Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.

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ObjectiveThe present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window.MethodsThis was a prospective, randomized, open‐label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24‐hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow.ResultsEach treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation.InterpretationFingolimod may enhance the efficacy of alteplase administration in the 4.5‐ to 6‐hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725–736

Summary. Proinflammatory cytokines such as interleukin 6 (IL-6), tumour necrosis factor a (TNF-a ) and IL-1b are considered to be involved in the pathogenesis of multiple myeloma (MM). In the present study, we examined a G/C polymorphism at position 2174 in the promoter region of IL-6, a biallelic polymorphism at position 2308 in the promoter region of TNF-a , the TaqI restriction fragment length polymorphism in exon 5 of IL-1b and a variable number of identical tandem repeat polymorphisms in intron 2 of IL-1 receptor antagonist (IL-1Ra) genes. The alleles of these loci are known to influence the level of production of the cytokines and the IL-1Ra. Seventy-three patients with MM, 27 with monoclonal gammopathy of undetermined significance (MGUS) and 129 healthy individuals were included. No difference was found between patients and healthy controls or between MM and MGUS patients in the distributions of genotypes and frequencies of alleles of the IL-6 (2174), TNF-a (2308), IL-1b TaqI and IL-1Ra gene polymorphisms. No associations between the polymorphisms at the loci under study and clinical factors such as age, sex, clinical stage at onset and M-protein type were observed. Our results indicate that the cytokine (IL-6, TNF-a and IL-1b) and IL-Ra gene polymorphisms do not confer susceptibility to the development of MM.

Summary. Multiple myeloma (MM) is a B-lineage malignancy with unknown aetiology. It has been considered that predisposing genetic factors might be implicated in the disease. In this study, the microsatellite polymorphism in the exon 3 of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene was analysed in patients with MM and monoclonal gammopathy of undetermined significance (MGUS), together with ethnically matched healthy controls.The results showed that frequencies of the genotype 86/86 and of the allele 86 were significantly decreased in MM and MGUS compared with matched healthy controls, indicating that the CTLA-4 microsatellite polymorphism might represent a susceptibility locus for MM and MGUS.