250 research outputs found

    Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

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    The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

    Histopathological placental lesions in mild gestational hyperglycemic and diabetic women

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    Objective: To investigate and compare the incidence of histopathological placental lesions in mild gestational hyperglycemia, gestational diabetes and overt diabetes at term and preterm gestation.Research design and methods: One-hundred-and-thirty-one placental samples were collected from Diabetes mellitus (DM) positive screened patients. Two diagnostic tests, glycemic profile and 100 g oral glucose tolerance test (OGTT) in parallel identified 4 groups normoglycemic, mild gestational hyperglycemia (MGH), gestational DM (GDM) or overt DM (DM). Placental tissue specimens and sections from 4 groups were obtained by uniform random sampling and stained with hematoxylin-eosin.Results: Placentas from MGH group presented 17 types of histopathological change and higher rates of syncytial nodes and endarteritis. GDM placentas presented only nine types of histopathological change, high rates of dysmaturity, low rates of calcification and no syncytial nodes. Overt DM placentas showed 22 types of histopathological change, 21 of which were present in the preterm period. There were histopathological similarities between MGH and DM placentas, but the former exhibited a higher incidence of endarteritis, which has been described as a post-mortem phenomenon.Conclusion: Our results confirmed that the distinct placental changes associated with DM and MGH depend on gestational period during which the diabetic insult occurs. It may reasonably be inferred that subclinical maternal hyperglycemia during pregnancy, as showed in MGH group, is responsible for increased placental endarteritis, a postmortem lesion in the live fetus

    Genome-wide expression profiling and functional characterization of SCA28 lymphoblastoid cell lines reveal impairment in cell growth and activation of apoptotic pathways

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    BACKGROUND: SCA28 is an autosomal dominant ataxia associated with AFG3L2 gene mutations. We performed a whole genome expression profiling using lymphoblastoid cell lines (LCLs) from four SCA28 patients and six unrelated healthy controls matched for sex and age. METHODS: Gene expression was evaluated with the Affymetrix GeneChip Human Genome U133A 2.0 Arrays and data were validated by real-time PCR. RESULTS: We found 66 genes whose expression was statistically different in SCA28 LCLs, 35 of which were up-regulated and 31 down-regulated. The differentially expressed genes were clustered in five functional categories: (1) regulation of cell proliferation; (2) regulation of programmed cell death; (3) response to oxidative stress; (4) cell adhesion, and (5) chemical homeostasis. To validate these data, we performed functional experiments that proved an impaired SCA28 LCLs growth compared to controls (p\u2009<\u20090.005), an increased number of cells in the G0/G1 phase (p\u2009<\u20090.001), and an increased mortality because of apoptosis (p\u2009<\u20090.05). We also showed that respiratory chain activity and reactive oxygen species levels was not altered, although lipid peroxidation in SCA28 LCLs was increased in basal conditions (p\u2009<\u20090.05). We did not detect mitochondrial DNA large deletions. An increase of TFAM, a crucial protein for mtDNA maintenance, and of DRP1, a key regulator of mitochondrial dynamic mechanism, suggested an alteration of fission/fusion pathways. CONCLUSIONS: Whole genome expression profiling, performed on SCA28 LCLs, allowed us to identify five altered functional categories that characterize the SCA28 LCLs phenotype, the first reported in human cells to our knowledge. \ua9 2013 Mancini et al.; licensee BioMed Central Ltd

    Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

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    A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

    Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV