) was investigated. Methods: The anti-inflammatory effects of three IDRs was measured in LPS-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3h after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 h before LPS or 3h after LPS+HI. Results: IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3h after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for e.g. Fadd and Tnfsf9) and inflammatory (for e.g. IL-1, TNF-α, chemokines and cell adhesion molecules) pathways and showed marked protection of both white and grey brain matter. Interpretation: IDR-1018 supresses pro-inflammatory mediators and cell injurious mechanisms in the developing brain, and post-insult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both grey and white matter, and lacks significant effects on the brain under normal conditions. Thus this peptide provides the features of a promising neuroprotective agent in newborns with brain injury. ANN NEUROL 2013. © 2013 American Neurological Association.
|
|
| 5. |
- Carlsson, Ylva, 1975, et al.
(författare)
-
Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury.
- 2011
-
Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:5, s. 781-9
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Perinatal brain injury is a major cause of neurodevelopmental handicaps. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to cell damage and death, including caspase-dependent apoptosis. Caspase-2 (Casp2; Nedd-2, Ich-1) is a developmentally regulated initiator caspase, which poorly cleaves other caspases but can initiate mitochondrial outer membrane permeabilization. We have investigated if Casp2 could mediate perinatal ischemic brain damage. METHODS: Casp2 expression in human neonatal brains and developmental patterns in rats and mice were evaluated. Casp2-deficient (Casp2(-/-) ), wild-type (WT), and heterozygous (Casp2(+/-) ) newborn C57BL/6 mice were subjected to hypoxia-ischemia (unilateral carotid occlusion + exposure to 10% oxygen for 50 minutes) or intracerebral injection of the excitotoxic N-methyl-D-aspartate-receptor agonist ibotenate. In addition, Casp2 specific siRNAs were preinjected into the brain of WT newborn mice 24 hours before ibotenate treatment. Brain tissues were examined by immunohistochemical staining (cresyl violet, MAP2, NF68, Casp2, Casp3) and Western blotting. Lesion volumes and injury in the cortical plates and white matter were quantified together with activated Casp3. RESULTS: Casp2 is highly expressed in the neonatal brain. Casp2-deficient mice subjected to hypoxia-ischemia at postnatal day 9 present significantly lower cerebral infarction, reduced white matter injury, and reduced Casp3 activation in the thalamus and hippocampus. Both Casp2(-/-) mice and siRNA-administered WT mice conferred reduction of gray and white matter injury after excitotoxic insult at postnatal day 5. Casp3 activation was also found reduced in Casp2-deficient mice subjected to excitotoxicity. INTERPRETATION: These data suggest for the first time a role of Casp2 in neonatal brain damage. ANN NEUROL 2011;
|
|
| 6. |
- Chelban, V., et al.
(författare)
-
PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
|
|
| 7. |
- Cinque, Paola, et al.
(författare)
-
The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations.
- 2004
-
Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 55:5, s. 687-94
-
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.
|
|
| 8. |
- Curtze, Sami, et al.
(författare)
-
Cerebral white matter lesions and post-thrombolytic remote parenchymal hemorrhage.
- 2016
-
Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 80:4, s. 593-9
-
Tidskriftsartikel (refereegranskat)abstract
- Parenchymal hematoma (PH) following intravenous thrombolysis (IVT) in ischemic stroke can occur either within the ischemic area (iPH) or as a remote PH (rPH). The latter could be, at least partly, related to cerebral amyloid angiopathy, which belongs to the continuum of cerebral small vessel disease. We hypothesized that cerebral white matter lesions (WMLs)-an imaging surrogate of small vessel disease-are associated with a higher rate of rPH.We analyzed 2,485 consecutive patients treated with IVT at the Helsinki University Hospital. Blennow rating scale of 5 to 6 points on baseline computed tomographic head scans was considered as severe WMLs. An rPH was defined as hemorrhage that-contrary to iPH-appears in brain regions without visible ischemic damage and is clinically not related to the symptomatic acute lesion site. The associations between severe WMLs and pure rPH versus no PH, pure iPH versus no PH, and pure rPH versus pure iPH were studied in multivariate logistic regression models.rPHs were mostly (74%) located in lobar regions. After adjustments, the presence of severe WMLs was associated with pure rPH (odds ratio [OR] = 6.79, 95% confidence interval [CI] = 2.57-17.94) but not with pure iPH (OR = 1.45, 95% CI = 0.83-2.53) when compared to patients with no PH. In direct comparison of pure rPH with pure iPH, severe cerebral WMLs were further associated with higher iPH rates (OR = 3.60, 95% CI = 1.06-12.19).Severe cerebral WMLs were associated with post-thrombolytic rPH but not with iPH within the ischemic area. Ann Neurol 2016;80:593-599.
|
|
| 9. |
- Danielson, Mattias, et al.
(författare)
-
Neuroinflammatory markers associate with cognitive decline after major surgery: Findings of an explorative study
- 2020
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 87:3, s. 370-382
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of >= 1.0 compared to patients without long-term cognitive decline at 3 months postsurgery. Methods Serum and CSF biomarkers of inflammation and blood-brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. Results Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48-hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long-term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long-term cognitive decline at 3 months. Patients both with and patients without long-term cognitive decline showed early transient increases of the astroglial biomarkers S-100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). Interpretation Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long-term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort.
|
|
| 10. |
- Dauvilliers, Y., et al.
(författare)
-
Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder
- 2020
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 87:3, s. 347-356
-
Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the dose-response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder. Methods Adults (<= 64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed. Results Of 1,005 subjects screened, 359 (64% female) were randomized and received >= 1 dose. A significant dose-response relationship (multiple comparison procedure-modeling, 2-sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose-dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment-emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment-related serious adverse events. Four subjects withdrew due to adverse events. Interpretation Daridorexant induced a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder ( NCT02839200). ANN NEUROL 2020
|
|
